Patent Grant
9856279
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.
IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM_005896.2 and NP_005887.2 respectively. The nucleotide and amino acid sequences for IDH1 are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684 (1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533 (1999); Wiemann et al., Genome Res. 11:422-435 (2001); The MGC Project Team, Genome Res. 14:2121-2127 (2004); Lubec et al., Submitted (December-2008) to UniProtKB; Kullmann et al., Submitted (June-1996) to the EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science 314:268-274 (2006).
Non-mutant, e.g., wild type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate thereby reducing NAD+ (NADP+) to NADP (NADPH), e.g., in the forward reaction:
Isocitrate+NAD+(NADP+)→α-KG+CO2+NADH(NADPH)+H+.
It has been discovered that mutations of IDH1 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH1. The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44).
The inhibition of mutant IDH1 and its neoactivity is therefore a potential therapeutic treatment for cancer. Accordingly, there is an ongoing need for inhibitors of IDH1 mutants having alpha hydroxyl neoactivity.
Described herein are compounds of Structural Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is —N(R5)—, —N(R5)—CH2—, —CH2—N(R5)—, or —CH(R5)—;
each R1a and R1b is independently hydrogen, —C1-C4 alkyl, —N(R7)(C1-C4 alkylene)-N(R7)(C1-C4 alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R7)-aryl, —N(R7)C(O)-aryl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-aryl, —O—(C0-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-heterocyclyl, —O—(C0-C4 alkylene)-carbocyclyl, —N(R7)-aryl, —N(R7)-hetero aryl, —N(R9)-aryl, —N(R9)-hetero aryl, —O—(C1-C4 alkeylene)-N(R7)C(O)O—(C1-C4 alkylene)-aryl, or —N(R9)—C(O)—(C2-C4 alkenyl) wherein:
at least one of R1a and R1b is not hydrogen or methyl;
any alkylene moiety present in R1a or R1b is optionally substituted with OH or F;
each R7 is independently selected from hydrogen and C1-C4 alkyl; and
any aryl, carbocyclyl, heteroaryl, or heterocyclyl of R1a or R1b is optionally substituted with one or more substituents selected from -G-L-M, halo, —NO2, C1-C6 alkyl, —C≡N, ═O, —CF3 and OCF3;
G is a bond or a bivalent C1-C6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR8—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR8)—, —N═N—, or —C(═N2)—;
L is a covalent bond or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR8—, —N(R8)C(O)—, —C(O)N(R8)—, —N(R8)SO2—, SO2N(R8)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR8)—, —N═N—, or —C(═N2)—;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO2, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
D is a covalent bond or a bivalent C1-C6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR8—, —S—, —O—, —C(O)—, —SO—, or —SO2—;
E is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and
each R8 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —S(O)2—C2-C4 alkenyl, —C1-C6 alkoxy, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R2 is selected from phenyl, a 3-7 membered cycloalkyl, C2-C4 alkyl, or CF3, wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
each R3 is independently selected from halo, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —C1-C4 fluoroalkyl, —C(O)—O—(C1-C4 alkyl), -phenyl, -heteroaryl, C3-C7 cycloalkyl, —CH2—N(C1-C4 alkyl)2, C(O)—N—(C1-C4 alkyl)2, —C(O)—NH—(C1-C4 alkyl), —C1-C4 alkyl optionally substituted with one or more halo or —OH, or two R3s are taken together to form a 3-8 saturated ring or a fused phenyl wherein said saturated ring or fused phenyl is optionally substituted with 1 to 2 methyl;
R4 is selected from hydrogen, —CN, halo, C1-C4 alkoxy, —CH2NH(C1-C4 alkyl), C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)-O—(C1-C4 alkyl), C1-C4 fluoroalkyl, C(O)—N—(C1-C4 alkyl)2, —C(O)—NH—(C1-C4 alkyl), —C(O)—O—(C1-C4 alkyl), —C(O)—OH, —S(O)2—(C1-C4 alkyl), and a 5-membered heteroaryl;
R5 is selected from: —C(O)—(C1-C5 alkyl), —C(O)—(C2-C6 alkenyl), —C(O)—(C0-C2 alkylene)-Q, —C(O)—(C1-C4 alkenylene)-Q, —C(O)—(C0-C2 alkylene)-N(R6)—(C0-C2 alkylene)-Q, —C(O)—O—(C0-C2 alkylene)-Q, —C(O)—(C1-C2 alkylene)-O—(C0-C2 alkylene)-Q, —C(O)—C(O)-Q, —S(O)2-Q, —C(O)—(C1-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —C(O)—(C1-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —C(O)—N(R6)—(C1-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —C(O)—N(R6)—(C1-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C1-C6 alkyl), —C(O)—(C0-C2 alkylene)N(R6)—(C2-C6 alkynyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C2-C6 alkenyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C0-C2 alkylene)-O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-C(O)C(O)N(R)(C1-C4 alkyl), —C(O)—O—(C1-C4 alkylene)-O—(C1-C4 alkyl), —(C0-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —(C0-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —(C0-C4 alkylene)-O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-S(O)0-2—(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), —C(O)—(C1-C4 alkylene)-C(O)C(O)N(R6)(C1-C6 alkyl), —C(O)—(C1-C4 alkylene)-N(R6)S(O)2—(C1-C6 alkyl), or —C(O)—(C1-C4 alkylene)-N(R6)S(O)2Q, wherein:
each R6 is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C1-C4 alkyl optionally substituted with —OH, C1-C4 alkoxy, —C(O)O—(C1-C4 alkyl), —(C1-C4 alkylene)-(C1-C4 alkoxy), —CN, —OH, fluoro, chloro, and bromo;
R9 is selected from aryl and heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from -G-L-M, halo, C1-C6 alkyl, —C≡N, ═O, —CF3 and OCF3; and
m is 0, 1, 2 or 3.
The compound of formula I inhibits mutant IDH1, particularly mutant IDH1 having alpha hydroxyl neoactivity. Also described herein are pharmaceutical compositions comprising a compound of formula I or a salt thereof and methods of using such compositions to treat cancers characterized by the presence of a mutant IDH1.
This invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having,” “containing”, “involving”, and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine.
The term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C12 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl). The terms “arylalkyl” or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
The term “alkylene” refers to a divalent alkyl, e.g., —CH2—, —CH2CH2—, —CH2CH2CH2— and CH2CH(CH3)CH2—.
The term “alkenyl” refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
The term “alkynyl” refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
The term “alkoxy” refers to an —O-alkyl radical. The term “haloalkoxy” refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).
The term “aryl” refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl, naphthyl, and anthracenyl. Unless otherwise specified, any ring atom in an aryl can be substituted by one or more substituents.
The term “carbocyclyl” refers to a non-aromatic, monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyls), and partially saturated ring systems.
The term “cycloalkyl” as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
The term “heteroaryl” refers to a fully aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (or the oxidized forms such as N+—O−, S(O) and S(O)2).
The term “heterocyclyl” refers to a nonaromatic, 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (or the oxidized forms such as N+—O−, S(O) and S(O)2). The heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl groups include fully saturated ring systems, and partially saturated ring systems.
Bicyclic and tricyclic ring systems containing one or more heteroatoms and both aromatic and non-aromatic rings where the point of attachment from the ring system to the rest of the molecule is through a non-aromatic ring are considered to be heterocyclyl groups. Bicyclic or tricyclic ring systems where an aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyl and the point of attachment from the ring system to the rest of the molecule is through an aromatic ring are considered to be aryl or heteroaryl groups.
Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclyl groups, either alone or a part of a group (e.g., the aryl portion of an aralkyl group), are optionally substituted at one or more substitutable atoms with, unless specified otherwise, substituents independently selected from: halo, —C≡N, C1-C4 alkyl, ═O, —ORb, —ORb′, —SRb, —SRb′, —(C1-C4 alkyl)-N(Rb)(Rb), —(C1-C4 alkyl)-N(Rb)(Rb′), —N(Rb)(Rb), —N(Rb)(Rb′), —O—(C1-C4 alkyl)-N(Rb)(Rb), —O—(C1-C4 alkyl)-N(Rb)(Rb′), —(C1-C4 alkyl)-O—(C1-C4 alkyl)-N(Rb)(Rb), —(C1-C4 alkyl)-O—(C1-C4 alkyl)-N(Rb)(Rb′), —C(O)—N(Rb)(Rb), —(C1-C4 alkyl)-C(O)—N(Rb)(Rb), —(C1-C4 alkyl)-C(O)—N(Rb)(Rb′), —ORb′, Rb′, —C(O)(C1-C4 alkyl), —C(O)Rb′, —C(O)N(Rb′)(Rb), —N(Rb)C(O)(Rb), —N(Rb)C(O)(Rb′), —N(Rb)SO2(Rb), —SO2N(Rb)(Rb), —N(Rb)SO2(Rb′), and —SO2N(Rb)(Rb′), wherein any alkyl substituent is optionally further substituted with one or more of —OH, —O—(C1-C4 alkyl), halo, —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2;
Heterocyclyl groups, either alone or as part of a group, are optionally substituted on one or more any substitutable nitrogen atom with oxo, —C1-C4 alkyl, or fluoro-substituted C1-C4 alkyl.
The term “substituted” refers to the replacement of a hydrogen atom by another group.
As used herein, the term “elevated levels of 2HG” means 10%, 20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG then is present in a subject that does not carry a mutant IDH1 allele. The term “elevated levels of 2HG” may refer to the amount of 2HG within a cell, within a tumor, within an organ comprising a tumor, or within a bodily fluid.
The term “bodily fluid” includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.
As used herein, the terms “inhibit” or “prevent” include both complete and partial inhibition and prevention. An inhibitor may completely or partially inhibit the intended target.
The term “treat” means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease/disorder (e.g., a cancer), lessen the severity of the disease/disorder (e.g., a cancer) or improve the symptoms associated with the disease/disorder (e.g., a cancer).
As used herein, an amount of a compound effective to treat a disorder, or a “therapeutically effective amount” refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.
As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient (referred to as a patient) having a disorder, e.g., a disorder described herein or a normal subject. The term “non-human animals” of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
Compounds
Provided is a compound of Structural Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is —N(R5)—, —N(R5)—CH2—, —CH2—N(R5)—, or —CH(R5)—;
each R1a and R1b is independently hydrogen, —C1-C4 alkyl, —N(R7)(C1-C4 alkylene)-N(R7)(C1-C4 alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R7)-aryl, —N(R7)C(O)-aryl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-aryl, —O—(C0-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-heterocyclyl, —O—(C0-C4 alkylene)-carbocyclyl, —N(R7)-aryl, —N(R7)-heteroaryl, —N(R9)-aryl, —N(R9)-heteroaryl, —O—(C1-C4 alkeylene)-N(R7)C(O)O—(C1-C4 alkylene)-aryl, or —N(R9)—C(O)—(C2-C4 alkenyl) wherein:
at least one of R1a and R1b is not hydrogen or methyl;
any alkylene moiety present in R1a or R1b is optionally substituted with OH or F;
each R7 is independently selected from hydrogen and C1-C4 alkyl; and
any aryl, carbocyclyl, heteroaryl, or heterocyclyl of R1a or R1b is optionally substituted with one or more substituents selected from -G-L-M, halo, —NO2, C1-C6 alkyl, —C≡N, ═O, —CF3 and —OCF3;
G is a bond or a bivalent C1-C6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR8—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR8)—, —N═N—, or —C(═N2)—;
L is a covalent bond or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR8—, —N(R8)C(O)—, —C(O)N(R8)—, —N(R8)SO2—, SO2N(R8)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR8)—, —N═N—, or —C(═N2)—;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO2, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
D is a covalent bond or a bivalent C1-C6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR8—, —S—, —O—, —C(O)—, —SO—, or —SO2—;
E is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and
each R8 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C1-C6 alkoxy, —S(O)2—C2-C4 alkenyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R2 is selected from phenyl, a 3-7 membered cycloalkyl, C2-C4 alkyl, or CF3, wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
each R3 is independently selected from halo, —(C1-C4 alkylene)-O—(C1-C4 alkyl), —C1-C4 fluoroalkyl, —C(O)—O—(C1-C4 alkyl), -phenyl, -heteroaryl, C3-C7 cycloalkyl, —CH2—N(C1-C4 alkyl)2, C(O)—N—(C1-C4 alkyl)2, —C(O)—NH—(C1-C4 alkyl), —C1-C4 alkyl optionally substituted with one or more halo or —OH, or two R3s are taken together to form a 3-8 saturated ring or a fused phenyl wherein said saturated ring or fused phenyl is optionally substituted with 1 to 2 methyl;
R4 is selected from hydrogen, —CN, halo, C1-C4 alkoxy, —CH2NH(C1-C4 alkyl), C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)-O—(C1-C4 alkyl), C1-C4 fluoroalkyl, C(O)—N—(C1-C4 alkyl)2, —C(O)—NH—(C1-C4 alkyl), —C(O)—O—(C1-C4 alkyl), —C(O)—OH, —S(O)2—(C1-C4 alkyl), and a 5-membered heteroaryl;
R5 is selected from: —C(O)—(C1-C5 alkyl), —C(O)—(C2-C6 alkenyl), —C(O)—(C0-C2 alkylene)-Q, —C(O)—(C1-C4 alkenylene)-Q, —C(O)—(C0-C2 alkylene)-N(R6)—(C0-C2 alkylene)-Q, —C(O)—O—(C0-C2 alkylene)-Q, —C(O)—(C1-C2 alkylene)-O—(C0-C2 alkylene)-Q, —C(O)—C(O)-Q, —S(O)2-Q, —C(O)—(C1-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —C(O)—(C1-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —C(O)—N(R6)—(C1-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —C(O)—N(R6)—(C1-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C1-C6 alkyl), —C(O)—(C0-C2 alkylene)N(R6)—(C2-C6 alkynyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C2-C6 alkenyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C0-C2 alkylene)-O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-C(O)C(O)N(R)(C1-C4 alkyl), —C(O)—O—(C1-C4 alkylene)-O—(C1-C4 alkyl), —(C0-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —(C0-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —(C0-C4 alkylene)-O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-S(O)0-2—(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), —C(O)—(C1-C4 alkylene)-C(O)C(O)N(R6)(C1-C6 alkyl), —C(O)—(C1-C4 alkylene)-N(R6)S(O)2—(C1-C6 alkyl), or —C(O)—(C1-C4 alkylene)-N(R6)S(O)2Q, wherein:
each R6 is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C1-C4 alkyl optionally substituted with —OH, C1-C4 alkoxy, —C(O)O—(C1-C4 alkyl), —(C1-C4 alkylene)-(C1-C4 alkoxy), —CN, —OH, fluoro, chloro, and bromo;
R9 is selected from aryl, and heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from -G-L-M, halo, C1-C6 alkyl, —C≡N, ═O, —CF3 and OCF3; and
m is 0, 1, 2 or 3.
In some embodiments, provided is a compound of Structural Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is —N(R5)— or —CH(R5)—;
each R1a and R1b is independently hydrogen, —C1-C4 alkyl, —N(R7)(C1-C4 alkylene)-N(R7)(C1-C4 alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R7)-aryl, —N(R7)C(O)-aryl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C1-C4 alkylene)-aryl, —O—(C1-C4 alkylene)-heteroaryl, —O—(C1-C4 alkylene)-heterocyclyl, —N(R7)-aryl, or —N(R7)-heteroaryl, wherein:
G is a bond or a bivalent C1-C6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR8—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR8)—, —N═N—, or —C(═N2)—;
L is a covalent bond or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR8—, —N(R8)C(O)—, —C(O)N(R8)—, —N(R8)SO2—, SO2N(R8)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR8)—, —N═N—, or —C(═N2)—; M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO2, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
D is a covalent bond or a bivalent C1-C6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR8—, —S—, —O—, —C(O)—, —SO—, or —SO2—;
E is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and
each R8 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R2 is selected from phenyl, a 3-7 membered cycloalkyl, and C2-C4 alkyl, wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
each R3 is independently selected from —C1-C4 alkyl, —(C1-C4 alkyl)-O—(C1-C4 alkyl), —C1-C4 fluoroalkyl, —C(O)—O—(C1-C4 alkyl), -phenyl, -heteroaryl, C3-C7 cycloalkyl, —CH2—N(C1-C4 alkyl)2, C(O)—N—(C1-C4 alkyl)2, and —C(O)—NH—(C1-C4 alkyl), or
or two R3s are taken together to form a 3-8 saturated ring or a fused phenyl wherein said saturated ring or fused phenyl is optionally substituted with 1 to 2 methyl groups;
R4 is selected from hydrogen, —CN, halo, C1-C4 alkoxy, —CH2NH(C1-C4 alkyl), C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)-O—(C1-C4 alkyl), C1-C4 fluoroalkyl, C(O)—N—(C1-C4 alkyl)2, —C(O)—NH—(C1-C4 alkyl), —C(O)—O—(C1-C4 alkyl), —C(O)—OH, —S(O)2—(C1-C4 alkyl), and a 5-membered heteroaryl;
R5 is selected from: —C(O)—(C1-C4alkyl), —C(O)—(CH2)0-2-Q, —C(O)—(CH2)0-2—N(R6)—(CH2)0-2-Q, —C(O)—O—(CH2)1-2-Q, —C(O)—(CH2)1-2—O—(CH2)0-2-Q, —C(O)—C(O)-Q, —S(O)2-Q, —C(O)—(C1-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —C(O)—(C1-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —C(O)—N(R6)—(C1-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —C(O)—N(R6)—(C1-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —C(O)—(CH2)0-2—N(R6)—(C1-C6 alkyl), —C(O)—(CH2)0-2—N(R6)—(C2-C6 alkynyl), —C(O)—(CH2)0-2—N(R6)—(C2-C6 alkenyl), —C(O)—(CH2)0-2-N(R6)—(CH2)0-2—O—(C1-C4 alkyl), —C(O)—(CH2)1-2—O—(C1-C4 alkyl), —C(O)—O—(C1-C4 alkylene)-O—(C1-C4 alkyl), —(CH2)0-4—O—C(O)—(C1-C4 alkyl), —(CH2)0-4—C(O)—O—(C1-C4 alkyl), —(CH2)0-4—O—(C1-C4 alkyl), —C(O)—(CH2)1-2—S—(C1-C4 alkyl), —S(O)2—(C1-C4 alkyl), —C(O)—(C1-C4 alkylene)-C(O)C(O)N(R6)(C1-C6 alkyl), —C(O)—(C1-C4 alkylene)-N(R6)S(O)2—(C1-C6 alkyl), and —C(O)—(C1-C4 alkylene)-N(R6)S(O)2Q, wherein:
each R6 is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, —CN, fluoro, chloro, and bromo; and
m is 0, 1, 2 or 3.
In some embodiments, m is 0, 1 or 2; and each R3, if present, is independently selected from methyl, ethyl, CF3, isopropyl, cyclopropyl and phenyl. In some embodiments, R3 is methyl or cyclopropyl. In some embodiments, R3 is methyl. In some embodiments, R3 is cyclopropyl.
In some embodiments, m is 1. In some embodiments, m is 2.
In some embodiments, m is 1 and R3 is C3-7 cycloalkyl (e.g., cyclopropyl). In some embodiments, m is 1 and R3 is C1-C4 (alkyl) (e.g., methyl or isopropyl). In some embodiments, m is 1 and R3 is haloalkyl (e.g., C1-C4 fluoroalkyl, e.g., CF3). In some embodiments, m is 2, one R3 is C1-4 alkyl (e.g., methyl) and the other R3 is halo (e.g., fluoro).
In some embodiments, R4 is —CN or —C(O)—O—(C1-C4 alkyl). In some embodiments, R4 is CN.
In some embodiments, R4 is:
In some embodiments, R4 is
In some embodiments, Y is —N(R5)—CH2— or —CH2—N(R5)—; R5 is —C(O)-Q and Q is cyclopropyl.
In some embodiments, Y is —N(R5)—; R5 is —C(O)R10; and R10 is selected from heteroaryl, aryl, —CH2-aryl, —CH2-heteroaryl, and —(CH2)2—O—CH3, wherein any aryl or heteroaryl portion of R8 is optionally substituted with methyl.
In some embodiments, Y is —N(R5)—; R5 is selected from selected from: —C(O)—(C1-C5 alkyl), —C(O)—(C2-C6 alkenyl), —C(O)—(C0-C2 alkylene)-Q, —C(O)—(C1-C4 alkenylene)-Q, —C(O)—(C0-C2 alkylene)-N(R6)—(C0-C2 alkylene)-Q, —C(O)—(C1-C2 alkylene)-O—(C0-C2 alkylene)-Q, —C(O)—(C1-C4 alkylene)-O—C(O)—(C1-C4 alkyl), —C(O)—(C1-C4 alkylene)-C(O)—O—(C1-C4 alkyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C1-C6 alkyl), —C(O)—(C0-C2 alkylene)N(R6)—(C2-C6 alkynyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C2-C6 alkenyl), —C(O)—(C0-C2 alkylene)-N(R6)—(C0-C2 alkylene)-O—(C1-C4 alkyl), —(C0 alkylene)-C(O)O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-O—(C1-C4 alkyl), —C(O)—(C1-C2 alkylene)-C(O)C(O)N(R)(C1-C4 alkyl), or —C(O)—(C1-C4 alkylene)-C(O)C(O)N(R6)(C1-C6 alkyl), wherein:
each R6 is independently selected from hydrogen and methyl;
In some embodiments, Y is —N(R5)—; and R5 is C(O)—(C1-C3 alkyl)-O—(C1-C2 alkyl), —C(O)-Q, —C(O)—(C1-C5 alkyl), —C(O)—(C1-C2 alkylene)-Q, —C(O)—(C2-C4 alkenyl), —C(O)O—(C1-C4 alkyl), or —C(O)—(C1-C4 alkenylene)-Q; wherein: any alkylene moiety present in R5 is optionally substituted with OH; any terminal methyl moiety present in R5 is optionally replaced with OH, CF3, OCH3, —C(O)H, OP(O)(C1-C4 alkoxy)2, or —OP(O)(OH)2 (or a salt thereof, such as a sodium salt); Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each member of Q is optionally substituted with one substituent independently selected from C1-C4 alkyl optionally substituted with OH, C1-C4 alkoxy, —(C1-C4 alkylene)-(C1-C4 alkoxy), and —OH.
In some embodiments, Y is —N(R5)—; and R5 is C(O)—(C1-C3 alkyl)-O—(C1-C2 alkyl). In some embodiments, Y is —N(R5)—; and R5 is —C(O)—(CH2)2—OCH3. In some embodiments, Y is —N(R5)— and R5 is C(O)—(C1-C3 alkyl)-CF3. In some embodiments, Y is —N(R5)— and R5 is —C(O)—CH2—CF3. In some embodiments, Y is —N(R5)—; R5 is —C(O)-Q and Q is cyclopropyl, oxetanyl or furanyl. In some embodiments, Y is —N(R5)— and R5 is —C(O)—CH2—CH2OH. In some embodiments, Y is —N(R5)—; R5 is —C(O)-Q where Q is substituted with C1-4 alkoxy. In some embodiments, Y is —N(R5)— and R5 is —C(O)-cyclopropyl substituted with C1-4 alkoxy (e.g., ethoxy). In some embodiments, Y is —N(R5)— and R5 is —C(O)—OCH3. In some embodiments, Y is —N(R5)— and R5—C(O)-Q where Q is substituted with (C1-4 alkylene)-OCH3. In some embodiments, Y is —N(R5)— and R5—C(O)-cyclopropyl substituted with CH2OCH3. In some embodiments, Y is —N(R5)— and R5—C(O)-Q where Q is substituted with C1-4 alkyl wherein alkyl is optionally substituted with —OH. In some embodiments, Y is —N(R5)— and R5—C(O)-cyclopropyl substituted with CH2OH. In some embodiments, Y is —N(R5)—; R5 is —C(O)-Q where Q is substituted with OH. In some embodiments, Y is —N(R5)—; R5 is —C(O)-cyclopropyl substituted with OH. In some embodiments, Y is —N(R5)—; R5 is —C(O)—(C1-4 alkyl)-OH. In some embodiments, Y is —N(R5)—; R5 is —C(O)—CH2C(OH)(CH3)2. In some embodiments, Y is —N(R5)—; R5 is —C(O)—CH2CH(OH)CH3. In some embodiments, Y is —N(R5)—; R5 is —C(O)—CH2CH2CH2OH. In some embodiments, Y is —N(R5)—; R5 is —C(O)—CH2CH2OH. In some embodiments, Y is —N(R5)—; and R5 is —C(O)—(C1-C4 alkyl). In some embodiments, Y is —N(R5)—; and R5 is —C(O)—CH3. In some embodiments, Y is —N(R5)—; R5 is —C(O)—(C1-4 alkyl)-(OCH3)2. In some embodiments, Y is —N(R5)—; R5 is —C(O)—CH2CH2C(H)(OCH3)2. In some embodiments, Y is —N(R5)—; R5 is —C(O)—(C1-4 alkyl)-C(O)H. In some embodiments, Y is —N(R5)—; R5 is —C(O)—CH2CH2C(O)H. In some embodiments, Y is —N(R5)—; R5 is —C(O)—C(cyclopropyl)(OH). In some embodiments, Y is —N(R5)—; R5 is —C(O)—(C1-4 alkyl)-C(O)OCH3. In some embodiments, Y is —N(R5)—; R5 is —C(O)—CH2CH2C(O)OCH3. In some embodiments, Y is —N(R5)— and R5 is —C(O)—(C0-C2 alkylene)-Q. In some embodiments, Y is —N(R5)— and R5 is —C(O)—(C0-C2 alkylene)-Q, where Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl. In some embodiments, Y is —N(R5)— and R5 is —C(O)—CH2-oxetanyl, —C(O)—CH2-azetidinonyl, —C(O)—CH2-pyrrolidinonyl, —C(O)—CH2-cyclobutyl, —C(O)—CH2-cyclopropyl, —C(O)—CH2CH2-cyclopropyl, —C(O)—CH2-tetrahydrofuranyl, —C(O)—CH2-dihydrofuranone, —C(O)—CH2CH2-oxetanyl, —C(O)—CH2CH2-furanyl, —C(O)—CH2-tetrahydrofuranyl, —C(O)—CH2CH2-tetrahydrofuranyl or —C(O)—CH2-cyclopentyl. In some embodiments, Y is —N(R5)— and R5 is —C(O)—(C2-C4 alkenyl)-OH. In some embodiments, Y is —N(R5)— and R5 is —C(O)—CH═CH—CH2CH2OH. In some embodiments, Y is —N(R5)— and R5—(C0-C4 alkylene)-C(O)—O—(C1-C4 alkyl). In some embodiments, Y is —N(R5)— and R5—C(O)—O-(t-butyl). In some embodiments, Y is —N(R5)— and R5—C(O)—(C1-C4 alkyl)-OP(O)(C1-C4 alkoxy)2. In some embodiments, Y is —N(R5)— and R5—C(O)—CH2CH2CH2—OP(O)(t-butoxy)2. In some embodiments, Y is —N(R5)— and R5—C(O)—(C1-C4 alkyl)-OP(O)(OH)2 or a salt thereof, such as a sodium salt. In some embodiments, Y is —N(R5)— and R5—C(O)—CH2CH2—OP(O)(t-butoxy)2. In some embodiments, Y is —N(R5)—; and R5 is —C(O)—(C1-C5 alkyl). In some embodiments, Y is —N(R5)—; and R5 is —C(O)-pentyl. In some embodiments, Y is —N(R5)—; and R5—C(O)—(C1-C4 alkenylene)-Q. In some embodiments, Y is —N(R5)—; and R5—C(O)—CH=cyclobutyl.
In some embodiments, one of R1a or R1b is selected from hydrogen and methyl; and the other of R1a or R1b is selected from isopropyl, —N(CH3)—(CH2)2—NH—CH3, aryl, heteroaryl, —CH2-aryl, —CH2-heteroaryl, —O—CH2-aryl, and —O—CH2-heteroaryl; wherein any aryl or heteroaryl of R1a or R1b is optionally substituted with one or more substituents independently selected from alkoxy, OH, halo, C1-C6 alkyl, —CF3, CN, —OC(O)CH3, and —OCF3.
In some embodiments, one of R1a or R1b is selected from hydrogen and methyl; and the other of R1a or R1b is selected from aryl, heteroaryl, heterocyclyl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-aryl, —O—(C0-C4 alkylene)-heteroaryl, —N(R7)-aryl, —N(R7)heteroaryl, —N(R9)-aryl, or —N(R9)-heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is substituted with -G-L-M, CH3, CN, alkoxy, OH, halo, C1-C6 alkyl, —CF3, —OC(O)CH3, or —OCF3.
In some embodiments, one of R1a or R1b is selected from hydrogen and methyl; and the other of R1a or R1b is selected from aryl, heteroaryl, heterocyclyl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-aryl, —O—(C0-C4 alkylene)-heteroaryl, —N(R7)-aryl, —N(R7)heteroaryl, —N(R9)-aryl, or —N(R9)-heteroaryl, wherein said aryl or heteroaryl is substituted with -G-L-M, CH3, or CN.
In some embodiments, R1a is H and R1b is aryl, heteroaryl, heterocyclyl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-aryl, or —O—(C0-C4 alkylene)-heteroaryl, —N(R7)-aryl, —N(R7)heteroaryl, —N(R9)-aryl, —N(R9)-heteroaryl, wherein said aryl or heteroaryl is substituted with -G-L-M, CH3, or CN. In some aspects of the preceding embodiments, R1a is H and R1b is aryl, heteroaryl, heterocyclyl, —CH2-aryl, —CH2-heteroaryl, —O-aryl, —O-heteroaryl, —O—(CH2)-aryl, —O—CH(CH3)-aryl, —O(CH)(C(CH3)2)-aryl, —O—CH(CH2CH3)-aryl, —NH-aryl, —NH-heteroaryl, —N(CH3)-aryl, —N(CH3)-heteroaryl, —N(aryl)-aryl, —N(heteroaryl)-heteroaryl, —O—(CH2)-heteroaryl or —O—CH(CH3)-heteroaryl, wherein aryl is phenyl, heteroaryl is pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl or pyrazolyl, and heterocyclyl is benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, dihydropyrrolyl and said phenyl, pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl, pyrazolyl, benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, or dihydropyrrolyl is substituted with -G-L-M, —CF3, —OCF3, halo (e.g., fluoro, chloro or bromo), CH3, or CN.
In some embodiments, R1a is methyl and R1b is aryl, heteroaryl, heterocyclyl, —O—(C0-C4 alkylene)-aryl, or —O—(C0-C4 alkylene)-heteroaryl, wherein said aryl or heteroaryl is substituted with -G-L-M, CH3, or CN. In some aspects of the preceding embodiments, R1a is methyl or H and R1b is aryl, heteroaryl, heterocyclyl, —O—(CH2)-aryl, —O—CH(CH3)-aryl, —O—(CH2)-heteroaryl or —O—CH(CH3)-heteroaryl, wherein aryl is phenyl or naphthyl and heteroaryl is quinolinyl, pyrazolyl, isoquinolinyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl, and heterocyclyl is tetrahydropyridinyl and said phenyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl is substituted with -G-L-M, halo (e.g., chloro or fluoro), CH3, or CN.
In some embodiments, -G-L-M is:
C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydrogen, tetrazolyl, morpholino, piperazinyl, pyrrolidinone, pyrazolyl, benzyl, —(CH2)1-4—SH, —(CH2)1-4—NH2, —NH2, (CH2)1-4—OH, —N(H)C(O)OCH(CH3)3, —(CH2)1-4—OCH3, —NH—(CH2)1-4—OH, —C(O)—(C1-C4 alkyl), —C(O)—(C1-C4 alkenyl), —O—(CH2)1-4—C(O)—O—(C1-C4 alkyl), —C(O)NH2, —(CH2)1-4C(O)CH3, —N(CH3)(CH3), —NHC(O)(C2-C4 alkenyl), —NHC(O)(C2-C4 alkyl), —SO2(CH2)1-4, —(CH2)1-4—NHSO2Me, —NHSO2(CH2)1-4, —O—SO2CF3, —SO2NH—(C1-C4 alkyl), —SO2NH—(C2-C4 alkenyl), SO2—NH2 or NHSO2Me.
In some embodiments, R2 is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is isopropyl.
In some embodiments, R4 is CN; Y is —N(R5)—; R5 is —C(O)R10; and the compound has Structural Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
one of R1a or R1b is selected from hydrogen and methyl;
the other of R1a or R1b is selected from aryl, heteroaryl, heterocyclyl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-aryl, —O—(C0-C4 alkylene)-heteroaryl, —N(R7)-aryl, —N(R7)heteroaryl, —N(R9)-aryl, or —N(R9)-heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is substituted with -G-L-M, CH3, CN, alkoxy, OH, halo, C1-C6 alkyl, —CF3, —OC(O)CH3, or —OCF3;
R2 is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
each R3, if present, is selected from methyl, ethyl, isopropyl, CF3, cyclopropyl and phenyl;
R10 is selected from —(C1-C3 alkyl)-O—(C1-C2 alkyl), Q, (C1-C5 alkyl), C1-C2 alkylene)-Q, (C2-C4 alkenyl), —O—(C1-C4 alkyl), or —(C1-C4 alkenylene)-Q; wherein: any alkylene moiety present in R10 is optionally substituted with OH; any terminal methyl moiety present in R10 is optionally replaced with OH, CF3, OCH3, —C(O)H, —OP(O)(C1-C4 alkoxy)2, or —OP(O)(OH)2 (or a salt thereof, such as a sodium salt); Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each member of Q is optionally substituted with one substituent independently selected from C1-C4 alkyl optionally substituted with OH, C1-C4 alkoxy, —(C1-C4 alkylene)-(C1-C4 alkoxy), and —OH; and
m is 0, 1, or 2.
In certain embodiments, m is 1; and the compound has Structural Formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
R1a is hydrogen or methyl;
R1b is selected from aryl, heteroaryl, heterocyclyl, —(C1-C4 alkylene)-aryl, —(C1-C4 alkylene)-heteroaryl, —O—(C0-C4 alkylene)-aryl, —O—(C0-C4 alkylene)-heteroaryl, —N(R7)-aryl, —N(R7)heteroaryl, —N(R9)-aryl, or —N(R9)-heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is substituted with -G-L-M, CH3, CN, alkoxy, OH, halo, C1-C6 alkyl, —CF3, —OC(O)CH3, or —OCF3;
R2 is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
each R3, if present, is selected from methyl, isopropyl, and cyclopropyl;
R10 is selected from —(C1-C3 alkyl)-O—(C1-C2 alkyl), Q, (C1-C5 alkyl), C1-C2 alkylene)-Q, (C2-C4 alkenyl), —O—(C1-C4 alkyl), or —(C1-C4 alkenylene)-Q; wherein: any alkylene moiety present in R10 is optionally substituted with OH; any terminal methyl moiety present in R10 is optionally replaced with —OH, CF3, OCH3, —C(O)H, —OP(O)(C1-C4 alkoxy)2, or —OP(O)(OH)2 (or a salt thereof, such as a sodium salt); Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each member of Q is optionally substituted with one substituent independently selected from C1-C4 alkyl optionally substituted with OH, C1-C4 alkoxy, —(C1-C4 alkylene)-(C1-C4 alkoxy), and —OH; and
m is 0, 1, or 2.
In some embodiments, R4 is CN; Y is —N(R5)—; R5 is —C(O)R10; and the compound has Structural Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
one of R1a or R1b is selected from hydrogen and methyl;
the other of R1a or R1b is selected from isopropyl, —N(CH3)—(CH2)2—NH—CH3, aryl, heteroaryl, —CH2-aryl, —CH2-heteroaryl, —O—CH2-aryl, and —O—CH2-heteroaryl; wherein any aryl or heteroaryl portion of R1a or R1b is optionally substituted with one or more substituents independently selected from alkoxy, hydroxy, halo, C1-C6 alkyl, —CF3, —OC(O)CH3, and —OCF3;
R2 is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
each R3, if present, is selected from methyl, ethyl, isopropyl, cyclopropyl and phenyl;
R10 is selected from heteroaryl, aryl, —CH2-aryl, —CH2-heteroaryl, and —(CH2)2—O—CH3, wherein any aryl or heteroaryl portion of R10 is optionally substituted with methyl; and
m is 0, 1, or 2.
In certain embodiments, m is 1; and the compound has Structural Formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
R1a is selected from hydrogen and methyl;
R1b is selected from aryl, and heteroaryl; wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from methoxy, fluoro, chloro, methyl, —CF3, —OCF3;
R2 is selected from isopropyl and cyclopropyl;
R3 is selected from methyl, ethyl, isopropyl and cyclopropyl; and
R10 is selected from —(CH2)2—O—CH3, furan-3-yl, 2-methylfuran-3-yl and thien-2-yl.
In some embodiments, R4 is CN; Y is —N(R5)—; R5 is —C(O)R10; and the compound has Structural Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R1a is H;
R1b is aryl, 1 heteroaryl, —O—(C1-C4 alkylene)-aryl, or —O—(C1-C4 alkylene)-heteroaryl, wherein said aryl or heteroaryl is substituted with -G-L-M, CH3, or CN;
R2 is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
each R3, if present, is selected from methyl, ethyl, isopropyl, cyclopropyl and phenyl;
R10 is selected from heteroaryl, aryl, —CH2-aryl, —CH2-heteroaryl, and —(CH2)2—O—CH3, wherein any aryl or heteroaryl portion of R10 is optionally substituted with methyl; and
m is 0, 1, or 2.
In certain embodiments, m is 1; and the compound has Structural Formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
R1a is H;
R1b is aryl, heteroaryl, —O—(CH2)-aryl, —O—CH(CH3)-aryl, —O—(CH2)-heteroaryl or —O—CH(CH3)-heteroaryl, wherein aryl is phenyl and heteroaryl is pyridyl, pyrimidinyl, indolyl, or pyrazolyl, and said phenyl, pyridyl, pyrimidinyl, indolyl or pyrazolyl is substituted with -G-L-M, CH3, or CN;
R2 is selected from isopropyl and cyclopropyl;
R3 is selected from methyl, ethyl, isopropyl and cyclopropyl; and
R10 is selected from —(CH2)2—O—CH3, furan-3-yl 2-methylfuran-3-yl and thien-2-yl.
In another embodiment, the compound is selected from any one of the compounds set forth in Table 1, below.
In another embodiment, the compound is selected from any one of the compounds set forth in Table 5, below.
The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, scalemic mixtures, and diastereomeric mixtures, as well as single enantiomers or individual stereoisomers that are substantially free from another possible enantiomer or stereoisomer. The term “substantially free of other stereoisomers” as used herein means a preparation enriched in a compound having a selected stereochemistry at one or more selected stereocenters by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. The term “enriched” means that at least the designated percentage of a preparation is the compound having a selected stereochemistry at one or more selected stereocenters. Methods of obtaining or synthesizing an individual enantiomer or stereoisomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.
The compounds of Formula I, II and IIa may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, 14C; O may be in any isotopic form, including 16O and 18O; and the like.
Unless otherwise indicated when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts.” J. Pharm. Sci. Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., —COOH may be —COO−), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NH3R+, NH2R2+, NHR3+, NR4+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.
If the compound is cationic, or has a functional group that may be cationic (e.g., —NH2 may be —NH3+), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
Compositions and Routes of Administration
The compounds utilized in the methods described herein may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to be administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a subject, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vCompound AGInally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleCompound AGInous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
The pharmaceutical compositions described above comprising a compound of Structural Formula I, II or IIa or a compound described in any one of the embodiments herein, may further comprise another therapeutic agent useful for treating cancer.
Methods of Use
Provided is a method for inhibiting a mutant IDH1 activity comprising contacting a subject in need thereof a compound of Structural Formula I, II or IIa, a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH1 wherein the IDH1 mutation result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDH1 has an R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132H or R132C. In yet another aspect, the R132X mutation is R132H.
Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising the step of administering to subject in need thereof (a) a compound of Structural Formula I, II or IIa, a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH1 wherein the IDH1 mutation result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate in a patient. In one aspect of this embodiment, the IDH1 mutation is an R132X mutation. In another aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132 H or R132C. A cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1.
Without being bound by theory, applicants believe that mutant alleles of IDH1 wherein the IDH1 mutation result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate, and in particular R132H mutations of IDH1, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body. Thus, the compounds and methods of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDH1 imparting such activity and in particular an IDH1 R132H or R132C mutation.
In one aspect of this embodiment, the efficacy of cancer treatment is monitored by measuring the levels of 2HG in the subject. Typically levels of 2HG are measured prior to treatment, wherein an elevated level is indicative of the use of the compound of Formula I to treat the cancer. Once the elevated levels are established, the level of 2HG is determined during the course of and/or following termination of treatment to establish efficacy. In certain embodiments, the level of 2HG is only determined during the course of and/or following termination of treatment. A reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy. Similarly, a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy. Typically, the these 2HG measurements will be utilized together with other well-known determinations of efficacy of cancer treatment, such as reduction in number and size of tumors and/or other cancer-associated lesions, improvement in the general health of the subject, and alterations in other biomarkers that are associated with cancer treatment efficacy.
2HG can be detected in a sample by LC/MS. The sample is mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degrees Celsius. The resulting supernatant can be collected and stored at −80 degrees Celsius prior to LC-MS/MS to assess 2-hydroxyglutarate levels. A variety of different liquid chromatography (LC) separation methods can be used. Each method can be coupled by negative electrospray ionization (ESI, −3.0 kV) to triple-quadrupole mass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on infused metabolite standard solutions. Metabolites can be separated by reversed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo et al. J Chromatogr A 1147, 153-64, 2007). One method allows resolution of TCA metabolites: t=0, 50% B; t=5, 95% B; t=7, 95% B; t=8, 0% B, where B refers to an organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50%-95% B (buffers as defined above) over 5 minutes. A Synergi Hydro-RP, 100 mm×2 mm, 2.1 μm particle size (Phenomonex) can be used as the column, as described above. Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentration. Metabolite flux studies from 13C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1179-86, 2008.
In one embodiment 2HG is directly evaluated.
In another embodiment a derivative of 2HG formed in process of performing the analytic method is evaluated. By way of example such a derivative can be a derivative formed in MS analysis. Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g., a Na adduct, e.g., as formed in MS analysis.
In another embodiment a metabolic derivative of 2HG is evaluated. Examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.
Exemplary 2HG derivatives include dehydrated derivatives such as the compounds provided below or a salt adduct thereof:
In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH1 mutation, and in particular an IDH1 R132H or R132C mutation, at the time of diagnosis or treatment.
IDH1 R132X mutations are known to occur in certain types of cancers as indicated in Table 2, below.
IDH1 R132H mutations have been identified in glioblastoma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblastic non-Hodgkin's lymphoma (NHL). Accordingly, in one embodiment, the methods described herein are used to treat glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC) or cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN) or colon cancer in a patient.
Accordingly in one embodiment, the cancer is a cancer selected from any one of the cancer types listed in Table 2, and the IDH R132X mutation is one or more of the IDH1 R132X mutations listed in Table 2 for that particular cancer type.
Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with a compound of Structural Formula I, II or IIa or a compound described in any one of the embodiments described herein.
In one embodiment, prior to and/or after treatment with a compound of Structural Formula I, II or IIa or a compound described in any one of the embodiments described herein, the method further comprises the step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer.
In one embodiment, prior to and/or after treatment with a compound of formula I or I-a or a compound described in any one of the embodiments described herein, the method further comprises the step of evaluating the IDH1 genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG.
In one embodiment, prior to and/or after treatment with a compound of formula I or I-a or a compound described in any one of the embodiments described herein, the method further comprises the step of determining the 2HG level in the subject. This may be achieved by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy.
Combination Therapies
In some embodiments, the methods described herein comprise the additional step of co-administering to a subject in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment. Exemplary additional cancer therapeutic agents include for example, chemotherapy, targeted therapy, antibody therapies, immunotherapy, and hormonal therapy. Additional cancer treatments include, for example: surgery, and radiation therapy. Examples of each of these treatments are provided below.
The term “co-administering” as used herein with respect to an additional cancer therapeutic agents means that the additional cancer therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional cancer therapeutic agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment. The term “co-administering” as used herein with respect to an additional cancer treatment means that the additional cancer treatment may occur prior to, consecutively with, concurrently with or following the administration of a compound of this invention.
In some embodiments, the additional cancer therapeutic agent is a chemotherapy agent. Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others) and hypomethylating agents (e.g., decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5-azacytidine), 5-flouro-2′-deoxycytidine, 5,6-dihydro-5-azacytidine and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, AsparCompound AGInase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.
Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more chemotherapy agents are used as combination chemotherapy.
In some embodiments, the additional cancer therapeutic agent is a differentiation agent. Such differentiation agent includes retinoids (such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs (such as azacytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate)); hybrid polar compounds (such as hexamethylene bisacetamide ((HMBA)); vitamin D; and cytokines (such as colony-stimulating factors including G-CSF and GM-CSF, and interferons).
In some embodiments the additional cancer therapeutic agent is a targeted therapy agent. Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies. Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusion proteins include Aflibercept and Denileukin diftitox. In some embodiments, the targeted therapy can be used in combination with a compound described herein, e.g., a biguanide such as metformin or phenformin, preferably phenformin.
Targeted therapy can also involve small peptides as “homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®.
In some embodiments, the additional cancer therapeutic agent is an immunotherapy agent. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the subject's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects.
Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft-versus-tumor effect. In some embodiments, the immunotherapy agents can be used in combination with a compound or composition described herein.
In some embodiments, the additional cancer therapeutic agent is a hormonal therapy agent. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in combination with a compound or a composition described herein.
Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
anhy.—anhydrous chromatography
aq.—aqueous Hz—hertz
min—minute(s) δ—chemical shift
mL—milliliter J—coupling constant
mmol—millimole(s) s—singlet
mol—mole(s) d—doublet
MS—mass spectrometry t—triplet
NMR—nuclear magnetic resonance q—quartet
TLC—thin layer chromatography m—multiplet
HPLC—high-performance liquid br—broad
qd—quartet of doublets Na2CO3—sodium carbonate
dquin—doublet of quintets TFA—trifluoroacetic acid
dd—doublet of doublets Na2SO4—sodium sulfate
dt—doublet of triplets NaBH4—sodium borohydride
CHCl3—chloroform NaHCO3—sodium bicarbonate
DCM—dichloromethane LiHMDS—lithium hexamethyldisilylamide
DMF—dimethylformamide NaHMDS—sodium hexamethyldisilylamide
Et2O—diethyl ether LAH—lithium aluminum hydride
EtOH—ethyl alcohol NaBH4—sodium borohydride
EtOAc—ethyl acetate LDA—lithium diisopropylamide
MeOH—methyl alcohol Et3N—triethylamine
MeCN—acetonitrile DMAP—4-(dimethylamino)pyridine
PE—petroleum ether DIPEA—N,N-diisopropylethylamine
THF—tetrahydrofuran NH4OH—ammonium hydroxide
AcOH—acetic acid EDCI—1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
HCl—hydrochloric acid
H2SO4—sulfuric acid HOBt—1-hydroxybenzotriazole
NH4Cl—ammonium chloride HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium
KOH—potassium hydroxide
NaOH—sodium hydroxide BINAP—2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl
K2CO3—potassium carbonate
In the following examples, reagents were purchased from commercial sources (including Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. Flash chromatography was performed on an Ez Purifier III using a column with silica gel particles of 200-300 mesh. Analytical and preparative thin layer chromatography plates (TLC) were HSGF 254 (0.15-0.2 mm thickness, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were run with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA). HPLC chromatographs were recorded on an Compound AGIlent 1200 Liquid Chromatography (Compound AGIlent, USA, column: Ultimate 4.6 mm×50 mm, 5 μm, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). Microwave reactions were run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).
For exemplary compounds disclosed in this section, the specification of a stereoisomer (e.g., an (R) or (S) stereoisomer) indicates a preparation of that compound such that the compound is enriched at the specified stereocenter by at least about 90%, 95%, 96%, 97%, 98%, or 99%.
(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (7, wherein R1a is hydrogen; m is 1; R3 is 3-methyl; and R8 is methoxyethyl) was prepared according to general Scheme 1, below.
To a solution of commerically available 3-methylbutan-2-one (1; 8.613 g, 100 mmol) in 150 mL of anhydrous DMF was added commercially available 1,1-dimethoxy-N,N-dimethylmethanamine (29.80 g, 250 mmol). The resulting mixture was stirred at 100° C. overnight. After removal of DMF and excess of acetal, 14 g of title compound was obtained as a crude product and used in subsequent reaction without further purification. 1H NMR (CHLOROFORM-d) δ 7.57 (d, J=12.8 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 2.80-3.10 (m, 6H), 2.56 (dt, J=13.7, 6.8 Hz, 1H), 1.06-1.14 (m, 6H).
8.8 g of 1-(dimethylamino)-4-methylpent-1-en-3-one (2; 62 mmol) and 5.3 g of commercially available cyanoacetamide (62 mmol) in 24 mL of H2O was treated with a premixed buffer solution of 0.7 mL of acetic acid, 1.8 mL of H2O, and enough piperidine to make the buffer solution basic. The resulting solution was refluxed for 2 hrs and LC-MS showed the formation of desired product. After cooling to room temperature, the mixture was acidified with glacial acetic acid, and a brown yellowish precipitate was formed. The filter cake was washed with H2O and air-dried to give 6.5 g of title compound. MS (ES) M+H expected 163.1. found 163.0. 1H NMR (DMSO-d6) δ 12.51 (br. s., 1H), 7.96-8.18 (m, 1H), 6.24 (d, J=7.5 Hz, 1H), 2.83 (spt, J=6.9 Hz, 1H), 1.19 (s, 29H), 1.17 (s, 3H).
To a solution of 2-hydroxy-6-isopropylnicotinonitrile (3; 3.0 g, 19 mmol) in 50 mL of DCE was added NBS (5 g, 28 mmol) at room temperature. The reaction mixture was then heated at reflux for 3 hours. After LC-MS showed the completion of reaction, the mixture was cooled to room temperature and poured into water and extracted with methylene chloride. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (4% MeOH/DCM) afforded 3.9 g of title compound as a brown solid. MS (ES) M+H expected 241.0. found 240.9. 1H NMR (DMSO-d6) δ 12.58 (br. s., 1H), 8.38 (s, 1H), 3.25-3.32 (m, 1H), 1.23 (s, 3H), 1.21 (s, 3H).
To a solution of 5-bromo-2-hydroxy-6-isopropylnicotinonitrile (4; 2.0 g, 8 mmol) in 20 mL of methylene chloride was added DMAP (100 mg, 0.8 mmol), and triethylamine (1.01 g, 10 mmol). The mixture was cooled to 0° C. in an ice-water bath, and trifluoromethanesulfonic anhydride (2.82 g, 10 mmol) was added dropwise by syringe. The resulting reaction mixture was stirred at 0° C. for 30 min before it was allowed to warm to room temperature and stirred for additional 2 hours. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc/petroleum ether) to afford 2.8 g of title compound. 1H NMR (CHLOROFORM-d) δ 8.22 (s, 1H), 3.57 (spt, J=6.7 Hz, 1H), 1.28 (d, J=6.8 Hz, 6H).
A mixture of the above triflate 5 (1.68 g, 4.5 mmol), (R)-2-methylpiperazine (770 mg, 6.77 mmol), and triethylamine (1.9 mL, 13.5 mmol) suspended in 5 mL of MeCN was subjected to microwave reaction at 175° C. for 45 min. After the mixture was concentrated in vacuo, the residue was purified by column chromatography (10% DCM/MeOH) to afford 0.91 g of title compound as a light yellowish solid. MS (ES) M+H expected 323.1. found 323.0. 1H NMR (CHLOROFORM-d) δ 7.79 (s, 1H), 4.35-4.40 (m, 0.5H), 4.32-4.35 (m, 1H), 4.30 (t, J=2.4 Hz, 0.5H), 3.37-3.45 (m, 1H), 3.08-3.13 (m, 0.5H), 3.05-3.08 (m, 1H), 3.04 (d, J=2.5 Hz, 0.5H), 2.96-3.01 (m, 1H), 2.89-2.96 (m, 1H), 2.65-2.74 (m, 1H), 1.21 (dd, J=6.8, 0.8 Hz, 6H), 1.13 (d, J=6.3 Hz, 3H).
To a 25 mL of round-bottom flask was added (R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (6; 680 mg, 2.1 mmol), 3-methoxypropanoic acid (438 mg, 4.2 mmol), HATU (1.6 g, 4.2 mmol), DIPEA (1.1 mL, 6.31 mmol) and 5 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature for 4 hours until TLC showed the completion of the reaction. After washing with Satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (20% EtOAc/petroleum ether) afforded 550 mg of title compound as a light yellowish solid. MS (ES) M+H expected 409.1. found 409.0. 1H NMR (CHLOROFORM-d) δ 7.83 (s, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=12.3 Hz, 0.5H), 4.19-4.39 (m, 3H), 3.76-3.85 (m, 0.5H), 3.73 (t, J=6.4 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.25-3.35 (m, 1H), 3.02-3.20 (m, 1H), 2.63-2.80 (m, 1H), 2.51-2.61 (m, 1H), 1.35 (d, J=7.0 Hz, 1.5H), 1.25 (d, J=6.3 Hz, 1.5H), 1.21-1.23 (m, 3H), 1.19-1.21 (m, 3H)
Other intermediates 7 were prepared by similar steps according to Scheme 1 and either: (1) replacing (R)-2-methylpiperazine in Step E with an alternately substituted or unsubstituted piperazine; and/or (2) replacing 3-methoxypropanoic acid in Step F with an alternate acid.
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (17; wherein R1a is hydrogen; R2 is cyclopropyl; m is 1; R3 is 3-methyl; and R8 is methoxyethyl) was prepared according to general Scheme 2, below.
To a solution of commercially available 1-cyclopropylethanone (11; 8.584 g, 100 mmol) in 200 mL of anhydrous DMF was added 1,1-dimethoxy-N,N-dimethylmethanamine (29.80 g, 250 mmol). The resulting mixture was stirred at 100° C. overnight. After removal of DMF and excess of acetal, 13.9 g of title compound was obtained as a crude product and used in subsequent reaction without further purification. 1H NMR (CHLOROFORM-d) δ 7.56 (d, J=12.8 Hz, 1H), 5.20 (d, J=12.5 Hz, 1H), 2.78-3.08 (m, 6H), 1.79 (tt, J=7.9, 4.5 Hz, 1H), 0.94-1.04 (m, 2H), 0.67-0.80 (m, 2H).
3.532 g of 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one 12 and 2.032 g of cyanoacetamide in 10 mL of H2O was treated with a premixed buffer solution of 0.33 mL of acetic acid, 0.82 mL of H2O, and enough amount of piperidine to make solution basic. The resulting solution was refluxed for 2 hrs and LC-MS showed the formation of desired product 13. After cooling to room temperature, the mixture was acidified with glacial acetic acid, and a brown yellowish precipitated was formed. The thick brown slurry was filtered and filter cake was washed with H2O and air-dried to give 1.30 g of title compound. MS (ES) M+H expected 161.1. found 161.0. 1H NMR (CHLOROFORM-d) δ 13.60 (br. s., 1H), 7.77 (d, J=7.8 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 1.96-2.12 (m, 1H), 1.29-1.36 (m, 2H), 1.04-1.11 (m, 2H).
To a solution of 6-cyclopropyl-2-hydroxynicotinonitrile (13; 0.32 g, 2.0 mmol) in 5 mL of DCE was added NBS (0.534 g, 3.0 mmol) at room temperature. The reaction mixture was heated at reflux for 3 hours. After LC-MS showed completion of reaction, the reaction mixture was cooled to room temperature and poured into water. After extraction with methylene chloride (3×5 mL), the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (4% MeOH/DCM) afforded 0.45 g of 14. MS (ES) M+H expected 239.0. found 238.9. 1H NMR (CHLOROFORM-d) δ 8.49-8.72 (br. s., 1H), 7.93 (s, 1H), 2.23-2.34 (m, 1H), 1.36-1.42 (m, 2H), 1.29-1.36 (m, 2H).
To a 5-bromo-6-cyclopropyl-2-hydroxynicotinonitrile (14; 0.45 g, 1.882 mmol) in 10 mL of methylene chloride was added DMAP (23.2 mg, 0.19 mmol), and triethylamine (0.247 g, 2.45 mmol). The mixture was cooled to 0° C. in an ice-water bath, and trifluoromethanesulfonic anhydride (0.69 g, 2.45 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 0° C. for 30 min before it was allowed to warm to room temperature and stirred for additional 2 hours. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% ethyl acetate/petroleum ether) to afford 537 mg of 15. 1H NMR (CHLOROFORM-d) δ 8.14-8.19 (m, 1H), 2.55-2.66 (m, 1H), 1.30 (dt, J=7.8, 3.1 Hz, 2H), 1.21-1.27 (m, 2H).
A mixture of above triflate 15 (1.68 g, 4.6 mmol), (R)-2-methylpiperazine (790 mg, 6.9 mmol), and triethylamine (1.9 mL, 13.8 mmol) suspended in 5 mL of MeCN was subjected to microwave reaction at 175° C. for 60 min. After the mixture was concentrated under reduced pressure, the residue was extracted between ethyl acetate and water. The combined organic layer was then washed with aq. NaHCO3, brine, dried —Na2SO4 and concentrated in vacuo to give 1.26 g of crude 16. MS (ES) M+H expected 321.1. found 321.2. 1H NMR (CHLOROFORM-d) δ 7.78 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, J=12.9, 10.2 Hz, 1H), 2.42-2.52 (m, 1H), 1.16 (d, J=6.3 Hz, 3H), 1.08 (s, 2H), 1.07 (d, J=3.8 Hz, 2H).
To a 25 mL of round-bottom flask was added (R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (16; 1.26 g, 3.9 mmol), 3-methoxypropanoic acid (0.74 mL, 7.8 mmol), HATU (2.98 g, 7.8 mmol), DIPEA (2 mL, 11.76 mmol) and 10 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature overnight until TLC showed the completion of the reaction. Reaction mixture was with Satd. NaHCO3 and brine. The combined organic layer was then dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (30% EtOAc/petroleum ether) afforded 1.28 g of title compound as a white solid. MS (ES) M+H expected 407.1. found 407.0. 1H NMR (CHLOROFORM-d) δ 7.78-7.85 (m, 1H), 4.82-4.92 (m, 0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H), 3.75-3.82 (m, 0.5H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 0.5H), 3.36 (s, 3H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).
Other intermediates 17 were similarly prepared according to Scheme 2 by either: (1) replacing (R)-2-methylpiperazine in Step P with an alternately substituted or unsubstituted piperazine; and/or (2) replacing 3-methoxypropanoic acid in Step Q with an alternate acid.
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile (28; wherein R1a is methyl; R2 is cyclopropyl; m is 1; R3 is 3-methyl; and R8 is methoxyethyl) was prepared according to general Scheme 3, below.
To a suspension of ammonium acetate (140 g, 1.82 mol) in 400 mL of EtOH was added successively commercially available 1-cyclopropylethanone (22; 22.5 mL, 22.7 mmol), acetaldehyde (21; 10 g, 22.7 mmol), and ethyl cyanoacetate (23; 24.2 mL, 22.7 mmol). The resulting mixture was stirred at reflux temperature for 2 hrs and subsequently at room temperature overnight. After the LC-MS showed the formation of the desired product, the solvent was removed under reduced pressure. Flash column chromatography (10% MeOH/DCM) afforded 1.3 g of 24 as a white solid. MS (ES) M+H expected 175.1. found 175.1. 1H NMR (DMSO-d6) δ 12.36 (br. s., 1H), 5.93 (s, 1H), 2.26 (s, 3H), 1.81-1.91 (m, 1H), 1.06-1.14 (m, 2H), 0.91-0.95 (m, 2H).
To a solution of 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (24; 2.6 g, 15 mmol) in 10 mL of DCE was added NBS (4 g, 22.5 mmol) at room temperature. The reaction mixture was then heated at reflux for 3 hours. After LC-MS showed the completion of reaction, the mixture was cooled to room temperature and poured into water and extracted with methylene chloride. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (4% MeOH/DCM) afforded 4 g of 25 as a brown solid. MS (ES) M+H expected 253.0. found 253.0. 1H NMR (CHLOROFORM-d) δ 2.68 (s, 3H), 1.79-1.88 (m, 1H), 1.03-1.09 (m, 2H), 0.93-1.01 (m, 2H).
To a solution of 5-bromo-2-hydroxy-6-isopropylnicotinonitrile (25; 4.0 g, 14.6 mmol) in 20 mL of methylene chloride was added DMAP (178 mg, 1.46 mmol), and triethylamine (2.5 mL, 17.5 mmol). The mixture was cooled to 0° C. in an ice-water bath, and trifluoromethanesulfonic anhydride (3.7 mL, 21.9 mmol) was added dropwise by syringe. The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to room temperature and stirred overnight. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc/petroleum ether) to afford 1.66 g of 26. 1H NMR (CHLOROFORM-d) δ 2.70 (s, 3H), 2.16-2.20 (m, 1H), 1.23-1.25 (m, 2H), 1.19-1.22 (m, 2H).
A mixture of above triflate 26 (1.66 g, 4.3 mmol), (R)-2-methylpiperazine (738 mg, 6.46 mmol), and triethylamine (1.8 mL, 12.9 mmol) suspended in 5 mL of MeCN was subjected to microwave reaction at 150° C. for 1 hour. After removal of solvent under reduced pressure, the residue was extracted between EtOAc and water. The organic layer was then washed with satd. aq. NaHCO3 and brine, dried over anhy. Na2SO4 and concentrated in vacuo. Flash column chromatography (10% DCM/MeOH) afforded 330 mg of 27 as a light yellowish solid. MS (ES) M+H expected 335.1. found 335.2. 1H NMR (CHLOROFORM-d) δ 4.08-4.16 (m, 0.5H), 4.05-4.08 (m, 1H), 4.01-4.04 (m, 0.5H), 2.99-3.08 (m, 1H), 2.97 (d, J=8.8 Hz, 2H), 2.88-2.95 (m, 1H), 2.58-2.65 (m, 1H), 2.55-2.57 (m, 3H), 1.77 (br. s., 1H), 1.12 (s, 1.5H), 1.10 (s, 1.5H), 1.05-1.09 (m, 2H), 1.00-1.05 (m, 2H).
To a 50 mL of round-bottom flask was added (R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (27; 1.12 g, 3.34 mmol), 3-methoxypropanoic acid (0.63 mL, 6.68 mmol), HATU (2.54 g, 6.68 mmol), DIPEA (3.8 g, 10 mmol) and 10 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature overnight until TLC showed the completion of the reaction. After washing the reaction mixture with Satd. NaHCO3, brine, the organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Flash column chromatography (20% EtOAc/petroleum ether) afforded 1.7 g of 28 as a yellowish solid. MS (ES) M+H expected 421.1. found 421.3. 1H NMR (CHLOROFORM-d) δ 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.22 (br. s., 0.5H), 3.95-4.13 (m, 2H), 3.78 (br. s., 0.5H), 3.74 (t, J=5.9 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H), 3.07-3.24 (m, 1.5H), 2.90-3.06 (m, 1H), 2.65-2.79 (m, 1H), 2.60 (s, 3H), 2.52-2.63 (m, 1H), 2.17-2.21 (m, 1H), 1.37 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=6.3 Hz, 1.5H), 1.09 (s, 2H), 1.05-1.08 (m, 2H).
Other intermediates 28 were similarly prepared according to Scheme 3 by either: (1) replacing (R)-2-methylpiperazine in Step Dd with an alternately substituted or unsubstituted piperazine; and/or (2) replacing 3-methoxypropanoic acid in Step Ee with an alternate acid.
A mixture of bromide 7 from Example 1 (26 mg, 0.06 mmol), 4-(trifluoromethyl)phenylboronic acid (17 mg, 0.089 mmol), Pd(PPh3)4 (3 mg, 0.003 mmol), and K2CO3 (16 mg, 0.119 mmol) suspended in 1 mL of DMF was subjected to microwave reaction at 150° C. for 45 min. After the reaction, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to afford 19 mg of Compound 189 as yellowish oil. MS (ES) M+H expected 475.2. found 475.1. 1H NMR (CHLOROFORM-d) δ 7.70 (d, J=8.0 Hz, 2H), 7.60 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=11.0 Hz, 0.5H), 4.44 (d, J=12.3 Hz, 1H), 4.32-4.39 (m, 1H), 4.28 (br. s., 0.5H), 3.83 (d, J=13.3 Hz, 0.5H), 3.68-3.79 (m, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.36 (br. s., 0.5H), 3.33 (br. s., 0.5H), 3.10-3.28 (m, 1.5H), 3.07 (dt, J=13.3, 1 Hz, 1H), 2.65-2.80 (m, 1H), 2.52-2.65 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.3 Hz, 1.5H), 1.16 (d, J=6.5 Hz, 6H).
Other Compounds of Formula II listed below, wherein R1b is aryl or heteroaryl; and R2 is isopropyl or cyclopropyl were similarly prepared using any of intermediates 7 (Scheme 1), 17 (Scheme 2), or 28 (Scheme 3) as starting material.
1H NMR (CHLOROFORM-d) δ 7.70 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.47-7.56 (m, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.07 (d, J=3.5 Hz, 1H), 6.48-6.55 (m, 1H), 4.86-4.96 (m, 1H), 4.43-4.59 (m, 2H), 4.38 (dt, J=13.3, 2.0 Hz, 1H), 3.56 (br. s., 1H), 3.46 (dd, J=13.3, 3.8 Hz, 1H), 3.28 (td, J=12.4, 3.4 Hz, 1H), 3.07 (quin, J=6.7 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.16 (dd, J=6.7, 1.6 Hz, 6H). LC-MS: m/z 483.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.76 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.44-7.49 (m, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.56-6.63 (m, 1H), 4.75 (br. s., 1H), 4.45 (d, J=13.1 Hz, 1H), 4.35-4.42 (m, 2H), 3.42-3.64 (m, 1H), 3.31-3.41 (m, 1H), 3.18 (td, J=12.5, 3.5 Hz, 1H), 3.07 (dt, J=13.2, 6.6 Hz, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.16 (dd, J=6.7, 1.9 Hz, 6H). LC-MS: m/z 483.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.69 (d, J=8.3 Hz, 2H), 7.59 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.22 (dd, J=5.1, 1.1 Hz, 1H), 6.95-7.00 (m, 1H), 6.89-6.95 (m, 1H), 4.95 (br. s., 0.5H), 4.59 (d, J=12.8 Hz, 0.5H), 4.19-4.48 (m, 3H), 3.89-4.06 (m, 2H), 3.82 (d, J=13.6 Hz, 0.5H), 3.57 (t, J=11.3 Hz, 0.5H), 3.20-3.38 (m, 1H), 3.08-3.20 (m, 1H), 3.00-3.08 (m, 1H), 1.35 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 513.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.51 (d, J=1.0 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.01-7.09 (m, 3H), 6.51 (dd, J=3.3, 1.8 Hz, 1H), 4.90 (br. s., 1H), 4.52 (d, J=13.3 Hz, 1H), 4.42 (d, J=13.8 Hz, 1H), 4.30-4.37 (m, 1H), 3.56 (br. s., 1H), 3.41 (dd, J=13.2, 3.6 Hz, 1H), 3.24 (td, J=12.4, 3.3 Hz, 1H), 3.15 (dt, J=13.3, 6.7 Hz, 1H), 2.40 (s, 3H), 1.48 (d, J=6.5 Hz, 3H), 1.15 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z 429.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.61 (s, 1H), 7.46 (t, J=1.6 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.00-7.08 (m, 2H), 6.59 (d, J=1.0 Hz, 1H), 4.74 (br. s., 1H), 4.20-4.50 (m, 3H), 3.41-3.61 (m, 1H), 3.32 (dd, J=13.1, 3.0 Hz, 1H), 3.08-3.19 (m, 2H), 2.40 (s, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.08-1.19 (m, 6H). LC-MS: m/z 429.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.28-7.35 (m, 1H), 7.16-7.25 (m, 2H), 7.00-7.07 (m, 2H), 6.89-6.99 (m, 2H), 4.94 (br. s., 0.5H), 4.58 (d, J=13.3 Hz, 0.5H), 4.33-4.43 (m, 1H), 4.19-4.33 (m, 2H), 3.90-4.05 (m, 2H), 3.80 (d, J=13.3 Hz, 0.5H), 3.51-3.63 (m, 0.5H), 3.17-3.33 (m, 1H), 3.10-3.17 (m, 1H), 2.99-3.10 (m, 1H), 2.40 (s, 3H), 1.36 (d, J=6.3 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 459.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.01-7.08 (m, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=13.1 Hz, 0.5H), 4.30-4.44 (m, 2H), 4.19-4.30 (m, 1H), 3.81 (d, J=13.6 Hz, 0.5H), 3.71-3.78 (m, 2H), 3.52-3.65 (m, 0.5H), 3.38 (s, 3H), 3.24-3.36 (m, 1H), 3.10-3.23 (m, 2H), 2.65-2.80 (m, 1H), 2.54-2.64 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 421.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.67-7.84 (m, 3H), 7.57-7.64 (m, 1H), 7.45-7.53 (m, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.58 (s, 1H), 4.84 (d, J=13.6 Hz, 1H), 4.49-4.69 (m, 2H), 3.81-4.22 (m, 1H), 3.22-3.57 (br. s., 3H), 3.07 (dt, J=13.3, 6.7 Hz, 1H), 2.19-2.38 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 0.88-1.05 (m, 6H). LC-MS: m/z 511.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.64-7.75 (m, 2H), 7.55-7.62 (m, 1H), 7.37-7.46 (d, J=8.5 Hz, 2H), 7.22 (ddd, J=4.8, 3.2, 1.3 Hz, 1H), 6.87-7.02 (m, 2H), 4.68-4.82 (m, 1.5H), 4.35-4.54 (m, 1.5H), 3.81-4.11 (m, 3H), 3.63 (d, J=10.3 Hz, 0.5H), 3.37-3.53 (m, 0.5H), 3.08-3.20 (m, 1H), 2.96-3.08 (m, 2H), 2.18-2.32 (m, 0.5H), 2.04-2.17 (m, 0.5H), 1.17 (dd, J=6.7, 3.6 Hz, 3H), 1.13 (d, J=6.5 Hz, 3H), 1.08 (dd, J=11.0, 6.5 Hz, 3H), 0.87-0.93 (m, 1.5H), 0.85 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 541.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.66-7.76 (m, 2H), 7.59 (d, J=2.3 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 4.68-4.84 (m, 1.5H), 4.47-4.5 (s, 1.5H), 3.88 (d, J=13.6 Hz, 0.5H), 3.69-3.82 (m, 2H), 3.61 (d, J=10.3 Hz, 0.5H), 3.42-3.52 (m, 0.5H), 3.38 (d, J=2.8 Hz, 3H), 3.12-3.27 (m, 2H), 3.02-3.12 (m, 1H), 2.90-3.02 (m, 0.5H), 2.53-2.83 (m, 2H), 2.17-2.30 (m, 0.5H), 1.98-2.16 (m, 0.5H), 1.18 (d, J=6.5 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 1.08 (dd, J=6.5, 2.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 1.5H), 0.85 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 407.4 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.17-7.24 (m, 2H), 7.08-7.16 (m, 2H), 6.38 (d, J=1.8 Hz, 1H), 4.68 (br. s., 1H), 4.41 (d, J=13.1 Hz, 1H), 4.36 (d, J=13.1 Hz, 1H), 4.20-4.28 (d, J=13.6 Hz, 1H), 3.39-3.59 (m, 1H), 3.25-3.37 (m, 1H), 3.03-3.18 (m, 2H), 2.41 (s, 3H), 1.41 (d, J=6.5 Hz, 3H), 1.14 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z 447.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.29 (d, J=2.0 Hz, 2H), 7.17-7.24 (m, 1H), 7.08-7.16 (m, 2H), 6.38 (d, J=1.8 Hz, 1H), 4.68 (br. s., 1H), 4.41 (d, J=13.1 Hz, 1H), 4.36 (d, J=13.1 Hz, 1H), 4.20-4.28 (d, J=13.6 Hz, 1H), 3.39-3.59 (m, 4H), 3.25-3.37 (m, 4H), 3.03-3.18 (m, 8H), 2.41 (s, 11H), 1.41 (d, J=6.5 Hz, 11H), 1.14 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z 443.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.70 (d, J=8.0 Hz, 2H), 7.57-7.64 (m, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.27-7.32 (m, 1H), 6.35-6.42 (m, 1H), 4.68 (br. s., 1H), 4.34-4.53 (m, 2H), 4.20-4.34 (m, 1H), 3.48 (d, J=4.8 Hz, 1H), 3.28-3.40 (m, 1H), 3.16 (td, J=12.6, 3.4 Hz, 1H), 3.00-3.11 (m, 1H), 2.41 (s, 3H), 1.38-1.48 (m, 3H), 1.16 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z 497.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58-7.65 (m, 1H), 7.28 (d, J=8.3 Hz, 3H), 7.11-7.20 (m, 2H), 6.37 (d, J=2.0 Hz, 1H), 4.59-4.68 (br. s., 1H), 4.30-4.43 (m, 2H), 4.19 (br. s., 1H), 3.40-3.54 (m, 1H), 3.30 (dd, J=12.8, 3.0 Hz, 1H), 3.14-3.22 (m, 1H), 3.06-3.14 (m, 1H), 2.96 (spt, J=6.9 Hz, 1H), 2.41 (s, 3H), 1.39-1.45 (m, 3H), 1.30 (d, J=7.0 Hz, 6H), 1.15 (dd, J=6.8, 3.0 Hz, 6H). LC-MS: m/z 471.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.49-7.53 (m, 1H), 7.43-7.47 (m, 1H), 7.29 (d, J=1.8 Hz, 1H), 6.45 (d, J=0.8 Hz, 1H), 6.36 (d, J=1.8 Hz, 1H), 4.68 (br. s., 1H), 4.39 (d, J=13.1 Hz, 1H), 4.34 (d, J=13.1 Hz, 1H), 4.18-4.26 (br. s., 1H), 3.38-3.56 (m, 1H), 3.22-3.35 (m, 2H), 3.11 (td, J=12.6, 3.4 Hz, 1H), 2.36-2.47 (m, 3H), 1.39 (d, J=6.5 Hz, 3H), 1.18 (dd, J=6.7, 1.6 Hz, 6H). LC-MS: m/z 419.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.72-7.77 (m, 1H), 7.64 (s, 1H), 7.50 (t, J=1.8 Hz, 1H), 7.44-7.47 (m, 2H), 6.58 (dd, J=1.8, 0.8 Hz, 1H), 6.45 (dd, J=1.8, 0.8 Hz, 1H), 5.30 (s, 1H), 4.73 (br. s., 1H), 4.38 (s, 1H), 4.41 (s, 1H), 4.31 (t, J=2.1 Hz, 1H), 4.35 (t, J=2.0 Hz, 1H), 3.48 (br. s., 1H), 3.32 (dd, J=9.9, 3.1 Hz, 1H), 3.24-3.30 (m, 1H), 3.14 (td, J=12.5, 3.5 Hz, 1H), 1.42 (d, J=7.0 Hz, 3H), 1.19 (dd, J=6.8, 1.0 Hz, 6H). LC-MS: m/z 405.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.63 (s, 1H), 7.50 (t, J=1.8 Hz, 1H), 7.42-7.47 (m, 1H), 6.44 (dd, J=1.8, 0.8 Hz, 1H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.38 (dd, J=12.2, 2.1 Hz, 1H), 4.17-4.35 (m, 2H), 3.80 (d, J=13.1 Hz, 0.5H), 3.74 (t, J=6.5 Hz, 2H), 3.51-3.62 (m, 0.5H), 3.36-3.39 (m, 3H), 3.23-3.35 (m, 2H), 3.06-3.17 (m, 1H), 2.64-2.80 (m, 1H), 2.51-2.63 (m, 1H), 1.38 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.0 Hz, 1.5H), 1.19 (d, J=6.8 Hz, 6H).
LC-MS: m/z 397.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.72-7.77 (m, 1H), 7.61 (s, 1H), 7.46 (t, J=1.6 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.12-7.19 (m, 2H), 6.59 (dd, J=1.8, 0.8 Hz, 1H), 4.74 (br. s., 1H), 4.39 (d, J=13.3 Hz, 1H), 4.33 (dt, J=13.2, 1.9 Hz, 2H), 3.49 (br. s., 1H), 3.32 (dd, J=13.2, 3.4 Hz, 1H), 3.08-3.23 (m, 2H), 2.96 (dt, J=13.8, 6.9 Hz, 1H), 1.45 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.0 Hz, 6H), 1.15 (dd, J=6.5, 2.3 Hz, 6H). LC-MS: m/z 457.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.17-7.24 (m, 2H), 7.08-7.16 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.0 Hz, 0.5H), 4.40 (dd, J=12.2, 1.9 Hz, 1H), 4.19-4.35 (m, 2H), 3.82 (d, J=12.5 Hz, 0.5H), 3.69-3.78 (m, 2H), 3.53-3.63 (m, 0.5H), 3.38 (s, 3H), 3.26-3.35 (m, 1H), 3.13-3.22 (m, 1H), 3.03-3.12 (m, 1H), 2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 425.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59-7.65 (m, 1H), 7.29-7.33 (m, 2H), 7.14-7.22 (m, 2H), 4.95 (br. s., 0.5H), 4.58 (d, J=13.1 Hz, 0.5H), 4.37-4.44 (m, 1H), 4.22-4.37 (m, 2H), 3.83 (d, J=13.3 Hz, 0.5H), 3.70-3.80 (m, 2H), 3.55-3.67 (m, 0.5H), 3.40 (s, 3H), 3.33 (t, J=12.3 Hz, 1H), 3.15-3.25 (m, 2H), 2.98 (quin, J=6.9 Hz, 1H), 2.67-2.83 (m, 1H), 2.55-2.67 (m, 1H), 1.43 (d, J=5.8 Hz, 1.5H), 1.34 (m, 1.5H), 1.32 (d, J=7.0 Hz, 6H), 1.17 (d, J=6.8 Hz, 6H). LC-MS: m/z 449.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 8.12 (s, 1H), 7.61 (dd, J=7.7, 0.9 Hz, 1H), 7.48-7.56 (m, 1H), 7.32 (td, J=7.7, 1.5 Hz, 1H), 7.24-7.29 (m, 1H), 6.78-6.88 (m, 1H), 4.93 (br. s., 0.5H), 4.38-4.64 (m, 2H), 4.27 (br. s., 0.5H), 3.83 (d, J=12.8 Hz, 1H), 3.75 (br. s., 2H), 3.55 (quin, J=6.7 Hz, 2H), 3.38 (s, 3H), 3.08-3.29 (m, 2H), 2.66-2.83 (m, 1H), 2.60 (br. s., 1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.33 (br. s., 1.5H), 1.28 (d, J=6.5 Hz, 6H). LC-MS: m/z 447.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 9.23-9.28 (m, 1H), 8.69 (s, 2H), 7.62 (s, 1H), 4.94 (br. s., 0.5H), 4.56 (d, J=9.5 Hz, 0.5H), 4.37-4.53 (m, 2H), 4.29 (br. s., 0.5H), 3.84 (d, J=13.3 Hz, 0.5H), 3.68-3.79 (m, 2H), 3.52-3.64 (m, 0.5H), 3.40-3.46 (m, 0.5H), 3.38 (s, 3H), 3.20-3.32 (m, 1H), 3.16 (d, J=9.5 Hz, 1H), 2.93-3.04 (m, 1H), 2.65-2.78 (m, 1H), 2.52-2.64 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 1.19 (dd, J=6.7, 1.1 Hz, 6H). LC-MS: m/z 409.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.83-7.97 (m, 3H), 7.66-7.77 (m, 2H), 7.49-7.60 (m, 2H), 7.36 (dd, J=8.4, 1.6 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d, J=12.8 Hz, 0.5H), 4.42 (d, J=12.8 Hz, 1H), 4.30-4.38 (m, 1H), 4.27 (br. s., 1H), 3.83 (d, J=13.3 Hz, 0.5H), 3.69-3.79 (m, 2H), 3.54-3.65 (m, 0.5H), 3.39 (s, 3H), 3.29-3.38 (m, 1H), 3.18-3.24 (m, 1H), 3.06-3.17 (m, 1H), 2.66-2.83 (m, 1H), 2.52-2.65 (m, 1H), 1.42 (d, J=7.3 Hz, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.17 (d, J=6.8 Hz, 6H). LC-MS: m/z 457.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.34 (t, J=7.9 Hz, 1H), 6.92 (dd, J=8.3, 1.8 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.74-6.79 (m, 1H), 4.93 (br. s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.39 (d, J=13.6 Hz, 1H), 4.21-4.34 (m, 2H), 3.84 (s, 3H), 3.79 (d, J=8.0 Hz, 0.5H), 3.70-3.77 (m, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.26-3.36 (m, 1H), 3.12-3.22 (m, 2H), 2.65-2.80 (m, 1H), 2.52-2.64 (m, 1H), 1.41 (d, J=1.5 Hz, 4H), 1.31 (d, J=6.5 Hz, 1.5H), 1.10-1.19 (m, 6H). LC-MS: m/z 437.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.3 Hz, 2H), 7.61 (s, 1H), 7.22 (d, J=5.5 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=9.8 Hz, 0.5H), 4.34-4.51 (m, 2H), 4.28 (br. s., 1H), 3.83 (d, J=13.3 Hz, 0.5H), 3.68-3.79 (m, 2H), 3.58 (t, J=11.0 Hz, 0.5H), 3.38 (s, 3H), 3.14-3.28 (m, 2H), 3.03-3.14 (m, 1H), 2.65-2.83 (m, 1H), 2.52-2.65 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H), 1.29 (d, J=6.5 Hz, 1.5H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z 408.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.11-7.20 (m, 2H), 6.92-7.01 (m, 2H), 4.92 (br. s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.37 (d, J=12.5 Hz, 1H), 4.29 (d, J=13.1 Hz, 2H), 3.86 (s, 3H), 3.81 (d, J=13.6 Hz, 0.5H), 3.75 (br. s., 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=13.2 Hz, 1H), 3.11-3.20 (m, 2H), 2.66-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.41 (d, J=6.0 Hz, 1.5H), 1.31 (d, J=5.8 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 437.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.38-7.43 (m, 2H), 7.14-7.20 (m, 2H), 4.93 (br. s., 0.5H), 4.55 (d, J=12.5 Hz, 0.5H), 4.40 (d, J=12.8 Hz, 1H), 4.21-4.36 (m, 2H), 3.82 (d, J=13.6 Hz, 0.5H), 3.69-3.78 (m, 2H), 3.53-3.63 (m, 0.5H), 3.38 (s, 3H), 3.27-3.37 (m, 1H), 3.11-3.23 (m, 1H), 3.02-3.11 (m, 1H), 2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.5 Hz, 6H). LC-MS: m/z 441.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 7.15 (d, J=8.0 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=12.5 Hz, 0.5H), 4.38 (d, J=12.3 Hz, 1H), 4.30 (d, J=12.3 Hz, 2H), 3.81 (d, J=13.3 Hz, 0.5H), 3.75 (br. s., 2H), 3.51-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=13.6 Hz, 1H), 3.12-3.22 (m, 2H), 3.10 (d, J=14.3 Hz, 0.5H), 2.77 (br. s., 0.5H), 2.71 (q, J=7.5 Hz, 2H), 2.61 (br. s., 1H), 1.41 (d, J=6.0 Hz, 1.5H), 1.32 (br. s., 1.5H), 1.29 (t, J=7.5 Hz, 3H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 435.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.92 (t, J=7.4 Hz, 2H), 7.63 (s, 1H), 7.49-7.57 (m, 2H), 7.39-7.47 (m, 2H), 7.27-7.34 (m, 1H), 4.96 (br. s., 0.5H), 4.59 (d, J=12.5 Hz, 0.5H), 4.45 (d, J=13.3 Hz, 1H), 4.32-4.41 (m, 1H), 4.30 (br. s., 1H), 3.85 (d, J=13.6 Hz, 0.5H), 3.70-3.81 (m, 2H), 3.55-3.67 (m, 0.5H), 3.39 (s, 3H), 3.07-3.27 (m, 2H), 2.67-2.76 (m, 2H), 2.53-2.66 (m, 1H), 1.45 (d, J=5.5 Hz, 1.5H), 1.36 (d, J=6.5 Hz, 1.5H), 1.06 (d, J=6.5 Hz, 6H). LC-MS: m/z 457.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.56-7.61 (m, 1H), 7.35-7.39 (m, 2H), 7.21-7.25 (m, 1H), 7.11-7.14 (m, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.42 (d, J=12.5 Hz, 1H), 4.29-4.37 (m, 1H), 4.26 (br. s., 1H), 3.82 (d, J=13.6 Hz, 0.5H), 3.68-3.78 (m, 2H), 3.53-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.37 (m, 1H), 3.12-3.24 (m, 1H), 3.04-3.12 (m, 1H), 2.65-2.80 (m, 1H), 2.50-2.64 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 441.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.97 (dd, J=7.7, 1.6 Hz, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=13.1 Hz, 0.5H), 4.32-4.42 (m, 1H), 4.29 (d, J=12.8 Hz, 1H), 3.78-3.85 (m, 0.5H), 3.71-3.77 (m, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.24-3.35 (m, 1H), 3.17 (dt, J=13.3, 6.7 Hz, 2H), 3.01-3.12 (m, 1H), 2.65-2.80 (m, 1H), 2.53-2.63 (m, 1H), 2.31 (d, J=3.0 Hz, 6H), 1.40 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.5 Hz, 6H). LC-MS: m/z 435.4 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.90-6.95 (m, 1H), 6.89 (dd, J=5.8, 1.3 Hz, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.21-4.45 (m, 3H), 3.81 (d, J=13.3 Hz, 0.5H), 3.70-3.77 (m, 2H), 3.52-3.63 (m, 0.5H), 3.38 (s, 3H), 3.26-3.37 (m, 1H), 3.10-3.18 (m, 2H), 2.65-2.80 (m, 1H), 2.53-2.63 (m, 1H), 2.33 (d, J=1.5 Hz, 3H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 439.4 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.56-7.61 (m, 1H), 7.35-7.39 (m, 3H), 7.21-7.25 (m, 2H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.42 (d, J=12.5 Hz, 1H), 4.29-4.37 (m, 1H), 4.26 (br. s., 1H), 3.82 (d, J=13.6 Hz, 0.5H), 3.68-3.78 (m, 2H), 3.53-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.37 (m, 1H), 3.12-3.24 (m, 1H), 3.04-3.12 (m, 1H), 2.65-2.80 (m, 1H), 2.50-2.64 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 407.4 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.78 (dd, J=8.2, 1.9 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 4.88-4.96 (m, 0.5H), 4.55 (d, J=13.1 Hz, 0.5H), 4.18-4.46 (m, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.78-3.86 (m, 0.5H), 3.71-3.78 (m, 2H), 3.52-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=10.8 Hz, 1H), 3.10-3.22 (m, 2H), 2.65-2.80 (m, 1H), 2.52-2.64 (m, 1H), 1.33 (s, 1.5H), 1.28 (s, 1.5H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z 467.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.57 (s, 1H), 6.83-6.90 (m, 1H), 6.64-6.73 (m, 2H), 6.02 (s, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.5 Hz, 0.5H), 4.20-4.43 (m, 3H), 3.81 (d, J=12.8 Hz, 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.25-3.36 (m, 1H), 3.10-3.22 (m, 2H), 2.64-2.80 (m, 1H), 2.52-2.64 (m, 1H), 1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 451.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58-7.63 (m, 1H), 7.42-7.51 (m, 1H), 7.22-7.26 (m, 1H), 7.18 (dd, J=7.8, 1.3 Hz, 1H), 7.11 (s, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.27-4.46 (m, 3H), 3.78-3.88 (m, 0.5H), 3.75 (t, J=6.4 Hz, 2H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.29-3.36 (m, 1H), 3.13-3.24 (m, 1H), 3.07 (dt, J=13.3, 6.7 Hz, 1H), 2.65-2.81 (m, 1H), 2.52-2.64 (m, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.3 Hz, 1.5H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 491.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.39 (td, J=8.0, 6.1 Hz, 1H), 7.05-7.13 (m, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.95 (dt, J=9.4, 2.1 Hz, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.26-4.45 (m, 3H), 3.82 (d, J=13.1 Hz, 0.5H), 3.75 (t, J=6.1 Hz, 2H), 3.51-3.64 (m, 0.5H), 3.38 (s, 3H), 3.27-3.35 (m, 1H), 3.16-3.23 (m, 1H), 3.09-3.14 (m, 1H), 2.65-2.81 (m, 1H), 2.60 (t, J=5.9 Hz, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 443.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.27 (s, 4H), 4.93 (br. s., 0.5H), 4.49-4.61 (m, 0.5H), 4.26-4.47 (m, 3H), 3.82 (d, J=13.6 Hz, 0.5H), 3.72-3.77 (m, 2H), 3.51-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H), 3.08 (dt, J=13.3, 6.7 Hz, 1H), 2.65-2.80 (m, 1H), 2.60 (t, J=5.9 Hz, 1H), 1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 491.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.27 (s, 4H), 4.93 (br. s., 0.5H), 4.49-4.61 (m, 0.5H), 4.26-4.47 (m, 3H), 3.82 (d, J=13.6 Hz, 0.5H), 3.72-3.77 (m, 2H), 3.51-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H), 3.08 (dt, J=13.3, 6.7 Hz, 1H), 2.65-2.80 (m, 1H), 2.60 (t, J=5.9 Hz, 1H), 1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 465.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 9.33 (s, 1H), 8.37 (s, 1H), 8.06-8.16 (m, 1H), 7.64-7.69 (m, 2H), 7.45-7.50 (m, 2H), 4.96 (br. s., 0.5H), 4.58 (br. s., 0.5H), 4.31-4.54 (m, 3H), 3.86 (d, J=12.5 Hz, 0.5H), 3.76 (t, J=6.4 Hz, 2H), 3.56-3.67 (m, 0.5H), 3.42 (d, J=3.8 Hz, 1H), 3.36-3.40 (m, 3H), 3.08-3.33 (m, 1H), 2.65-2.78 (m, 2H), 2.54-2.64 (m, 1H), 1.44 (d, J=4.5 Hz, 1.5H), 1.35 (d, J=6.0 Hz, 1.5H), 1.05-1.11 (m, 6H). LC-MS: m/z 458.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.57 (s, 1H), 7.31-7.39 (m, 2H), 7.27 (s, 1H), 7.10-7.18 (m, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.07-4.33 (m, 3H), 3.77-3.84 (m, 0.5H), 3.71-3.76 (m, 2H), 3.48-3.60 (m, 0.5H), 3.36-3.41 (m, 3H), 3.25 (t, J=10.4 Hz, 1H), 3.06-3.18 (m, 1H), 2.63-2.79 (m, 1H), 2.51-2.62 (m, 1H), 1.95-2.07 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.12-1.18 (m, 2H), 0.91-0.97 (m, 2H). LC-MS: m/z 423.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.30-7.36 (m, 1H), 7.14-7.22 (m, 3H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 3.80-4.36 (m, 3H), 3.80 (br. s., 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.19-3.29 (m, 1H), 3.07-3.17 (m, 1H), 2.63-2.80 (m, 1H), 2.53-2.62 (m, 1H), 2.41 (s, 3H), 2.03-2.13 (m, 1H), 1.39 (d, J=5.8 Hz, 1.5H), 1.29 (d, J=6.5 Hz, 1.5H), 1.11-1.17 (m, 2H), 0.89-0.97 (m, 2H). LC-MS: m/z 419.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.71 (d, J=8.0 Hz, 2H), 7.60 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 4.82-4.95 (m, 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 4.17-4.39 (m, 3H), 3.80 (d, J=13.6 Hz, 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.49-3.62 (m, 0.5H), 3.37 (s, 3H), 3.24-3.33 (m, 1H), 3.03-3.15 (m, 1H), 2.63-2.80 (m, 1H), 2.51-2.62 (m, 1H), 1.93-2.02 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=3.5 Hz, 1.5H), 1.14-1.20 (m, 2H), 0.93-0.99 (m, 2H). LC-MS: m/z 473.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.41-7.44 (m, 1H), 7.38-7.41 (m, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=11.5 Hz, 0.5H), 4.12-4.34 (m, 3H), 3.81 (br. s., 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.55 (t, J=11.4 Hz, 0.5H), 3.37 (s, 3H), 3.26 (br. s., 1H), 3.11 (br. s., 1H), 2.63-2.78 (m, 1H), 2.58 (d, J=5.8 Hz, 1H), 1.95-2.05 (m, 1H), 1.38 (d, J=5.8 Hz, 1.5H), 1.28 (d, J=5.8 Hz, 1.5H), 1.13-1.18 (m, 2H), 0.93-0.99 (m, 2H). LC-MS: m/z 489.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.27 (br. s., 1H), 7.21-7.26 (m, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 4.17-4.36 (m, 3H), 3.77-3.86 (m, 0.5H), 3.74 (t, J=6.1 Hz, 2H), 3.51-3.62 (m, 0.5H), 3.37 (s, 3H), 3.28 (t, J=8.9 Hz, 1H), 3.12 (d, J=10.8 Hz, 1H), 2.64-2.80 (m, 1H), 2.52-2.63 (m, 1H), 1.96-2.04 (m, 1H), 1.35-1.42 (m, 1.5H), 1.28 (d, J=5.5 Hz, 1.5H), 1.14-1.20 (m, 2H), 0.93-1.01 (m, 2H). LC-MS: m/z 489.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.41 (td, J=7.8, 6.1 Hz, 1H), 7.14-7.19 (m, 1H), 7.04-7.13 (m, 2H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.12-4.34 (m, 3H), 3.77-3.85 (m, 0.5H), 3.74 (t, J=6.1 Hz, 2H), 3.48-3.61 (m, 0.5H), 3.37 (s, 3H), 3.26 (t, J=9.4 Hz, 1H), 3.06-3.16 (m, 1H), 2.64-2.79 (m, 1H), 2.51-2.62 (m, 1H), 1.99-2.08 (m, 1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.12-1.19 (m, 2H), 0.93-0.99 (m, 2H). LC-MS: m/z 423.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.57 (s, 1H), 7.21-7.26 (m, 1H), 7.06 (s, 1H), 7.01-7.05 (m, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=12.8 Hz, 0.5H), 4.11-4.33 (m, 3H), 3.80 (br. s., 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.49-3.60 (m, 0.5H), 3.36-3.41 (m, 3H), 3.25 (t, J=9.8 Hz, 1H), 3.03-3.15 (m, 1H), 2.63-2.79 (m, 1H), 2.51-2.61 (m, 1H), 2.32 (d, J=1.5 Hz, 3H), 2.01-2.09 (m, 1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.26-1.30 (m, 1.5H), 1.12-1.17 (m, 2H), 0.92-0.97 (m, 2H).
LC-MS: m/z 437.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.32-7.38 (m, 1H), 6.94-6.99 (m, 1H), 6.87-6.94 (m, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1 Hz, 0.5H), 4.18-4.26 (m, J=12.7 Hz, 3H), 3.84 (s, 3H), 3.81 (d, J=5.5 Hz, 0.5H), 3.74 (t, J=6.1 Hz, 2H), 3.55 (t, J=11.0 Hz, 0.5H), 3.37 (s, 3H), 3.25 (t, J=10.2 Hz, 1H), 3.03-3.15 (m, 1H), 2.63-2.79 (m, 1H), 2.51-2.62 (m, 1H), 2.05-2.15 (m, 1H), 1.39 (d, J=6.0 Hz, 1.5H), 1.29 (d, J=6.3 Hz, 1.5H), 1.11-1.18 (m, 2H), 0.91-0.96 (m, 2H). LC-MS: m/z 435.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 6.92-6.95 (m, 2H), 6.88 (s, 1H), 4.89 (br. s., 0.5H), 4.53 (d, J=14.1 Hz, 0.5H), 4.16-4.30 (m, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.78-3.84 (m, 0.5H), 3.71-3.77 (m, 2H), 3.55 (br. s., 0.5H), 3.37 (s, 1H), 3.24 (br. s., 1H), 3.03-3.09 (m., 1H), 2.66-2.79 (m, 1H), 2.59 (br. s., 1H), 2.08-2.15 (m, 1.5H), 1.38 (br. s., 1.5H), 1.13-1.17 (m, 2H), 0.93 (dd, J=8.0, 3.3 Hz, 2H). LC-MS: m/z 465.1 (M+H)+.
1H NMR (DMSO-d6) δ 7.47 (dd, J=5.0, 3.0 Hz, 1H), 7.17 (dd, J=2.8, 1.3 Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H), 4.91 (br. s., 0.5H), 4.55 (d, J=10.8 Hz, 0.5H), 3.98-4.27 (m, 3H), 3.75 (q, J=6.0 Hz, 2.5H), 3.53-3.63 (m, 0.5H), 3.40 (s, 3H), 3.11-3.25 (m, 1H), 2.94-3.06 (m, 1H), 2.69-2.81 (m, 1H), 2.67 (d, J=7.3 Hz, 1H), 2.25 (s, 3H), 1.71-1.78 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.06-1.08 (m, 2H), 0.83-0.88 (m, 2H). LC-MS: m/z 456.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.41 (dd, J=4.8, 3.0 Hz, 1H), 7.29 (dd, J=3.0, 1.3 Hz, 1H), 7.18 (dd, J=5.0, 1.3 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.14-4.32 (m, 2.5H), 3.67-3.84 (m, 2.5H), 3.55 (br. s., 0.5H), 3.18-3.34 (m, 1H), 2.96-3.18 (m, 1.5H), 2.50-2.71 (m, 2H), 2.12-2.23 (m, 1H), 1.34-1.41 (m, 1.5H), 1.24-1.30 (m, 1.5H), 1.12-1.18 (m, 2H), 0.92-1.02 (m, 2H). LC-MS: m/z 411.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.82-7.87 (m, 1H), 7.78-7.82 (m, 1H), 7.77 (s, 1H), 7.33-7.42 (m, 2H), 7.32 (s, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=12.8 Hz, 0.5H), 4.24-4.39 (m, 3H), 3.70-3.80 (m, 2.5H), 3.35-3.41 (m, 3H), 3.29 (t, J=9.8 Hz, 1H), 3.03-3.20 (m, 1.5H), 2.63-2.78 (m, 1H), 2.52-2.63 (m, 1H), 2.34-2.44 (m, 1H), 1.37 (d, J=6.0 Hz, 1.5H), 1.23-1.29 (m, 1.5H), 1.15-1.21 (m, 2H), 0.95-1.06 (m, 2H). LC-MS: m/z 461.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.45 (dd, J=6.9, 1.9 Hz, 1H), 7.22-7.28 (m, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=12.8 Hz, 0.5H), 4.16-4.37 (m, 3H), 3.70-3.81 (m, 2.5H), 3.50-3.64 (m, 0.5H), 3.37-3.42 (m, 3H), 3.28 (t, J=10.2 Hz, 1H), 3.12 (d, J=11.0 Hz, 1H), 2.65-2.87 (m, 1H), 2.55-2.65 (m, 1H), 1.94-2.05 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=4.0 Hz, 1.5H), 1.14-1.21 (m, 2H), 0.94-1.03 (m, 2H). LC-MS: m/z 457.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ7.62 (s, 1H), 7.37-7.45 (m, 1H), 7.30-7.36 (m, 1H), 7.22-7.27 (m, 1H), 7.19 (t, J=9.0 Hz, 1H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.19-4.37 (m, 3H), 3.78-3.86 (m, 0.5H), 3.70-3.78 (m, 2H), 3.51-3.61 (m, 0.5H), 3.39 (s, 3H), 3.27 (t, J=12.5 Hz, 1H), 3.02-3.16 (m, 1H), 2.65-2.82 (m, 1H), 2.54-2.64 (m, 1H), 1.83-1.90 (m, 1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.12-1.19 (m, 2H), 0.92-0.98 (m, 2H). LC-MS: m/z 423.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.26-7.35 (m, 1H), 6.91-7.04 (m, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.18-4.37 (m, 3H), 3.78-3.85 (m, 0.5H), 3.71-3.78 (m, 2H), 3.51-3.62 (m, 0.5H), 3.39 (s, 3H), 3.23-3.33 (m, 1H), 3.14 (d, J=10.5 Hz, 1H), 2.65-2.80 (m, 1H), 2.53-2.63 (m, 1H), 1.77-1.85 (m, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.11-1.19 (m, 2H), 0.96 (dd, J=7.8, 3.0 Hz, 2H). LC-MS: m/z 441.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 8.18 (d, J=2.3 Hz, 1H), 7.60 (dd, J=8.5, 2.5 Hz, 1H), 7.56 (s, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.15-4.36 (m, 3H), 3.96-4.02 (m, 3H), 3.76-3.86 (m, 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.53-3.61 (m, 0.5H), 3.37 (s, 3H), 3.21-3.31 (m, 1H), 3.12 (d, J=11.3 Hz, 1H), 2.63-2.80 (m, 1H), 2.51-2.62 (m, 1H), 1.93-2.04 (m, 1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.28 (d, J=6.3 Hz, 1.5H), 1.12-1.19 (m, 2H), 0.92-1.00 (m, 2H). LC-MS: m/z 436.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 8.28 (br. s., 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.29 (t, J=2.8 Hz, 1H), 7.20 (dd, J=8.3, 1.8 Hz, 1H), 6.60 (t, J=2.1 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.12-4.33 (m, 3H), 3.81 (br. s., 0.5H), 3.75 (t, J=6.4 Hz, 2H), 3.51-3.63 (m, 0.5H), 3.38 (s, 3H), 3.22 (d, J=14.1 Hz, 1H), 3.01-3.17 (m, 1H), 2.66-2.81 (m, 1H), 2.62 (t, J=5.8 Hz, 1H), 2.11-2.21 (m, 1H), 1.41 (d, J=5.5 Hz, 1.5H), 1.31 (d, J=6.3 Hz, 1.5H), 1.11-1.17 (m, 2H), 0.87-0.94 (m, 2H). LC-MS: m/z 444.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.17 (s, 2H), 7.16 (d, J=1.8 Hz, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.03-4.22 (m, 3H), 3.79 (br. s., 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.52-3.63 (m, 0.5H), 3.38 (s, 3H), 3.16-3.25 (m, 1H), 2.92-3.08 (m, 1H), 2.64-2.79 (m, 1H), 2.51-2.63 (m, 1H), 2.18 (s, 3H), 1.56-1.63 (m, 1H), 1.41 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.03-1.09 (m, 2H), 0.79-0.84 (m, 2H). LC-MS: m/z 437.2 (M+H)+.
1H NMR (DMSO-d6) δ 7.36 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 6.97-7.04 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.3 Hz, 0.5H), 4.24 (br. s., 0.5H), 4.03-4.19 (m, 2H), 3.76 (s, 0.5H), 3.75 (s, 2H), 3.55-3.64 (m, 0.5H), 3.40 (s, 3H), 3.11-3.26 (m, 1H), 2.93-3.08 (m, 1H), 2.68-2.80 (m, 1H), 2.61 (d, J=11.0 Hz, 1H), 2.42 (s, 3H), 2.20 (s, 3H), 1.62-1.71 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.34 (d, J=6.0 Hz, 1.5H), 1.01-1.11 (m, 2H), 0.80-0.85 (m, 2H).
LC-MS: m/z 433.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.37 (t, J=7.8 Hz, 1H), 6.93 (dd, J=8.3, 2.5 Hz, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.74 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 3.96-4.21 (m, 3H), 3.83 (s, 3H), 3.71-3.77 (m, 2H), 3.52-3.63 (m, 1H), 3.37 (s, 3H), 3.09-3.25 (m, 1H), 2.89-3.04 (m, 1H), 2.63-2.79 (m, 1H), 2.59 (br. s., 1H), 2.16-2.29 (m, 3H), 1.63-1.72 (m, 1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.29-1.33 (m, 1.5H), 1.06 (d, J=7.3 Hz, 2H), 0.78-0.84 (m, 2H).
LC-MS: m/z 449.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.31-7.36 (m, J=8.0 Hz, 2H), 7.23-7.28 (m, J=8.3 Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.8 Hz, 0.5H), 4.01-4.22 (m, 2.5H), 3.69-3.85 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.36-3.43 (m, 3H), 3.12-3.28 (m, 1.5H), 2.94-3.12 (m, 1H), 2.66-2.83 (m, 1H), 2.61 (br. s., 1H), 2.16-2.22 (m, 3H), 1.54-1.65 (m, 1H), 1.39-1.46 (m, 1.5H), 1.32 (d, J=6.3 Hz, 1.5H), 1.03-1.12 (m, 2H), 0.80-0.89 (m, 2H). LC-MS: m/z 503.3 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.16-7.25 (m, 1H), 6.93-7.07 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.03-4.30 (m, 2.5H), 3.71-3.86 (m, 2.5H), 3.51-3.67 (m, 0.5H), 3.40 (s, 3H), 3.12-3.30 (m, 1.5H), 2.95-3.11 (m, 1H), 2.73 (td, J=15.3, 7.3 Hz, 1H), 2.54-2.64 (m, 1H), 2.18-2.25 (m, 3H), 1.53-1.61 (m, 1H), 1.39-1.47 (m, 1.5H), 1.32 (t, J=5.8 Hz, 1.5H), 1.03-1.17 (m, 2H), 0.82-0.93 (m, 2H). LC-MS: m/z 455.4 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.41-7.51 (m, 1H), 7.12 (td, J=8.5, 2.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.04-4.22 (m, 2.5H), 3.72-3.84 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.40 (s, 3H), 3.12-3.29 (m, 1.5H), 2.93-3.11 (m, 1H), 2.66-2.83 (m, 1H), 2.61 (d, J=6.3 Hz, 1H), 2.16-2.25 (m, 3H), 1.57-1.64 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.33 (d, J=6.8 Hz, 1.5H), 1.08 (t, J=4.6 Hz, 2H), 0.80-0.91 (m, 2H). LC-MS: m/z 437.4 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.23-7.33 (m, 2H), 6.89 (s, 1H), 6.87 (d, J=3.5 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.23 (br. s., 1H), 4.01-4.21 (m, 1.5H), 3.70-3.84 (m, 2.5H), 3.50-3.66 (m, 0.5H), 3.39 (s, 3H), 3.10-3.28 (m, 1.5H), 2.92-3.09 (m, 1H), 2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 2.32-2.39 (m, 3H), 2.20 (s, 3H), 1.60-1.70 (m, 1H), 1.39-1.47 (m, 1.5H), 1.30-1.35 (m, 1.5H), 1.07 (t, J=4.6 Hz, 2H), 0.83 (dt, J=7.5, 3.5 Hz, 2H). LC-MS: m/z 451.4 (M+H)+.
1H NMR (DMSO-d6) δ 7.96 (d, J=8.5 Hz, 1H), 7.91-7.95 (m, 1H), 7.88 (dd, J=6.1, 3.4 Hz, 1H), 7.71 (s, 1H), 7.53-7.59 (m, 2H), 7.34 (dd, J=8.4, 1.4 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d, J=13.3 Hz, 0.5H), 4.05-4.32 (m, 3H), 3.83 (br. s., 0.5H), 3.77 (t, J=6.3 Hz, 2H), 3.56-3.67 (m, 0.5H), 3.41 (s, 3H), 3.17-3.29 (m, 1H), 2.96-3.12 (m, 1H), 2.67-2.83 (m, 1H), 2.55-2.65 (m, 1H), 2.23 (s, 3H), 1.63-1.71 (m, 1H), 1.45 (d, J=5.8 Hz, 1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.05-1.14 (m, 2H), 0.77-0.83 (m, 2H). LC-MS: m/z 469.4 (M+H)+.
1H NMR (DMSO-d6) δ 8.87 (br. s., 2H), 7.86 (br. s., 2H), 4.94 (br. s., 0.5H), 4.71 (s, 0.5H), 4.31-4.35 (s, 3H), 3.82 (br. s., 0.5H), 3.71-3.79 (m, 2H), 3.58 (br. s., 0.5H), 3.40 (s, 3H), 3.21 (br. s., 1H), 3.14 (br. s., 1H), 2.68 (br. s., 1H), 2.61 (br. s., 1H), 2.04 (br. s., 1H), 1.45 (d, J=5.8 Hz, 1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.05-1.14 (m, 2H), 0.77-0.83 (m, 2H). LC-MS: m/z 420.5 (M+H)+.
1H NMR (DMSO-d6) δ 6.91 (d, J=8.0 Hz, 1H), 6.62-6.71 (m, 2H), 6.03-6.10 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.6 Hz, 0.5H), 4.03-4.24 (m, 3H), 3.80 (br. s., 0.5H), 3.76 (t, J=6.1 Hz, 2H), 3.59 (t, J=11.7 Hz, 0.5H), 3.39 (s, 3H), 3.18-3.25 (m, 1H), 2.92-3.08 (m, 1H), 2.65-2.80 (m, 1H), 2.54-2.65 (m, 1H), 2.22 (s, 3H), 1.68-1.77 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H), 1.06 (t, J=5.3 Hz, 2H), 0.84 (t, J=6.1 Hz, 2H)
LC-MS: m/z 463.3 (M+H)+.
1H NMR (DMSO-d6) δ 7.47 (dd, J=5.0, 3.0 Hz, 1H), 7.17 (dd, J=2.8, 1.3 Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H), 4.91 (br. s., 0.5H), 4.55 (d, J=10.8 Hz, 0.5H), 3.98-4.27 (m, 3H), 3.75 (q, J=6.0 Hz, 2.5H), 3.53-3.63 (m, 0.5H), 3.40 (s, 3H), 3.11-3.25 (m, 1H), 2.94-3.06 (m, 1H), 2.69-2.81 (m, 1H), 2.67 (d, J=7.3 Hz, 1H), 2.25 (s, 3H), 1.71-1.78 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.06-1.08 (m, 2H), 0.83-0.88 (m, 2H). LC-MS: m/z 425.3 (M+H)+.
A mixture of the bromide 7 from Example 1 (20 mg, 0.049 mmol) and PdCl2(dppf).CH2Cl2 (4 mg, 0.005 mmol) in 1 mL of dry THF was stirred at room temperature for 5 min under nitrogen atmosphere. Benzyl zinc bromide (2 mL of 0.5M solution in THF, 0.098 mmol) was then added via a transfer needle, and the resulting reaction mixture was then refluxed for 4 h before the volatile was evaporated under reduced pressure. The black solid was applied to the top of a flash silica gel column, which was eluted with CH2Cl2 and then 8:1 CH2Cl2-EtOAc to obtain 5.1 mg of Compound 239 as a reddish solid. MS (ES) M+H expected 421.3. found 421.2. 1H NMR (CHLOROFORM-d) δ 7.43 (s, 1H), 7.28-7.36 (m, 2H), 7.19-7.25 (m, 1H), 7.08 (d, J=7.0 Hz, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.16-4.36 (m, 3H), 3.91 (s, 2H), 3.79 (br. s., 0.5H), 3.73 (t, J=6.5 Hz, 2H), 3.51-3.61 (m, 0.5H), 3.37 (s, 3H), 3.22-3.30 (m, 1H), 3.12-3.21 (m, 1H), 2.63-2.78 (m, 1H), 2.51-2.61 (m, 1H), 1.38 (d, J=5.8 Hz, 1.5H), 1.28-1.32 (m, 1.5H), 1.12 (d, J=6.5 Hz, 6H). Other Compounds of Formula II listed below, wherein R1b is alkyl, —CH2-aryl or —CH2-heteroaryl; and R2 is isopropyl or cyclopropyl were similarly prepared using any of intermediates 7 (Scheme 1), 17 (Scheme 2), or 28 (Scheme 3) as starting material.
1H NMR (CHLOROFORM-d) δ 7.29-7.35 (m, 2H), 7.24 (d, J=7.5 Hz, 1H), 7.09 (d, J=7.3 Hz, 2H), 4.91 (br. s., 0.5H), 4.54 (d, J=14.1 Hz, 0.5H), 4.22 (br. s., 0.5H), 4.16 (s, 2H), 4.09 (d, J=15.6 Hz, 1.5H), 3.97-4.05 (m, 1H), 3.69-3.82 (m, 2H), 3.53-3.63 (m, 1H), 3.36-3.42 (m, 3H), 3.15 (t, J=13.9 Hz, 1H), 2.90-3.05 (m, 1H), 2.66-2.81 (m, 1H), 2.54-2.63 (m, 1H), 2.40 (s, 3H), 2.04 (dd, J=8.0, 4.8 Hz, 1H), 1.42 (d, J=6.8 Hz, 1.5H), 1.35 (br. s., 1.5H), 1.07-1.15 (m, 2H), 0.90-0.92 (m, 2H). LC-MS: m/z 433.3 (M+H)+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(methyl(2-(methyl amino)ethyl)amino)nicotinonitrile (Compound 238) was prepared by mixing bromide 7 (30 mg, 0.074 mmol), CuI (0.7 mg, 0.004 mmol), K2CO3 (20 mg, 0.147 mmol), and N1,N2-dimethylethane-1,2-diamine (3.25 mg, 0.035 mmol) in a 5 mL microwave tube capped with a rubber septum. The tube was placed under vacuum and refilled with nitrogen three times. Piperidine (19 mg, 0.22 mmol) and DMSO (1 mL) were added to the tube and the rubber septum was quickly replaced with microwave tube cap. The reaction was heated in an oil bath at 120° C. overnight before it was cooled, diluted with EtOAc, and filtered through a pad of Celite. The EtOAc was removed on a rotary evaporator. Compound 238 was obtained in 10 mg of quantity via preparative TLC (DCM:MeOH/10:1) separation. MS (ES) M+H expected 417.3. found 417.5. 1H NMR (CHLOROFORM-d) δ 7.56 (s, 1H), 4.91 (br. s., 0.5H), 4.53 (d, J=12.3 Hz, 0.5H), 4.02-4.31 (m, 3H), 3.67-3.83 (m, 3H), 3.47-3.64 (m, 2H), 3.34-3.41 (m, 3H), 3.16-3.30 (m, 1H), 2.93-3.13 (m, 4H), 2.74-2.84 (m, 2H), 2.61 (s, 3H), 2.53 (s, 3H), 1.39 (d, J=5.8 Hz, 1.5H), 1.30-1.34 (m, 1.5H), 1.17 (d, J=6.5 Hz, 6H).
(R)-5-amino-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile was prepared according to Scheme 4.
To a solution of (R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (7; 747 mg, 1.8 mmol) in DMF (8 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2 dioxaborolane) (563 mg, 2.2 mmol) and KOAc (538 mg, 5.5 mmol). The resulting mixture was stirred at room temperature for 5 min before addition of PdCl2(dppf).CH2Cl2 (45 mg, 0.03 mmol). After flushing with nitrogen, the reaction mixture was heated at 85° C. for 18 hours. LC-MS analysis indicated starting material still present, the temperature was raised to 120° C. and stirred overnight. After cooling, the reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was then washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo. Column chromatography (25% EtOAc/petroleum ether) afforded 334 mg of 30 as a white solid. MS (ES) M+H expected 457.3. found 457.4. 1H NMR (CHLOROFORM-d) δ 8.16 (s, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=12.3 Hz, 0.5H), 4.19-4.39 (m, 3H), 3.76-3.85 (m, 0.5H), 3.73 (t, J=6.4 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.25-3.35 (m, 1H), 3.02-3.20 (m, 1H), 2.63-2.80 (m, 1H), 2.51-2.61 (m, 1H), 1.45 (d, J=7.0 Hz, 1.5H), 1.35 (d, J=6.3 Hz, 1.5H), 1.34 (s, 12H), 1.19-1.21 (dd, J=6.8, 2.0 Hz, 3H), 1.23-1.25 (d, J=6.8 Hz, 3H).
To a solution of above boronate 30 (10 mg, 0.022 mmol) and Cu(OAc)2.H2O (0.5 mg, 0.0025 mmol) in MeOH (0.2 mL) was added slowly NaN3 (2.4 mg, 0.037 mmol) with stirring. After the addition, the reaction mixture was heated to 50° C. and stirred overnight. After cooling and dilution with water, the reaction mixture was extracted with methylene chloride. The organic layer was then washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo. Column chromatography (25% ethyl acetate/petroleum ether) afforded 3.7 mg of 31 as a yellowish solid. MS (ES) M+H expected 372.2. found 372.3.
To a solution of above azide 31 (10 mg, 0.027 mmol) in 1 mL of MeOH was added 10% Pd/C (0.5 mg). The resulting mixture was purged with hydrogen and stirred at room temperature for 1 h under hydrogen atmosphere. After LC-MS analysis showed the formation of desired product, the reaction mixture was filtered, the filtrate was concentrated in vacuo. Column chromatography (25% EtOAc/petroleum ether) afforded 9 mg of 32 as a pink solid. MS (ES) M+H expected 346.2. found 346.1. 1H NMR (CHLOROFORM-d) δ 7.25 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1 Hz, 0.5H), 4.20 (br. s., 1H), 3.95-4.07 (m, 1H), 3.93 (br. s., 1H), 3.75 (br. s., 0.5H) 3.73 (t, J=6.4 Hz, 2H), 3.52-3.63 (m, 0.5H), 3.37 (s, 3H), 3.02-3.21 (m, 2H), 2.88-3.02 (m, 1H), 2.62-2.78 (m, 1H), 2.59 (t, J=5.8 Hz, 1H), 1.41 (d, J=5.8 Hz, 1.5H), 1.31-1.32 (m, 1.5H), 1.26 (s, 6H).
Compound 254 was prepared according to general Scheme 5, below:
wherein Rc is —CH2-aryl or —CH2-heteroaryl.
To a solution of boronate 30 from Example 7 (30 mg, 0.066 mmol) in 15 mL of THF, at room temperature, was added aq. NaOH solution (2.86 g, 0.07 mmol). After stirring for 5 min, a solution of 30% of H2O2 (2.43 mg, 0.07 mmol) was added. The reaction mixture was allowed to stir at room temperature for additional 30 min before it was adjusted to neutral pH and concentrated in vacuo. Column chromatography (50% EtOAc/petroleum ether) afforded 21 mg of 33. MS (ES) M+H expected 347.2. found 347.3. 1H NMR (METHANOL-d4) δ 7.26 (s, 1H), 4.82 (br. s., 0.5H), 4.47 (d, J=13.1 Hz, 0.5H), 4.39 (br. s., 0.5H), 3.95 (d, J=13.1 Hz, 0.5H), 3.79-3.92 (m, 2H), 3.55-3.74 (m, 3H), 3.36 (s, 3H), 3.10-3.23 (m, 1H), 2.95-3.10 (m, 1H), 2.81-2.93 (m, 1H), 2.71-2.81 (m, 1H), 2.59-2.69 (m, 1H), 1.45 (d, J=6.8 Hz, 1.5H), 1.36 (br. s., 1.5H), 1.23 (d, J=6.8 Hz, 6H).
To a solution of (R)-5-hydroxy-6-isopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile (33; 15 mg, 0.043 mmol) in 1 mL of THF was added 60% NaH (2.1 mg, 0.052 mmol) at 0° C. After stirring at room temperature for 30 min, benzyl bromide (8.9 mg, 0.052 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature overnight. After the reaction mixture was concentrated, preparative TLC separation of the crude (50% ethyl acetate/petroleum ether) afforded 6.5 mg of Compound 254 as a yellowish solid. MS (ES) M+H expected 437.3. found 437.4. 1H NMR (CHLOROFORM-d) δ 7.33-7.43 (m, 5H), 7.23 (s, 1H), 5.02 (s, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.21 (br. s., 0.5H), 4.02-4.09 (m, 1H), 3.90-4.02 (m, 1H), 3.65-3.85 (m, 3H), 3.51-3.61 (m, 0.5H), 3.42-3.51 (m, 1H), 3.37 (s, 3H), 3.09-3.23 (m, 1H), 2.91-3.07 (m, 1H), 2.63-2.78 (m, 1H), 2.51-2.62 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 6H).
Other Compounds of Formula II listed below, wherein R1b is —O—CH2-aryl or —O—CH2-heteroaryl; and R2 is isopropyl or cyclopropyl were similarly prepared according to Scheme 5 by replacing (R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile 30 with alternate boronates prepared from any of intermediates 7 (Scheme 1), 17 (Scheme 2), or 28 (Scheme 3) using similar procedures set forth in Example 7 to prepare 30.
1H NMR (CHLOROFORM-d) δ 7.33-7.43 (m, 5H), 7.23 (s, 1H), 5.02 (s, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.21 (br. s., 0.5H), 4.02-4.09 (m, 1H), 3.90-4.02 (m, 1H), 3.65-3.85 (m, 3H), 3.51-3.61 (m, 0.5H), 3.42-3.51 (m, 1H), 3.37 (s, 3H), 3.09-3.23 (m, 1H), 2.91-3.07 (m, 1H), 2.63-2.78 (m, 1H), 2.51-2.62 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 6H). LC-MS: m/z 437.4 (M+H)+.
Compound 164 (45, wherein m is 1; R3 is 3-methyl; and R8 is 2-methylfuran-3yl) was prepared according to the general scheme set forth below in general Scheme 6.
To a solution of 3-methyl-1-phenylbutan-2-one (40; 3.38 g, 20 mmol) in 40 mL of anhydrous DMF was added 1,1-dimethoxy-N,N-dimethylmethanamine (5.958 g, 50 mmol). The resulting mixture was stirred at 100° C. overnight. After removal of DMF and excess of acetal, 4.3 g of 41 was obtained as a crude product and used in subsequent reaction without further purification. MS (ES) M+H expected 218.2. found 218.0.
To a 20 mL of anhydrous DMF solution containing 960 mg of sodium hydride (22 mmol, 60% dispersion in mineral oil) was added dropwise a solution of crude 1-(dimethylamino)-4-methyl-2-phenylpent-1-en-3-one (41; 4.3 g, 20 mmol DMF solution), cyano acetamide (1.72 g, 20 mmol), and 2 mL of MeOH in 35 mL of DMF. After the addition was completed, the resulting mixture was stirred at 80° C. overnight. After removal of DMF under reduced pressure, the residue was re-dissolved in methylene chloride and washed with water, and brine. The organic layer was then dried over anhy. Na2SO4 and concentrated in vacuo. Flash column chromatography (1:10 ethyl acetate/petroleum ether) afforded 3.84 g of 42 as a white solid. MS (ES) M+H expected 239.1. found 239.0. 1H NMR (DMSO-d6) δ 8.03 (s, 1H), 7.43-7.50 (m, 2H), 7.37-7.43 (m, 1H), 7.30-7.33 (m, 1H), 7.29 (s, 1H), 2.85-2.97 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H).
A mixture of 2-hydroxy-6-isopropyl-5-phenylnicotinonitrile (42; 2.3 g, 10 mmol), 5 mL of phosphoryl trichloride and one drop of DMF were heated to reflux overnight until LC-MS indicated the complete conversion to the product. After evaporation of excess of phosphoryl trichloride under reduced pressure, the residue was re-dissolved in methylene chloride and neutralized carefully with satd. aq. NaHCO3 and washed subsequently with 1N HCl and brine. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Flash column chromatography (1:5 ethyl acetate/petroleum ether) afforded 2.4 g of 43 as a yellowish solid. MS (ES) M+H expected 257.1. found 257.0. 1H NMR (CHLOROFORM-d) δ 7.76-7.82 (m, 1H), 7.43-7.54 (m, 3H), 7.28 (br. s., 1H), 7.22-7.26 (m, 1H), 3.20 (spt, J=6.7 Hz, 1H), 1.22 (s, 3H), 1.20 (s, 3H).
A mixture of above chloride 43 (192.5 mg, 0.75 mmol), (R)-2-methylpiperazine (187.8 mg, 1.875 mmol), and triethylamine (0.261 mL, 1.875 mmol) suspended in 2 mL of acetonitrile was subjected to microwave reaction at 175° C. for 45 min. After the reaction mixture was concentrated in vacuo, the residue was purified by flash column chromatography to give 184 mg of 44 as yellowish oil. MS (ES) M+H expected 321.2. found 321.1. 1H NMR (CHLOROFORM-d) δ 7.56-7.66 (m, 1H), 7.34-7.51 (m, 3H), 7.19-7.28 (m, 2H), 4.31-4.59 (m, 2H), 3.11-3.27 (m, 3H), 3.01-3.11 (m, 2H), 2.84 (dd, J=12.8, 10.3 Hz, 1H), 1.22 (d, J=6.3 Hz, 3H), 1.15 (dd, J=6.7, 1.1 Hz, 6H).
In a 5-mL of amber glass vial was placed (R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-5-phenyl-nicotinonitrile (50 mg, 0.156 mmol), 2-methylfuran-3-carboxylic acid (39 mg, 0.312 mmol), EDCI (60 mg, 0.312 mmol), HOBt (42 mg, 0.312 mmol), triethylamine (40 mg, 0.312 mmol) and 2 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature overnight. The mixture was quenched with 1 N HCl aqueous solution, extracted with EtOAc three times. The combined organic layer was washed with satd. NaHCO3 and brine, dried over anhy. Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC (EtOAc: petroleum ether/100:20) to afford 28 mg of the title compound as a white solid. MS (ES) M+H expected 429.2. found 429.1. 1H NMR (METHANOL-d4) δ 7.59-7.67 (m, 1H), 7.37-7.50 (m, 3H), 7.31 (d, J=2.0 Hz, 1H), 7.21-7.28 (m, 2H), 6.39 (d, J=2.0 Hz, 1H), 4.70 (br. s., 1H), 4.29-4.50 (m, 2H), 4.23 (br. s., 1H), 3.49 (br. s., 1H), 3.33 (dd, J=12.9, 3.1 Hz, 1H), 3.08-3.23 (m, 2H), 2.40-2.47 (m, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.16 (dd, J=6.8, 2.8 Hz, 6H).
Other Compounds of Formula II listed below, wherein R1a is hydrogen; R1b is optionally substituted phenyl; were similarly prepared according to Scheme 6 by replacing one or more of: (1) methyl-1-phenylbutan-2-one (40) with an alternate phenyl ketone as starting material; (2) (R)-2-methylpiperazine with an alternate piperazine in Step U; and (3) 2-methylfuran-3-carboxylic acid with an alternate acid in Step V.
1H NMR (CHLOROFORM-d) δ 7.65 (s, 1H), 7.53-7.58 (m, 1H), 7.38-7.49 (m, 3H), 7.24-7.28 (m, 2H), 7.10 (d, J=3.3 Hz, 1H), 6.54 (dd, J=3.3, 1.8 Hz, 1H), 4.03 (br. s., 4H), 3.89 (dd, J=6.4, 3.6 Hz, 4H), 3.17 (dt, J=13.4, 6.7 Hz, 1H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z 401.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.62-7.69 (m, 1H), 7.54 (d, J=0.8 Hz, 1H), 7.40-7.47 (m, 3H), 7.23-7.28 (m, 2H), 7.08 (d, J=3.5 Hz, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 4.93 (br. s., 1H), 4.54 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.3 Hz, 1H), 4.37 (d, J=13.3 Hz, 1H), 3.58 (br. s., 1H), 3.44 (dd, J=13.3, 3.8 Hz, 1H), 3.27 (td, J=12.4, 3.4 Hz, 1H), 3.16 (dt, J=13.3, 6.7 Hz, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.7, 1.9 Hz, 6H). LC-MS: m/z 414.9 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.64 (s, 1H), 7.40-7.51 (m, 4H), 7.24-7.28 (m, 2H), 6.61 (d, J=1.3 Hz, 1H), 4.76 (br. s., 1H), 4.33-4.52 (m, 3H), 3.51 (s, 1H), 3.35 (dd, J=13.2, 3.1 Hz, 1H), 3.12-3.22 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.5, 2.0 Hz, 6H).
LC-MS: m/z 414.9 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.76-7.81 (m, 1H), 7.65 (s, 1H), 7.36-7.51 (m, 4H), 7.23-7.28 (m, 2H), 6.62 (dd, J=1.9, 0.9 Hz, 1H), 3.91 (br. s., 4H), 3.84 (br. s., 4H), 3.17 (dt, J=13.4, 6.6 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H). LC-MS: m/z 401.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 8.97 (br. s., 1H), 7.74-7.81 (m, 1H), 7.64 (s, 1H), 7.53 (br. s., 1H), 7.38-7.50 (m, 4H), 7.28-7.31 (m, 1H), 7.24-7.28 (m, 3H), 3.94 (br. s., 4H), 3.85 (br. s., 4H), 3.16 (dt, J=13.2, 6.6 Hz, 1H), 1.17 (d, J=6.5 Hz, 6H). LC-MS: m/z 450.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.62 (s, 1H), 7.41-7.47 (m, 3H), 7.38-7.41 (m, 1H), 7.37 (s, 1H), 7.34-7.36 (m, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.24 (s, 1H), 3.84-3.89 (m, 2H), 3.83 (s, 2H), 3.73-3.78 (m, 2H), 3.64-3.68 (m, 2H), 3.58-3.63 (m, 2H), 3.15 (dt, J=13.3, 6.7 Hz, 1H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 425.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.37-7.51 (m, 4H), 7.33-7.37 (m, 2H), 7.29-7.33 (m, 2H), 7.22-7.27 (m, 2H), 4.62 (d, J=13.6 Hz, 0.5H), 4.42 (d, J=12.5 Hz, 0.5H), 4.19-4.35 (m, 2H), 3.81 (br. s., 1H), 3.76 (d, J=13.1 Hz, 0.5H), 3.49 (t, J=12.0 Hz, 0.5H), 2.91-3.29 (m, 3H), 1.31 (br. s., 3H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 439.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61-7.64 (m, 1H), 7.41-7.48 (m, 3H), 7.38-7.41 (m, 1H), 7.37 (s, 1H), 7.34-7.36 (m, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.23-7.26 (m, 1H), 4.90 (br. s., 1H), 4.46 (br. s., 2H), 4.20 (br. s., 1H), 3.82 (s, 2H), 3.12-3.22 (m, 2H), 3.11 (br. s., 1H), 1.43 (d, J=7.0 Hz, 6H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z 453.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.77 (dd, J=1.5, 0.8 Hz, 1H), 7.65 (s, 1H), 7.47-7.49 (m, 1H), 7.45-7.47 (m, 1H), 7.44 (s, 1H), 7.40-7.43 (m, 1H), 7.24-7.28 (m, 2H), 6.65 (dd, J=1.9, 0.9 Hz, 1H), 4.71 (br. s., 2H), 4.47 (s, 1H), 4.50 (s, 1H), 3.27 (dd, J=12.9, 4.1 Hz, 2H), 3.18 (dt, J=13.3, 6.7 Hz, 1H), 1.55 (d, J=7.0 Hz, 6H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z 429.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.39-7.47 (m, 3H), 7.34-7.39 (m, 2H), 7.29-7.33 (m, 2H), 7.22-7.28 (m, 3H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.8 Hz, 0.5H), 4.42 (d, J=12.0 Hz, 0.5H), 4.15-4.35 (m, 2H), 3.81 (br. s., 2H), 3.72-3.79 (m, 0.5H), 3.49 (t, J=11.3 Hz, 0.5H), 3.29 (d, J=10.0 Hz, 0.5H), 3.04-3.21 (m, 2.5H), 2.88-3.01 (m, 0.5H), 1.27-1.34 (m, 3H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 439.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.74-7.80 (m, 1H), 7.64 (s, 1H), 7.36-7.52 (m, 4H), 7.27 (dd, J=7.9, 6.4 Hz, 2H), 6.59-6.64 (m, 1H), 4.76 (br. s., 1H), 4.20-4.50 (m, 3H), 3.51 (br. s., 1H), 3.35 (dd, J=13.3, 3.3 Hz, 1H), 3.06-3.24 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.5, 2.0 Hz, 6H). LC-MS: m/z 415.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.29-7.47 (m, 7H), 7.22-7.28 (m, 3H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.6 Hz, 0.5H), 4.42 (d, J=12.8 Hz, 0.5H), 4.15-4.37 (m, 2H), 3.80-3.85 (m, 2H), 3.76 (d, J=12.8 Hz, 0.5H), 3.49 (t, J=11.2 Hz, 0.5H), 3.25-3.37 (m, 0.5H), 3.02-3.23 (m, 2.5H), 2.88-3.01 (m, 0.5H), 1.26-1.35 (m, 3H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 439.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.77 (dd, J=1.5, 1.0 Hz, 1H), 7.63-7.66 (m, 1H), 7.38-7.50 (m, 4H), 7.23-7.28 (m, 2H), 6.61 (dd, J=1.8, 0.8 Hz, 1H), 4.76 (br. s., 1H), 4.30-4.51 (m, 3H), 3.52 (br. s., 1H), 3.35 (dd, J=13.2, 3.6 Hz, 1H), 3.06-3.24 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.8, 2.0 Hz, 6H). LC-MS: m/z 415.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59-7.74 (m, 1H), 7.56 (s, 1H), 7.33-7.50 (m, 8H), 7.29 (d, J=7.3 Hz, 1H), 7.17-7.25 (m, 2H), 6.54 (br. s., 1H), 5.74 (br. s., 1H), 4.79 (br. s., 1H), 4.51 (br. s., 1H), 4.33 (d, J=9.5 Hz, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.58 (br. s., 2H), 3.12 (spt, J=6.6 Hz, 1H), 1.08-1.18 (m, 6H). LC-MS: m/z 477.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.72 (br. s., 1H), 7.48-7.60 (m, 5H), 7.46 (br. s., 3H), 7.40 (br. s., 2H), 7.27 (br. s., 1H), 7.20 (d, J=6.8 Hz, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 5.14-5.37 (m, 1H), 4.25 (br. s., 2H), 3.87 (br. s., 3H), 3.64 (br. s., 1H), 2.81-2.95 (m, 1H), 1.16 (d, J=6.5 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H). LC-MS: m/z 477.2 (M+H)+.
1H NMR (METHANOL-d4) δ 7.62 (s, 1H), 7.35-7.57 (m, 3H), 7.21-7.28 (m, 3H), 6.87-7.11 (m, 2H), 4.60 (d, J=13.3 Hz, 1H), 4.29-4.37 (m, 2H), 3.98 (s, 2H), 3.59 (t, J=11.4 Hz, 1H), 3.04-3.27 (m, 4H), 1.36 (dd, J=15.2, 5.9 Hz, 3H), 1.16 (d, J=6.5 Hz, 6H). LC-MS: m/z 445.0 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.54-7.56 (m, 2H), 7.52 (br. s., 3H), 7.43 (br. s., 2H), 7.24-7.30 (m, 3H), 7.20 (d, J=7.3 Hz, 1H), 7.08 (d, J=3.3 Hz, 1H), 6.77 (s, 1H), 6.52 (br. s., 1H), 5.31-5.37 (br. s., 1H), 4.40 (br. s., 1H), 4.32 (br. s., 1H), 3.85-4.03 (m, 2H), 3.79 (d, J=13.1 Hz, 1H), 3.68 (d, J=4.8 Hz, 1H), 2.87 (dt, J=13.4, 6.8 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.5 Hz, 3H). LC-MS: m/z 477.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 9.09 (br. s., 1H), 7.76 (br. s., 1H), 7.51 (s, 2H), 7.55 (s, 3H), 7.39 (br. s., 3H), 7.29 (s, 2H), 7.33 (s, 1H), 7.24 (br. s., 3H), 6.77 (br. s., 1H), 5.29 (br. s., 1H), 4.30 (d, J=11.5 Hz, 1H), 4.18 (br. s., 1H), 3.93 (br. s., 3H), 3.64 (br. s., 1H), 2.89 (br. s., 1H), 1.16 (d, J=5.8 Hz, 3H), 1.07 (d, J=5.8 Hz, 3H). LC-MS: m/z 526.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.74 (br. s., 1H), 7.61 (s, 1H), 7.47 (t, J=1.6 Hz, 1H), 7.35-7.46 (m, 3H), 7.20-7.26 (m, 2H), 6.58 (s, 1H), 4.79 (d, J=12.8 Hz, 1H), 4.54-4.68 (br. s., 1H), 4.45 (br. s., 1H), 3.8-4.07 (m, 1H), 3.56-3.74 (m, 1H), 3.19 (br. s., 1H), 3.06-3.18 (m, 3H), 1.52-1.59 (m, 3H), 1.40-1.48 (m, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.8 Hz, 3H). LC-MS: m/z 443.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.74 (s, 1H), 7.58-7.65 (m, 1H), 7.35-7.50 (m, 4H), 7.20-7.26 (m, 2H), 6.58 (dd, J=1.8, 0.8 Hz, 1H), 5.02 (s, 1H), 4.69 (br. s., 1H), 4.50 (d, J=13.1 Hz, 1H), 4.41 (d, J=12.3 Hz, 1H), 4.23-4.31 (br. s., 1H), 3.46-3.86 (m, 2H), 3.27 (dd, J=13.3, 3.3 Hz, 1H), 3.10-3.21 (m, 2H), 1.79-1.96 (m, 2H), 1.54 (d, J=6.5 Hz, 1.5H), 1.45 (d, J=6.5 Hz, 1.5H), 1.15 (dd, J=6.8, 3.5 Hz, 6H). LC-MS: m/z 429.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59-7.64 (m, 1H), 7.51 (dd, J=1.8, 0.8 Hz, 1H), 7.36-7.46 (m, 3H), 7.21-7.26 (m, 2H), 7.02-7.10 (m, 1H), 6.51 (dd, J=3.5, 1.8 Hz, 1H), 4.71 (br. s., 1H), 4.38-4.60 (m, 3H), 3.50 (br. s., 1H), 3.35 (dd, J=13.3, 3.5 Hz, 1H), 3.22 (td, J=12.5, 3.4 Hz, 1H), 3.08-3.18 (m, 1H), 1.90-2.06 (m, 1H), 1.83 (dquin, J=14.2, 7.2 Hz, 1H), 1.15 (dd, J=6.7, 3.1 Hz, 6H), 0.97 (t, J=7.4 Hz, 3H). LC-MS: m/z 429.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.58-7.66 (m, 1H), 7.35-7.47 (m, 3H), 7.29 (d, J=2.0 Hz, 1H), 7.21-7.26 (m, 2H), 6.32-6.41 (m, 1H), 4.59-4.80 (m, 1H), 4.50 (d, J=13.1 Hz, 1H), 4.42 (br. s., 1H), 3.91-3.97 (br. s., 1H), 3.45-3.65 (m, 1H), 3.27 (dd, J=13.1, 3.3 Hz, 1H), 3.05-3.19 (m, 2H), 2.41 (s, 3H), 1.86-1.95 (m, 1H), 1.79 (dt, J=14.1, 7.0 Hz, 1H), 1.15 (dd, J=6.8, 2.0 Hz, 6H), 0.87-0.99 (m, 3H). LC-MS: m/z 443.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.35-7.49 (m, 3H), 7.17-7.25 (m, 3H), 6.92-6.99 (m, 2H), 4.75 (br. s., 0.5H), 4.59-4.71 (m, 0.5H), 4.30-4.50 (m, 2H), 3.79-4.07 (m, 3H), 3.46-3.56 (m, 0.5H), 3.17-3.30 (m, 0.5H), 2.97-3.17 (m, 3H), 1.78-1.89 (m, 1H), 1.69-1.78 (m, 1H), 1.10-1.16 (m, 6H), 0.90-0.97 (m, 3H). LC-MS: m/z 459.1 (M+H)+.
Compound 117 was synthesized was synthesized was synthesized using 1,2-diphenylethanone as starting material.
1H NMR (CHLOROFORM-d) δ 7.87 (s, 1H), 7.53 (dd, J=1.5, 0.8 Hz, 1H), 7.37-7.44 (m, 2H), 7.27-7.35 (m, 6H), 7.12-7.19 (m, 2H), 7.06-7.12 (m, 1H), 6.53 (dd, J=3.4, 1.9 Hz, 1H), 4.94 (br. s., 1H), 4.53 (t, J=11.7 Hz, 2H), 4.36-4.46 (m, 1H), 3.62 (br. s., 1H), 3.44-3.54 (m, 1H), 3.26-3.37 (m, 1H), 1.52 (d, J=6.5 Hz, 3H). LC-MS: m/z 448.9 (M+H)+.
Compound 118 was synthesized using 1,2-diphenylethanone as starting material.
1H NMR (CHLOROFORM-d) δ 7.88 (s, 1H), 7.77 (s, 1H), 7.48 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.27-7.33 (m, 6H), 7.13-7.16 (m, 2H), 6.61 (s, 1H), 4.71-4.79 (br. s., 1H), 4.47-4.50 (s, 1H), 4.38 (s, 1H), 4.41 (s, 1H), 3.48-3.64 (m, 1H), 3.38-3.42 (m, 1H), 3.21 (td, J=12.4, 3.0 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H). LC-MS: m/z 448.9 (M+H)+.
Compound 122 was synthesized using 1,2-diphenylethanone as starting material.
1H NMR (CHLOROFORM-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.47-7.51 (m, 1H), 7.37-7.42 (m, 2H), 7.27-7.35 (m, 6H), 7.15 (dd, J=6.5, 3.0 Hz, 2H), 6.62 (s, 1H), 3.92 (br. s., 4H), 3.89 (br. s., 4H). LC-MS: m/z 435.1 (M+H)+.
Compound 123 was synthesized using 1,2-diphenylethanone as starting material.
1H NMR (CHLOROFORM-d) δ 7.85 (s, 1H), 7.34-7.39 (m, 4H), 7.28-7.33 (m, 8H), 7.22-7.26 (m, 1H), 7.13 (dd, J=6.5, 3.0 Hz, 2H), 3.85-3.91 (m, 2H), 3.79-3.84 (m, 4H), 3.66 (s, 4H). LC-MS: m/z 459.1 (M+H)+.
Compound 161 was synthesized using 1-(3-fluorophenyl)-3-methylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.73-7.79 (m, 1H), 7.61 (s, 1H), 7.47 (t, J=1.6 Hz, 1H), 7.35-7.44 (m, 1H), 7.06-7.13 (m, 1H), 7.00-7.04 (m, 1H), 6.96 (dt, J=9.3, 2.1 Hz, 1H), 6.54-6.63 (m, 1H), 4.61-4.90 (m, 1H), 4.41 (s, 0.5H), 4.44 (s, 0.5H), 4.19-4.39 (m, 2H), 3.42-3.49 (br. s., 1H), 3.34 (dd, J=13.2, 3.1 Hz, 1H), 3.14-3.23 (m, 1H), 3.06-3.14 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.15 (dd, J=6.8, 1.8 Hz, 6H). LC-MS: m/z 433.1 (M+H)+.
Compound 175 was synthesized using 1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.56 (s, 1H), 7.46 (t, J=1.5 Hz, 1H), 7.34-7.41 (m, 1H), 7.06-7.12 (m, 1H), 7.01 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.55-6.62 (m, 1H), 4.74 (br. s., 1H), 4.18-4.46 (m, 3H), 3.77 (s, 3H), 3.49 (br. s., 1H), 3.31 (dd, J=13.2, 3.1 Hz, 1H), 3.14 (td, J=12.5, 3.0 Hz, 1H), 2.86 (quin, J=6.7 Hz, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.15 (br. s., 3H), 1.04 (br. s., 3H). LC-MS: m/z 445.2 (M+H)+.
Compound 176 was synthesized using 1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.56 (s, 1H), 7.50-7.53 (m, 1H), 7.34-7.41 (m, 1H), 7.07-7.13 (m, 1H), 7.03-7.06 (m, 1H), 6.99-7.02 (m, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.51 (dd, J=3.3, 1.8 Hz, 1H), 4.90 (br. s., 1H), 4.51 (d, J=13.6 Hz, 1H), 4.41 (d, J=13.8 Hz, 1H), 4.34 (d, J=13.3 Hz, 1H), 3.77 (s, 3H), 3.57 (d, J=10.5 Hz, 1H), 3.39 (dd, J=13.1, 3.5 Hz, 1H), 3.23 (td, J=12.4, 3.1 Hz, 1H), 2.86 (dt, J=13.3, 6.7 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.16 (br. s., 3H), 1.05 (br. s., 3H). LC-MS: m/z 445.2 (M+H)+.
Compound 177 was synthesized using 1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.54 (s, 1H), 7.33-7.41 (m, 1H), 7.20-7.24 (m, 1H), 7.05-7.11 (m, 1H), 6.98-7.04 (m, 1H), 6.89-6.98 (m, 3H), 4.94 (br. s., 0.5H), 4.58 (d, J=12.8 Hz, 0.2H), 4.17-4.46 (m, 3H), 3.91-4.04 (m, 2H), 3.76 (s, 3H), 3.56 (t, J=11.2 Hz, 0.5H), 3.27 (d, J=12.8 Hz, 0.5H), 3.13-3.23 (m, 1H), 2.98-3.11 (m, 1H), 2.85 (dt, J=13.3, 6.7 Hz, 1H), 1.33-1.39 (m, 3H), 1.15 (br. s., 3H), 1.04 (br. s., 3H). LC-MS: m/z 475.2 (M+H)+.
Compound 178 was synthesized using 1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.52-7.59 (m, 1H), 7.34-7.41 (m, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.08 (dd, J=7.3, 1.8 Hz, 1H), 7.01 (t, J=7.2 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.38 (d, J=1.8 Hz, 1H), 4.69 (br. s., 1H), 4.29-4.43 (m, 2H), 4.00-4.29 (m, 1H), 3.77 (s, 3H), 3.46 (br. s., 1H), 3.24-3.39 (m, 1H), 3.11 (td, J=12.5, 3.0 Hz, 1H), 2.86 (spt, J=6.6 Hz, 1H), 2.41 (s, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.12-1.19 (m, 3H), 1.04 (br. s., 3H). LC-MS: m/z 459.1 (M+H)+.
Compound 179 was synthesized using 3-methyl-1-p-tolylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.60 (s, 1H), 7.44-7.49 (m, 1H), 7.24 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 6.55-6.62 (m, 1H), 4.74 (br. s., 1H), 4.20-4.49 (m, 3H), 3.38-3.57 (m, 1H), 3.31 (dd, J=13.1, 3.0 Hz, 1H), 3.07-3.22 (m, 2H), 2.37-2.46 (m, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.07-1.20 (m, 6H). LC-MS: m/z 429.1 (M+H)+.
Compound 180 was synthesized using 3-methyl-1-p-tolylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.50-7.53 (m, 1H), 7.24 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.05 (d, J=3.5 Hz, 1H), 6.46-6.55 (m, 1H), 4.90 (br. s., 1H), 4.51 (d, J=13.6 Hz, 1H), 4.42 (d, J=14.1 Hz, 1H), 4.33 (dt, J=13.3, 2.0 Hz, 1H), 3.57 (d, J=10.3 Hz, 1H), 3.40 (dd, J=13.2, 3.6 Hz, 1H), 3.18-3.30 (m, 1H), 3.09-3.18 (m, 1H), 2.41 (s, 3H), 1.48 (d, J=6.8 Hz, 3H), 1.07-1.20 (m, 6H). LC-MS: m/z 429.2 (M+H)+.
Compound 181 was synthesized using 3-methyl-1-p-tolylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.58 (s, 1H), 7.20-7.25 (m, 3H), 7.12 (d, J=7.8 Hz, 2H), 6.88-7.00 (m, 2H), 4.94 (br. s., 0.5H), 4.58 (d, J=13.1 Hz, 0.5H), 4.32-4.43 (m, 1H), 4.27 (s, 1H), 4.30 (s, 1H), 3.91-4.05 (m, 2H), 3.80 (d, J=13.6 Hz, 0.5H), 3.51-3.63 (m, 0.5H), 3.20-3.33 (m, 1H), 3.11-3.20 (m, 1H), 2.98-3.10 (m, 1H), 2.41 (s, 3H), 1.36 (d, J=6.3 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.13 (d, J=6.5 Hz, 6H). LC-MS: m/z 459.1 (M+H)+.
Compound 182 was synthesized using 3-methyl-1-p-tolylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.28-7.32 (m, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 6.36-6.41 (m, 1H), 4.69 (br. s., 1H), 4.38 (d, J=13.3 Hz, 1H), 4.33 (d, J=13.1 Hz, 1H), 4.23 (d, J=12.0 Hz, 1H), 3.46 (br. s., 1H), 3.26-3.34 (m, 1H), 3.13-3.21 (m, 1H), 3.05-3.13 (m, 1H), 2.41 (s, 6H), 1.41 (d, J=6.8 Hz, 3H), 1.14 (dd, J=6.7, 3.4 Hz, 6H).
LC-MS: m/z 443.2 (M+H)+.
Compound 183 was synthesized using 1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.55 (s, 1H), 7.34-7.42 (m, 1H), 7.05-7.12 (m, 1H), 6.99-7.05 (m, 1H), 6.96 (d, J=8.3 Hz, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=13.1 Hz, 0.5H), 4.19-4.43 (m, 3H), 3.82 (d, J=7.5 Hz, 0.5H), 3.76 (s, 3H), 3.70-3.76 (m, 2H), 3.54-3.64 (m, 0.5H), 3.38 (s, 3H), 3.30 (t, J=13.3 Hz, 1H), 3.02-3.22 (m, 1H), 2.82-2.92 (m, 1H), 2.66-2.80 (m, 1H), 2.53-2.65 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.16 (br. s., 3H), 1.05 (br. s., 3H). LC-MS: m/z 437.1 (M+H)+.
Compound 184 was synthesized using 1-(2-ethoxyphenyl)-3-methylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.55 (s, 1H), 7.48-7.53 (m, 1H), 7.31-7.38 (m, 1H), 7.05-7.11 (m, 2H), 6.96-7.02 (m, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.45-6.56 (m, 1H), 4.77 (br. s., 1H), 4.53 (d, J=11.3 Hz, 1H), 4.36 (d, J=13.3 Hz, 1H), 4.23-4.33 (m, 1H), 4.02 (q, J=6.8 Hz, 2H), 3.38-3.67 (m, 3H), 2.84-2.97 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 1.27-1.30 (m, 3H), 1.24-1.27 (m, 6H). LC-MS: m/z 459.1 (M+H)+.
Compound 198 was synthesized using 3-methyl-1-p-tolylbutan-2-one as starting material.
1H NMR (CHLOROFORM-d) δ 7.59 (s, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.21-4.42 (m, 3H), 3.81 (d, J=13.8 Hz, 0.5H), 3.69-3.77 (m, 62H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=12.3 Hz, 1H), 3.11-3.19 (m, 2H), 2.65-2.81 (m, 1H), 2.54-2.63 (m, 1H), 2.41 (s, 3H), 1.40 (d, J=6.3 Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 421.1 (M+H)+.
Compound 240 was synthesized using 1,2-diphenylethanone as starting material.
1H NMR (CHLOROFORM-d) δ 7.84 (s, 1H), 7.33-7.40 (m, 2H), 7.26-7.33 (m, 4H), 7.20-7.25 (m, 2H), 7.08-7.16 (m, 2H), 4.94 (br. s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.38-4.49 (m, 1H), 4.23-4.38 (m, 2H), 3.77-3.90 (m, 1H), 3.74 (t, J=6.0 Hz, 2H), 3.54-3.64 (m, 0.5H), 3.37 (s, 3H), 3.34 (d, J=6.3 Hz, 0.5H), 3.19-3.26 (m, 1H), 3.06-3.19 (m, 1H), 2.66-2.78 (m, 1H), 2.55-2.63 (m, 1H), 1.39-1.46 (m, 1.5H), 1.33 (d, J=6.0 Hz, 1.5H). LC-MS: m/z 441.3 (M+H)+.
Compound 130 (55, wherein m is 1, R3 is methyl; and R8 is furan-3-yl) was synthesized according to general Scheme 7.
To a suspension of ammonium acetate (31.46 g, 0.4 mol) in 200 mL of EtOH was added successively the 3-methyl-2-butanone (51; 5.38 mL, 50 mmol), benzaldehyde (50; 5.21 g, 50 mmol), and ethyl cyanoacetate (23; 5.6 mL, 50 mmol). The resulting mixture was stirred at reflux temperature for 3 hrs and subsequently at room temperature overnight. After the LC-MS showed the formation of the desired product, the precipitate formed was filtered and washed with EtOH (10 mL×3 times) and hexane (10 mL×3 times). After air-drying, 2.18 g of 52 was obtained as a white solid. MS (ES) M+H expected 239.1. found 239.0. 1H NMR (CHLOROFORM-d) δ 7.61-7.70 (m, 2H), 7.51-7.58 (m, 3H), 6.33 (s, 1H), 3.06 (dt, J=13.8, 6.9 Hz, 1H), 1.42 (d, J=7.0 Hz, 6H).
A mixture of 2-hydroxy-6-isopropyl-4-phenylnicotinonitrile 52; (0.702 g, 2.94 mmol), 7 mL of phosphoryl trichloride and one drop of DMF were heated to reflux overnight until LC-MS indicated the complete conversion to the product. After evaporation of excess of phosphoryl trichloride under reduced pressure, the residue was re-dissolved in methylene chloride and neutralized carefully with satd. aq. NaHCO3 and washed subsequently with 1N HCl and brine. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Flash column chromatography (1:5 ethyl acetate/petroleum ether) afforded 717 mg of 53 as a yellowish solid. MS (ES) M+H expected 257.1. found 257.0. 1H NMR (CHLOROFORM-d) δ 7.52-7.64 (m, 5H), 7.26 (s, 1H), 3.09-3.21 (m, 1H), 1.37 (d, J=7.0 Hz, 6H).
A mixture of above chloride 53 (192.6 mg, 0.75 mmol), (R)-2-methylpiperazine (150 mg, 1.5 mmol), and triethylamine (0.21 mL, 1.5 mmol) suspended in 1.5 mL of acetonitrile was subjected to microwave reaction at 175° C. for 45 min. After the reaction mixture was concentrated in vacuo, the residue was purified by flash column chromatography to give 197 mg of 54 as yellowish oil. MS (ES) M+H expected 321.2. found 321.1. 1H NMR (CHLOROFORM-d) δ 7.54-7.60 (m, 2H), 7.47-7.53 (m, 3H), 6.71 (s, 1H), 4.21-4.35 (m, 2H), 3.03-3.18 (m, 4H), 2.99 (dt, J=13.8, 6.9 Hz, 1H), 2.78 (dd, J=12.7, 10.2 Hz, 1H), 1.30 (d, J=7.0 Hz, 6H), 1.15-1.20 (m, 3H).
In a 5-mL of amber glass vial was placed (R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-4-phenyl-nicotinonitrile (54; 32 mg, 0.1 mmol), furan-3-carboxylic acid (22.4 mg, 0.312 mmol), EDCI (38.2 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol), triethylamine (35 μL, 0.2 mmol) and 1.5 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature overnight. The mixture was quenched with 1 N HCl aqueous solution, extracted with EtOAc three times. The combined organic layer was washed with satd. NaHCO3 and brine, dried over anhy. Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC (EtOAc: petroleum ether/20:100) to afford 23 mg of Compound 130 as a light yellowish solid. MS (ES) M+H expected 415.2. found 415.1. 1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.55-7.58 (m, 2H), 7.50-7.53 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.60-6.62 (m, 1H), 4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6 Hz, 1H), 3.17 (td, J=12.5, 3.5 Hz, 1H), 3.01 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H).
Other Compounds of Formula II listed below, wherein R1a is optionally substituted phenyl; and R1b is hydrogen; were similarly prepared by general Scheme 7 replacing one or more of: (1) 3-methyl-2-butanone (51) with an alternate ketone as starting material; (2) benzaldehyde (50) with an alternate aldehyde as starting material; (3) (R)-2-methylpiperazine with an alternate piperazine in Step Y; and (4) 2-methylfuran-3-carboxylic acid with an alternate acid in Step Z. In addition, a compound wherein R1a is isopropyl; R1b is hydrogen and R2 is phenyl was also prepared by the same method of general Scheme 7.
1H NMR (DMSO-d6) δ 7.54-7.59 (m, 2H), 7.50-7.54 (m, 3H), 7.47 (s, 5H), 6.80 (s, 1H), 4.01 (br. s., 2H), 3.74-3.89 (m, 3H), 3.66 (br. s., 3H), 3.01 (quin, J=6.8 Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H). LC-MS: m/z 411.1 (M+H)+.
1H NMR (DMSO-d6) δ 7.53-7.58 (m, 2H), 7.49-7.53 (m, 3H), 7.40-7.47 (m, 5H), 6.79 (s, 1H), 4.54 (br. s., 2H), 4.24 (s, 1H), 4.27 (s, 1H), 3.28 (dd, J=13.1, 4.3 Hz, 2H), 3.01 (dt, J=13.6, 6.9 Hz, 1H), 1.52 (d, J=6.8 Hz, 6H), 1.31 (d, J=7.0 Hz, 6H). LC-MS: m/z 439.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.54-7.61 (m, 2H), 7.45-7.54 (m, 4H), 7.08 (d, J=3.5 Hz, 1H), 6.78 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.90 (br. s., 2H), 4.30 (s, 1H), 4.34 (s, 1H), 3.32 (dd, J=12.9, 4.4 Hz, 2H), 3.01 (quin, J=6.9 Hz, 1H), 1.60 (d, J=7.0 Hz, 6H), 1.31 (d, J=7.0 Hz, 6H). LC-MS: m/z 429.1 (M+H)+.
Compound 103 was synthesized using isobutyraldehyde and acetophenone as starting materials.
1H NMR (DMSO-d6) δ 8.02-8.08 (m, 2H), 7.50-7.56 (m, 2H), 7.46-7.50 (m, 2H), 7.30 (s, 1H), 7.08 (dd, J=3.4, 0.6 Hz, 1H), 6.53 (dd, J=3.3, 1.8 Hz, 1H), 4.05 (br. s., 4H), 3.79-3.85 (m, 4H), 3.40 (dt, J=13.7, 6.8 Hz, 1H), 1.38 (d, J=6.8 Hz, 6H). LC-MS: m/z 400.8 (M+H)+.
Compound 104 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.51-7.57 (m, 1H), 7.43-7.51 (m, 1H), 7.23-7.28 (m, 1H), 7.03-7.11 (m, 3H), 6.75 (s, 1H), 6.53 (dd, J=3.0, 1.5 Hz, 1H), 4.02 (br. s., 4H), 3.89 (s, 3H), 3.74-3.82 (m, 4H), 3.00 (dt, J=13.8, 6.9 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 430.9 (M+H)+.
Compound 105 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (DMSO-d6) δ 7.43-7.50 (m, 6H), 7.25 (dd, J=7.4, 1.6 Hz, 1H), 7.07-7.10 (m, 1H), 7.02-7.06 (m, 1H), 6.75 (s, 1H), 3.99 (br. s., 2H), 3.87 (s, 3H), 3.78 (br. s., 2H), 3.64 (br. s., 4H), 2.99 (dt, J=13.8, 6.9 Hz, 1H), 1.31 (s, 3H), 1.29 (s, 3H). LC-MS: m/z 440.8 (M+H)+.
Compound 106 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 9.02 (br. s., 1H), 7.73-7.80 (m, 1H), 7.41-7.51 (m, 3H), 7.21-7.28 (m, 3H), 7.01-7.11 (m, 2H), 6.75 (s, 1H), 3.94 (br. s., 4H), 3.87 (s, 3H), 3.75 (br. s., 4H), 3.02 (dt, J=13.7, 6.8 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 480 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.55-7.60 (m, 2H), 7.48-7.54 (m, 4H), 7.06 (dd, J=3.5, 0.8 Hz, 1H), 6.77 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.91 (br. s., 1H), 4.52 (d, J=13.6 Hz, 1H), 4.29-4.36 (m, 1H), 4.23 (dt, J=13.1, 2.1 Hz, 1H), 3.62 (br. s., 1H), 3.43 (dd, J=13.1, 3.8 Hz, 1H), 3.26 (td, J=12.4, 3.5 Hz, 1H), 3.00 (quin, J=6.9 Hz, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H)+.
Compound 108 was synthesized using benzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 8.00-8.08 (m, 2H), 7.50-7.57 (m, 2H), 7.45-7.50 (m, 2H), 7.29 (s, 1H), 7.07 (dd, J=3.5, 0.5 Hz, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.94 (br. s., 1H), 4.54 (d, J=13.3 Hz, 1H), 4.34 (dd, J=12.5, 2.3 Hz, 1H), 4.24 (dt, J=13.1, 2.1 Hz, 1H), 3.65 (br. s., 1H), 3.41-3.46 (m, 1H), 3.38-3.41 (m, 1H), 3.25 (td, J=12.4, 3.3 Hz, 1H), 1.53 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 8.00-8.06 (m, 2H), 7.77 (s, 1H), 7.50 (br. s., 1H), 7.48 (d, J=4.3 Hz, 3H), 7.30 (s, 1H), 6.61 (s, 1H), 4.78 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz, 1H), 3.58 (br. s., 1H), 3.40 (quin, J=6.9 Hz, 1H), 3.33 (dd, J=12.9, 3.1 Hz, 1H), 3.17 (td, J=12.4, 3.3 Hz, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.0 (M+H)+.
Compound 111 was synthesized using benzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.53-7.61 (m, 2H), 7.49-7.53 (m, 3H), 7.47 (s, 1H), 6.79 (s, 4H), 6.61 (s, 1H), 4.71-4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.34 (dd, J=13.1, 3.3 Hz, 1H), 3.17 (td, J=12.5, 3.4 Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.29 (d, J=7.3 Hz, 6H). LC-MS: m/z 414.9 (M+H)+.
Compound 113 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.42-7.53 (m, 2H), 7.25 (dd, J=7.5, 1.5 Hz, 1H), 7.02-7.13 (m, 2H), 6.76 (s, 1H), 6.59-6.66 (m, 1H), 3.90 (br. s., 4H), 3.88 (s, 3H), 3.73 (br. s., 4H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 431.0 (M+H)+.
Compound 114 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.42-7.56 (m, 2H), 7.36 (dq, J=7.7, 0.9 Hz, 1H), 7.17-7.27 (m, 2H), 7.09 (dd, J=3.4, 0.9 Hz, 1H), 6.76 (s, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 4.03 (br. s., 4H), 3.83 (dd, J=6.3, 4.0 Hz, 4H), 2.95-3.10 (m, 1H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 419.1 (M+H)+.
Compound 115 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.77-7.80 (m, 1H), 7.45-7.53 (m, 2H), 7.36 (dt, J=7.7, 1.2 Hz, 1H), 7.17-7.28 (m, 2H), 6.77 (s, 1H), 6.62 (dd, J=1.9, 0.6 Hz, 1H), 3.92 (br. s., 4H), 3.77 (br. s., 4H), 2.92-3.10 (m, 1H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 419.0 (M+H)+.
Compound 116 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.75 (d, J=7.0 Hz, 1H), 7.40-7.63 (m, 3H), 7.36 (d, J=7.8 Hz, 1H), 7.17-7.28 (m, 3H), 6.77 (s, 1H), 3.94 (br. s., 4H), 3.79 (br. s., 4H), 3.67 (s, 1H), 3.02-3.13 (m, 1H), 1.32 (d, J=6.8 Hz, 6H). LC-MS: m/z 468.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.48-7.58 (m, 5H), 7.33-7.39 (m, 3H), 7.30 (d, J=1.5 Hz, 1H), 7.25-7.28 (m, 1H), 6.75 (s, 1H), 4.71 (s, 1H), 4.27 (br. s., 1H), 4.09-4.20 (m, 2H), 3.80 (br. s., 2H), 3.52 (s, 1H), 3.19-3.26 (s, 1H), 3.06-3.15 (m, 1H), 2.98 (dt, J=13.7, 6.8 Hz, 1H), 1.40 (s, 3H), 1.30 (d, J=4.5 Hz, 19H). LC-MS: m/z 439.2 (M+H)+.
Compound 127 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.44-7.58 (m, 2H), 7.31-7.40 (m, 1H), 7.14-7.27 (m, 2H), 7.07 (d, J=3.5 Hz, 1H), 6.74 (s, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 4.92 (br. s., 1H), 4.52 (d, J=13.6 Hz, 1H), 4.34 (d, J=10.5 Hz, 1H), 4.24 (dt, J=13.1, 2.1 Hz, 1H), 3.62 (br. s., 1H), 3.45 (dd, J=13.3, 3.8 Hz, 1H), 3.28 (td, J=12.4, 3.4 Hz, 1H), 3.01 (dt, J=13.6, 6.9 Hz, 1H), 1.44-1.54 (m, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 433.0 (M+H)+.
Compound 128 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.73-7.81 (m, 1H), 7.44-7.56 (m, 2H), 7.35 (dt, J=8.0, 1.1 Hz, 1H), 7.12-7.27 (m, 2H), 6.75 (s, 1H), 6.61 (dd, J=1.8, 0.8 Hz, 1H), 4.77 (br. s., 1H), 4.31 (d, J=12.0 Hz, 2H), 4.23 (d, J=13.1 Hz, 1H), 3.57 (br. s., 1H), 3.36 (d, J=10.0 Hz, 1H), 3.19 (td, J=12.4, 3.5 Hz, 1H), 3.01 (dt, J=13.5, 6.9 Hz, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 433.1 (M+H)+.
Compound 129 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 8.85 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.40-7.54 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.15-7.28 (m, 4H), 6.74 (s, 1H), 4.84 (br. s., 1H), 4.28 (t, J=15.3 Hz, 3H), 3.59 (d, J=11.8 Hz, 1H), 3.41 (d, J=11.0 Hz, 1H), 3.21 (t, J=10.8 Hz, 1H), 3.00 (dt, J=13.8, 6.9 Hz, 1H), 1.45 (d, J=6.5 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 482.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.55-7.58 (m, 2H), 7.50-7.53 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.60-6.62 (m, 1H), 4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6 Hz, 1H), 3.17 (td, J=12.5, 3.5 Hz, 1H), 3.01 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.52-7.57 (m, 2H), 7.47-7.52 (m, 3H), 7.29-7.41 (m, 4H), 7.24-7.28 (m, 1H), 6.75 (s, 1H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.3 Hz, 0.5H), 4.28 (d, J=13.1 Hz, 1H), 4.06-4.20 (m, 2H), 3.81 (br. s., 2H), 3.70-3.79 (m, 0.5H), 3.54 (t, J=11.3 Hz, 0.5H), 3.18-3.33 (m, 1H), 3.03-3.17 (m, 1H), 2.99 (dt, J=13.8, 6.9 Hz, 1H), 1.33 (br. s., 3H), 1.29 (d, J=7.0 Hz, 6H). LC-MS: m/z 439.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.54-7.59 (m, 2H), 7.49-7.54 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.59-6.63 (m, 1H), 4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.3 Hz, 1H), 3.57 (br. s., 1H), 3.34 (dd, J=13.2, 3.6 Hz, 1H), 3.17 (td, J=12.5, 3.4 Hz, 1H), 3.01 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.53-7.56 (m, 2H), 7.47-7.53 (m, 3H), 7.33-7.39 (m, 2H), 7.29-7.33 (m, 2H), 7.24-7.28 (m, 1H), 6.75 (s, 1H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.3 Hz, 0.5H), 4.28 (d, J=12.8 Hz, 1H), 4.08-4.20 (m, 2H), 3.81 (br. s., 2H), 3.70-3.79 (m, 0.5H), 3.54 (t, J=11.3 Hz, 0.5H), 3.17-3.32 (m, 1H), 3.10 (t, J=12.7 Hz, 1H), 2.98 (dt, J=13.7, 6.8 Hz, 1H), 1.31-1.35 (m, 3H), 1.29 (d, J=7.0 Hz, 6H). LC-MS: m/z 439.1 (M+H)+.
Compound 134 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (DMSO-d6) δ 7.77 (s, 1H), 7.45-7.53 (m, 2H), 7.35 (d, J=8.3 Hz, 1H), 7.17-7.25 (m, 2H), 6.76 (s, 1H), 6.65 (d, J=1.0 Hz, 1H), 4.71 (br. s., 1H), 4.31 (d, J=12.8 Hz, 2H), 3.50-3.69 (m, 1H), 3.27 (dd, J=13.2, 4.4 Hz, 2H), 3.01 (quin, J=7.0 Hz, 1H), 1.56 (d, J=7.0 Hz, 6H), 1.32 (s, 3H), 1.30 (s, 3H). LC-MS: m/z 447.1 (M+H)+.
Compound 135 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.43-7.55 (m, 1H), 7.12-7.40 (m, 8H), 6.74 (s, 1H), 4.90 (br. s., 1H), 4.26 (br. s., 3H), 3.82 (s, 2H), 3.14 (br. s., 2H), 3.00 (dt, J=13.8, 6.9 Hz, 1H), 1.44 (d, J=6.8 Hz, 6H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 471.1 (M+H)+.
Compound 136 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.45-7.55 (m, 2H), 7.32-7.38 (m, 1H), 7.15-7.28 (m, 2H), 7.08 (d, J=3.5 Hz, 1H), 6.74 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.90 (br. s., 2H), 4.34 (d, J=13.1 Hz, 2H), 3.33 (dd, J=13.1, 4.5 Hz, 2H), 2.93-3.08 (m, 1H), 1.59 (d, J=7.0 Hz, 6H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 447.0 (M+H)+.
Compound 137 was synthesized using benzaldehyde and 1-cyclohexylethanone as starting materials.
1H NMR (CHLOROFORM-d) δ 7.46-7.61 (m, 6H), 7.08 (dd, J=3.4, 0.9 Hz, 1H), 6.78 (s, 1H), 6.53 (dd, J=3.4, 1.9 Hz, 1H), 4.03 (br. s., 4H), 3.76-3.86 (m, 4H), 2.66 (tt, J=11.6, 3.3 Hz, 1H), 1.92-2.00 (m, 2H), 1.83-1.91 (m, 2H), 1.74-1.82 (m, 1H), 1.55 (qd, J=12.3, 2.8 Hz, 2H), 1.41 (qt, J=12.6, 3.1 Hz, 2H), 1.25-1.35 (m, 1H). LC-MS: m/z 441.0 (M+H)+.
Compound 138 was synthesized using benzaldehyde and 1-cyclohexylethanone as starting materials.
1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.43-7.61 (m, 6H), 6.77 (s, 1H), 6.61 (s, 1H), 4.76 (br. s., 1H), 4.29 (d, J=12.3 Hz, 2H), 4.20 (d, J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.33 (dd, J=13.2, 3.1 Hz, 1H), 3.16 (td, J=12.5, 3.1 Hz, 1H), 2.56-2.72 (m, 1H), 1.95 (d, J=12.5 Hz, 2H), 1.87 (d, J=12.8 Hz, 2H), 1.78 (d, J=12.8 Hz, 1H), 1.49-1.60 (m, 2H), 1.46 (d, J=6.5 Hz, 3H), 1.35-1.44 (m, 2H), 1.25-1.34 (m, 1H). LC-MS: m/z 455.1 (M+H)+.
Compound 142 was synthesized using benzaldehyde and 1-cyclohexylethanone as starting materials.
1H NMR (CHLOROFORM-d) δ 7.77 (s, 1H), 7.54-7.58 (m, 2H), 7.49-7.53 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.65 (d, J=2.0 Hz, 1H), 4.73 (br. s., 2H), 4.27 (d, J=13.1 Hz, 2H), 3.25 (dd, J=13.1, 4.5 Hz, 2H), 2.66 (tt, J=11.6, 3.4 Hz, 1H), 1.95 (d, J=12.5 Hz, 2H), 1.84-1.92 (m, 2H), 1.78 (d, J=12.5 Hz, 1H), 1.57 (d, J=7.0 Hz, 6H), 1.49-1.54 (m, 2H), 1.38-1.47 (m, 2H), 1.31-1.37 (m, 1H). LC-MS: m/z 469.1 (M+H)+.
Compound 146 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.42-7.48 (m, 1H), 7.28-7.40 (m, 5H), 7.23 (dd, J=7.5, 1.8 Hz, 1H), 7.01-7.10 (m, 2H), 6.73 (s, 1H), 3.83-3.90 (m, 5H), 3.82 (s, 2H), 3.62-3.70 (m, 4H), 3.49-3.56 (m, 2H), 2.91-3.03 (m, 1H), 1.29 (d, J=6.8 Hz, 6H). LC-MS: m/z 455.2 (M+H)+.
Compound 147 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.52 (dd, J=1.8, 0.8 Hz, 1H), 7.41-7.48 (m, 1H), 7.25 (dd, J=7.5, 1.8 Hz, 1H), 7.00-7.16 (m, 3H), 6.73 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.91 (br. s., 1H), 4.51 (d, J=12.3 Hz, 1H), 4.32 (d, J=12.5 Hz, 1H), 4.22 (dt, J=13.2, 2.0 Hz, 1H), 3.88 (s, 3H), 3.62 (br. s., 1H), 3.39 (dd, J=13.2, 3.6 Hz, 1H), 3.22 (td, J=12.4, 3.5 Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.49 (d, J=6.8 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 455.1 (M+H)+.
Compound 148 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.76 (dd, J=1.5, 0.8 Hz, 1H), 7.40-7.51 (m, 2H), 7.22-7.28 (m, 1H), 7.01-7.11 (m, 2H), 6.70-6.76 (m, 1H), 6.61 (dd, J=1.8, 0.8 Hz, 1H), 4.75 (br. s., 1H), 4.16-4.45 (m, 3H), 3.88 (s, 3H), 3.55 (br. s., 1H), 3.31 (dd, J=12.9, 3.4 Hz, 1H), 3.14 (td, J=12.5, 3.4 Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 445.2 (M+H)+.
Compound 149 was synthesized using 3-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.41-7.49 (m, 1H), 7.29-7.40 (m, 4H), 7.20-7.28 (m, 2H), 7.01-7.09 (m, 2H), 6.71 (s, 1H), 4.97 (br. s., 1H), 4.60 (d, J=13.3 Hz, 1H), 4.25 (br. s., 1H), 4.16 (d, J=13.3 Hz, 1H), 3.87 (s, 3H), 3.64-3.81 (m, 2H), 3.53 (t, J=11.4 Hz, 1H), 3.14-3.29 (m, 1H), 2.85-3.14 (m, 2H), 1.62 (s, 3H), 1.29 (s, 6H). LC-MS: m/z 469.1 (M+H)+.
Compound 151 was synthesized using 3-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.76 (dd, J=1.5, 0.8 Hz, 1H), 7.38-7.50 (m, 2H), 7.00-7.17 (m, 3H), 6.76-6.81 (m, 1H), 6.61 (dd, J=1.9, 0.9 Hz, 1H), 4.76 (br. s., 1H), 4.29 (d, J=12.8 Hz, 2H), 4.21 (d, J=13.1 Hz, 1H), 3.84-3.92 (m, 3H), 3.56 (br. s., 1H), 3.33 (dd, J=13.2, 3.6 Hz, 1H), 3.17 (td, J=12.5, 3.4 Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.0 Hz, 6H). LC-MS: m/z 445.1 (M+H)+.
Compound 152 was synthesized using 3-hydroxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.74-7.81 (m, 1H), 7.41-7.51 (m, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.97 (dd, J=8.2, 2.4 Hz, 1H), 6.79 (s, 1H), 6.57-6.64 (m, 1H), 4.79 (br. s., 1H), 4.15-4.44 (m, 3H), 3.59 (br. s., 1H), 3.34 (d, J=10.5 Hz, 1H), 3.17 (td, J=12.5, 3.1 Hz, 1H), 2.93-3.04 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.27-1.31 (m, 6H).
LC-MS: m/z 431.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61 (br. s., 1H), 7.50-7.54 (m, 2H), 7.46-7.50 (m, 3H), 7.37-7.43 (m, 3H), 7.34 (t, J=7.7 Hz, 2H), 7.22-7.27 (m, 1H), 6.67 (s, 1H), 6.52 (br. s., 1H), 5.75 (br. s., 1H), 4.57 (br. s., 2H), 4.29 (d, J=11.5 Hz, 1H), 4.00 (d, J=11.0 Hz, 1H), 3.60-3.74 (m, 1H), 3.55 (d, J=10.5 Hz, 1H), 2.94 (dt, J=13.6, 6.8 Hz, 1H), 1.25-1.27 (m, 3H), 1.23 (d, J=7.0 Hz, 3H). LC-MS: m/z 477.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.51-7.55 (m, 2H), 7.46-7.50 (m, 4H), 7.45 (d, J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.20-7.25 (m, 1H), 6.92-7.07 (m, 1H), 6.68 (s, 1H), 6.45 (br. s., 1H), 5.95 (t, J=4.5 Hz, 1H), 4.63 (s, 1H), 4.66 (s, 1H), 4.33 (d, J=11.0 Hz, 1H), 4.06 (dd, J=13.6, 4.0 Hz, 1H), 3.69 (br. s., 1H), 3.56-3.65 (m, 1H), 2.97 (dt, J=13.7, 6.8 Hz, 1H), 1.24-1.28 (m, 6H). LC-MS: m/z 477.1 (M+H)+.
Compound 156 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.77 (dd, J=1.5, 1.0 Hz, 1H), 7.43-7.53 (m, 2H), 7.35 (dq, J=7.7, 0.9 Hz, 1H), 7.12-7.28 (m, 2H), 6.67-6.80 (m, 1H), 6.61 (dd, J=1.9, 0.9 Hz, 1H), 4.76 (br. s., 1H), 4.17-4.45 (m, 3H), 3.56 (br. s., 1H), 3.36 (dd, J=13.1, 3.5 Hz, 1H), 3.18 (td, J=12.5, 3.5 Hz, 1H), 2.95-3.07 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.29-1.32 (m, 6H). LC-MS: m/z 433.1 (M+H)+.
Compound 157 was synthesized using 2-hydroxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 8.01 (dd, J=8.2, 1.4 Hz, 1H), 7.73-7.77 (m, 1H), 7.50-7.60 (m, 1H), 7.46 (t, J=1.6 Hz, 1H), 7.31-7.37 (m, 2H), 7.21 (s, 1H), 6.60 (dd, J=1.6, 0.6 Hz, 1H), 4.71 (br. s., 1H), 4.25 (br. s., 1H), 4.07 (d, J=13.3 Hz, 1H), 3.98 (d, J=13.8 Hz, 1H), 3.71 (br. s., 1H), 3.45-3.56 (m, 1H), 3.15-3.26 (m, 1H), 3.06 (dt, J=13.7, 6.8 Hz, 1H), 1.32-1.37 (m, 9H). LC-MS: m/z 432.2 (M+H)+.
Compound 158 was synthesized using 2-methylbenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (CHLOROFORM-d) δ 7.72-7.79 (m, 1H), 7.47 (t, J=1.6 Hz, 1H), 7.29-7.40 (m, 3H), 7.19 (d, J=6.8 Hz, 1H), 6.65 (s, 1H), 6.60 (dd, J=1.9, 0.9 Hz, 1H), 4.75 (br. s., 1H), 4.17-4.46 (m, 3H), 3.42-3.67 (m, 1H), 3.34 (dd, J=13.1, 3.5 Hz, 1H), 3.16 (td, J=12.5, 3.5 Hz, 1H), 2.92-3.03 (m, 1H), 2.24 (s, 3H), 1.45 (d, J=6.3 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 429.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.69 (br. s., 1H), 7.64 (s, 1H), 7.45 (br. s., 2H), 7.36-7.44 (m, 4H), 7.31 (br. s., 2H), 7.16-7.26 (m, 3H), 6.57 (br. s., 1H), 5.37 (br. s., 1H), 4.15 (d, J=9.8 Hz, 2H), 3.96 (d, J=8.8 Hz, 4H), 2.98-3.12 (m, 1H), 1.13 (d, J=6.8 Hz, 6H). LC-MS: m/z 477.2 (M+H)+.
Compound 162 was synthesized from (R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6-isopropylnicotinonitrile (Compound 157) by reaction with acetyl chloride.
1H NMR (METHANOL-d4) δ 7.76 (s, 1H), 7.39-7.58 (m, 3H), 7.31 (t, J=1.9 Hz, 1H), 7.24 (dd, J=7.7, 1.9 Hz, 1H), 6.78 (s, 1H), 6.61 (d, J=1.3 Hz, 1H), 4.76 (br. s., 1H), 4.17-4.44 (m, 3H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.4 Hz, 1H), 3.17 (td, J=12.5, 3.5 Hz, 1H), 2.93-3.06 (m, 1H), 2.27-2.43 (m, 3H), 1.46 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.0 Hz, 6H). LC-MS: m/z 473.1 (M+H)+.
Compound 163 was synthesized from (R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6-isopropylnicotinonitrile (Compound 157) by treatment with NaH/DMF followed by ethyl bromide quench.
1H NMR (METHANOL-d4) δ 7.76 (s, 1H), 7.37-7.51 (m, 2H), 6.98-7.16 (m, 3H), 6.79 (s, 1H), 6.57-6.64 (m, 1H), 4.76 (br. s., 1H), 4.17-4.45 (m, 3H), 4.12 (q, J=7.0 Hz, 2H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6 Hz, 1H), 3.17 (td, J=12.4, 3.3 Hz, 1H), 3.00 (quin, J=6.9 Hz, 1H), 1.47 (dt, J=6.8, 3.5 Hz, 6H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 459.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.52 (s, 1H), 7.36-7.48 (m, 5H), 7.31 (br. s., 2H), 7.22 (d, J=6.5 Hz, 3H), 7.07 (d, J=3.0 Hz, 1H), 6.52 (br. s., 1H), 5.37-5.59 (br. s., 1H), 4.17 (br. s., 3H), 3.98 (br. s., 2H), 3.92 (br. s., 1H), 3.00-3.12 (m, 1H), 1.13 (d, J=6.5 Hz, 3H), 0.79 (br. s., 3H). LC-MS: m/z 477.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 9.00 (br. s., 1H), 7.71 (d, J=6.3 Hz, 1H), 7.64 (s, 1H), 7.42 (d, J=7.3 Hz, 6H), 7.24-7.34 (m, 4H), 7.22 (d, J=6.3 Hz, 4H), 5.53 (br. s., 1H), 4.13-4.35 (m, 2H), 4.01 (br. s., 2H), 3.76-3.96 (m, 2H), 3.00-3.13 (m, 1H), 1.14 (d, J=6.5 Hz, 3H), 0.80 (d, J=6.5 Hz, 3H). LC-MS: m/z 526.1 (M+H)+.
Compound 244 was prepared according to Scheme 8.
To a solution of (R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (6; Example 1; 1 g, 3.10 mmol) and triethylamine (375 mg, 3.72 mmol) in 20 mL THF was added 1-(chloromethyl)-4-methoxybenzene (485 mg, 3.10 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 4 hrs before warmed up to room temperature and quenched by adding 20 mL of water. Solvent was removed under reduced pressure and the residue was extracted with EtOAc (3×20 mL). The combined organic layer was then washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Flash column chromatography separation (20% EtOAc/petroleum ether) then afforded 1.3 g of 58 as thick brown oil. MS (ES) M+H expected 443.1. found 443.2
To a solution of (R)-5-bromo-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)-nicotinonitrile (58; 1 g, 2.18 mmol) and 4-fluorophenylboronic acid (610 mg, 4.36 mmol) in 5 mL of DMF was added Pd(PPh3)4 (340 mg 0.218 mmol) and K2CO3 (360 mg, 2.62 mmol) under nitrogen protection. The reaction was subjected to microwave reaction at 150° C. for 1 hour. After dilution with 20 mL of water, the mixture was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Flash column chromatography separation (20% EtOAc/petroleum ether) then afforded 600 mg of 59 as thick brown oil. MS (ES) M+H expected 459.3. found 459.2.
To a solution of (R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methyl-piperazin-1-yl)nicotinonitrile (600 mg, 1.31 mmol) in 20 mL of ethanol was added 20 mL 50% aq. NaOH solution. The reaction mixture was heated to 120° C. overnight, and then acidified with 2N aq. HCl to pH<6. Ethanol was removed under reduced pressure and the residue was washed with water several times and filtered. After air-drying, 500 mg of crude title compound was obtained as a yellowish solid. MS (ES) M+H expected 478.2. found 478.2.
To a 25 mL of round-bottom flask was charged with 10 mL of methanol. After cooling at 0° C., 1 mL of thionyl chloride was added dropwise and the solution was stirred at room temperature for 30 min, before adding (R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)nicotinic acid (500 mg, 1.05 mmol) slowly. The resulting mixture was then heated to reflux temperature for 2 hrs. After removing the volatile under reduced pressure, 500 mg of crude title compound was obtained and used without further purification. MS (ES) M+H expected 492.3. found 492.2.
(R)-methyl-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)nicotinate (61; 500 mg, 1.02 mmol) was dissolved in 15 mL of 2,2,2-trifluoroacetic acid. The mixture was heated to reflux overnight. After removal of excess of TFA under reduced pressure, the residue was re-dissolved in methylene chloride and washed with satd. NaHCO3, brine. The organic layer was then dried over anhy. Na2SO4, and concentrated in vacuo. 300 mg of title compound was obtained as yellowish oil and used subsequently without further purification. MS (ES) M+H expected 372.2. found 372.2.
1H NMR (CHLOROFORM-d) δ 7.84 (s, 1H), 7.20-7.25 (m, 2H), 7.06-7.15 (m, 2H), 4.86 (br. s., 0.5H), 4.43 (d, J=12.5 Hz, 0.5H), 4.21 (d, J=6.0 Hz, 0.5H), 3.92 (d, J=13.1 Hz, 0.5H), 3.87 (s, 3H), 3.81 (d, J=16.3 Hz, 1H), 3.74 (t, J=6.7 Hz, 3H), 3.64 (br. s., 1H), 3.37 (s, 3H), 3.18-3.34 (m, 1H), 2.96-3.15 (m, 2H), 2.64-2.80 (m, 1H), 2.60 (br. s., 1H), 1.34-1.40 (m, 1.5H), 1.29-1.32 (m, 1.5H), 1.17 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H). LC-MS: m/z 458.2 (M+H)+.
Assays were conducted in a volume of 76 μl assay buffer (150 mM NaCl, 10 mM MgCl2, 20 mM Tris pH 7.5, 0.03% bovine serum albumin) as follows in a standard 384-well plate: To 25 ul of substrate mix (8 uM NADPH, 2 mM aKG), 1 μl of test compound was added in DMSO. The plate was centrifuged briefly, and then 25 μl of enzyme mix was added (0.2 μg/ml IDH1 R132H) followed by a brief centrifugation and shake at 100 RPM. The reaction was incubated for 50 minutes at room temperature, then 25 μl of detection mix (30 μM resazurin, 36 μg/ml) was added and the mixture further incubated for 5 minutes at room temperature. The conversion of resazurin to resorufin was detected by fluorescent spectroscopy at Ex544 Em590 c/o 590.
Certain of the compounds of Formula I set forth in Tables 1 and 5 were tested in this assay and the results set forth below in Table 3. As used in Table 3, “A” refers to an inhibitory activity against IDH1 R132H with an IC50≦1.0 μM; “B” refers to an inhibitory activity against IDH1 R132H with an IC50 greater than 1 μM and ≦5 μM; “C” refers to an inhibitory activity against IDH1 R132H with an IC50 greater than 5 μM and ≦15 μM.
Certain of the compounds of Formula I set forth in Table 5 were tested in this assay and the assay in Example 13 and the results set forth below in Table 4. As used in Table 4, “A1” refers to an inhibitory activity against IDH1 R132H with an IC50≦0.5 μM or an IC50 for inhibition of 2-HG production ≦0.5 μM; “B1” refers to an inhibitory activity against IDH1 R132H with an IC50 greater than 0.5 μM and ≦1 μM or an IC50 for inhibition of 2-HG production greater than 0.5 μM and ≦1 μM; “C1” refers to an inhibitory activity against IDH1 R132H with an IC50 greater than 1 μM and ≦10 μM or an IC50 for inhibition of 2-HG production greater than 1 μM and ≦10 μM; and “D1” refers to an inhibitory activity against IDH1 R132H with an IC50 greater than 10 μM or an IC50 for inhibition of 2-HG production greater than 10 μM.
In some embodiments, the invention provides a compound selected from any one of compound numbers 182, 187, 191, 207, 212, 219, 222, 223, 224, 225, 226, 227, 229, 234, 235, 236, 241, 242, 243, 246, 248, 249, 250, 251, 252, 253, 255, 256, 257, 258, 259, 260, 261, and 262.
In some embodiments, the invention provides a compound selected from any one of compound numbers 263, 265, 266, 269, 271, 275, 276, 277, 280, 283, 285, 286, 287, 288, 289, 290, 292, 293, 294, 295, 296, 297, 299, 301, 302, 303, 304, 307, 308, 309, 312, 313, 315, 318, 319, 320, 321, 322, 323, 325, 326, 328, 330, 331, 333, 335, 338, 340, 341, 342, 343, 345, 346, 347, 348, 350, 351, 352, 353, 356, 358, 359, 360, 361, 362, 363, 364, 372, 373, 374, 376, 377, 378, 380, 381, 382, 383, 384, 386, 387, 388, 389, 390, 391, 392, 393, 396, 397, 398, 402, 403, 405, 406, 407, 408, 409, 410, 411, 412, 415, 417, 418, 419, 420, 424, 427, 428, 429, 433, 434, 436, 438, 439, 440, 442, 443, 444, 445, 446, 448, 451, 452, 453, 454, 456, 457, 458, 459, 460, 463, 466, 468, 469, 470, 471, 472, 473, 474, 475, 476, 480, 481, 482, 483, 485, 487, 488, 491, 494, 497, 498, 500, 503, 505, 508, 511, 512, 514, 516, 517, 518, 521, 524, 525, 527, 528, 529, 530, 531, 532, 534, 535, 536, 537, 538, 539, 540, 541, 542, 544, 546, 547, 549, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 568, 569, 570, 571, 572, 573, 574, 575, 577, 578, 579, 580, 581, 582, 585, 586, 587, 588, 589, 590, 591, 592, 594, 595, 596, 597, 598, 599, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 624, 625, 626, 627, 628, 629, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 773, 774, 775, 776, 777, 778, 780, 781, 782, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 811, 812, 813, 815, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, and 830.
Cells (e.g., HT1080 or U87MG) and are grown in T125 flasks in DMEM containing 10% FBS, 1× penicillin/streptomycin and 500 ug/mL G418. They are harvested by trypsin and seeded into 96 well white bottom plates at a density of 5000 cell/well in 100 ul/well in DMEM with 10% FBS. No cells are plates in columns 1 and 12. Cells are incubated overnight at 37° C. in 5% CO2. The next day compounds are made up at 2× concentration and 100 ul are added to each cell well. The final concentration of DMSO is 0.2% and the DMSO control wells are plated in row G. The plates are then placed in the incubator for 48 hours. At 48 hours, 100 μl of media is removed from each well and analyzed by LC-MS for 2-HG concentrations. The cell plate is placed back in the incubator for another 24 hours. At 72 hours post compound addition, 10 mL/plate of Promega Cell Titer Glo reagent is thawed and mixed. The cell plate is removed from the incubator and allowed to equilibrate to room temperature. Then 100 ul of reagent is added to each well of media. The cell plate is then placed on an orbital shaker for 10 minutes and then allowed to sit at room temperature for 20 minutes. The plate is then read for luminescence with an integration time of 500 ms.
The IC50 for inhibition of 2-HG production (concentration of test compound to reduce 2HG production by 50% compared to control) in these two cell lines for various compounds of formula I is set forth in Table 4 above.
General Procedure 1:
To a solution of 1-cyclopropylethanone (100 g, 1.2 mol) in anhydrous DMF (1300 mL) was added DMFDMA (300 g, 2.5 mol). The resulting mixture was stirred at 100° C. overnight. The solvent was removed in vacuum to give crude 2 (110 g) as yellow solid. 1H NMR (CHLOROFORM-d) δ 7.56 (d, J=12.8 Hz, 1H), 5.20 (d, J=12.5 Hz, 1H), 2.78-3.08 (m, 6H), 1.79 (tt, J=7.9, 4.5 Hz, 1H), 0.94-1.04 (m, 2H), 0.67-0.80 (m, 2H).
To a mixture of 1-cyclopropyl-3-dimethylamino-propenone (315 g, 2.3 mol) and cyanoacetamide (270 g, 2.3 mol) in a buffer solution of 47.4 mL of acetic acid and 1485 mL of water was added piperidine to adjust to pH 9. The mixture was then heated at reflux for 2 hours, cooled and acidified by 6N HCl to pH 5 below 25 degree. The yellow precipitate was filtered, washed with water and dried to give 3 as a white solid (561 g). MS (ES) M+H expected 161.1. found 161.0. 1H NMR (CHLOROFORM-d) δ 13.60 (br. s., 1H), 7.77 (d, J=7.8 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 1.96-2.12 (m, 1H), 1.29-1.36 (m, 2H), 1.04-1.11 (m, 2H).
A mixture of 6-cyclopropyl-2-hydroxynicotinonitrile (561 g, 3.6 mol) and NBS (624 g, 5.4 mol) in DCE (4500 mL) was heated at reflux for 3 hrs. The mixture was cooled to room temperature and the precipitate was filtered, washed with water and dried to give crude 4 (473 g) as a white solid. MS (ES) M+H expected 239.0. found 238.9. 1H NMR (CHLOROFORM-d) δ 8.49-8.72 (br. s., 1H), 7.93 (s, 1H), 2.23-2.34 (m, 1H), 1.36-1.42 (m, 2H), 1.29-1.36 (m, 2H).
To a 1 L flask were added 5-bromo-4-cyclopropyl-2-hydroxybenzonitrile (47.6 g, 0.2 mol), pyridine (32 g, 0.4 mol) and Cat. DMAP (500 mg) in DCM (300 mL), and the mixture was cooled to 0° C., and trifluoromethanesulfonic anhydride (59 g, 0.21 mol) in DCM (100 mL) was added dropwise. After addition, the mixture was stirred for another 1 h. TLC (PE:EtOAc=10:1) showed conversion of starting material to product. After reaction, diluted with DCM (300 mL), and washed with 1N HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo afforded the title compound (70 g) as a yellow solid. 1H NMR (CHLOROFORM-d) δ 8.14-8.19 (m, 1H), 2.55-2.66 (m, 1H), 1.30 (dt, J=7.8, 3.1 Hz, 2H), 1.21-1.27 (m, 2H).
A mixture of above triflate 5 (1.68 g, 4.6 mmol), (R)-2-methylpiperazine (790 mg, 6.9 mmol), and triethylamine (1.9 mL, 13.8 mmol) suspended in 5 mL of MeCN was heated at 70° C. for 2 h. After the mixture was concentrated under reduced pressure, the residue was extracted between ethyl acetate and water. The combined organic layer was then washed with aq. NaHCO3, brine, dried over anhy. Na2SO4 and concentrated in vacuo to give 1.26 g of crude title compound. MS (ES) M+H expected 321.1. found 321.2. 1H NMR (CHLOROFORM-d) δ 7.78 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, J=12.9, 10.2 Hz, 1H), 2.42-2.52 (m, 1H), 1.16 (d, J=6.3 Hz, 3H), 1.08 (s, 2H), 1.07 (d, J=3.8 Hz, 2H).
(R)-5-bromo-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)nicotinonitrile (6-2) (R′=isopropyl) was synthesized by the same procedure described above except using (R)-2-isopropylpiperazine instead of (R)-2-methylpiperazine. MS (ES) M+H expected 349.1. found 349.2. 1H NMR (CHLOROFORM-d) δ□7.79 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, 1H), 2.12-2.22 (m, 1H), 1.26 (d, 6H), 1.08 (d, 2H), 1.07 (d, 2H).
(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile (6-3) (R′=cyclopropyl) was synthesized by the same procedure described above except using (R)-2-cyclopropylpiperazine (building block 1) instead of (R)-2-methylpiperazine. MS (ES) M+H expected 347.1. found 349.1. 1H NMR (CHLOROFORM-d) δ□7.77 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, 1H), 2.12-2.24 (m, 1H), 1.25 (d, 2H), 1.16 (d, 2H), 1.08 (d, 2H), 1.07 (d, 2H).
To a 25 mL of round-bottom flask was added (R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl) nicotinonitrile (6-1) (1.26 g, 3.9 mmol), 3-methoxypropanoic acid (0.74 mL, 7.8 mmol), HATU (2.98 g, 7.8 mmol), DIPEA (2 mL, 11.76 mmol) and 10 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature overnight until TLC showed the completion of the reaction. Reaction mixture was with satd. NaHCO3 and brine. The combined organic layer was then dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (30% EtOAc/petroleum ether) afforded 1.28 g of title compound as a white solid. MS (ES) M+H expected 407.1. found 407.0. 1H NMR (CHLOROFORM-d) δ□7.78-7.85 (m, 1H), 4.82-4.92 (m, 0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H), 3.75-3.82 (m, 0.5H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 0.5H), 3.36 (s, 3H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).
To a 25 mL of round-bottom flask was added (R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl) nicotinonitrile (6-1) (1 g, 3.2 mmol), cyclopropanecarbonyl chloride (0.4 mL, 3.3 mmol), DIPEA (0.4 mL, 3.4 mmol) and 10 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature overnight until TLC showed the completion of the reaction. Reaction mixture was with Satd. NaHCO3 and brine. The combined organic layer was then dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (10% EtOAc/petroleum ether) afforded 1.1 g of title compound as a white solid. MS (ES) M+H expected 389.1. found 389.0. 1H NMR (CHLOROFORM-d) δ□7.85 (s, 1H), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H), 3.70-3.75 (m, 2H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz, 1.5H), 1.25-1.36 (m, 4H), 1.09 (d, 2H), 1.08 (d, 2H).
To a 25 mL of round-bottom flask was added (R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl) nicotinonitrile (6-1) (2 g, 6.2 mmol), sodium 2□carboxyethanolate (0.70 g, 6.4 mmol), DIPEA (2 mL, 11.5 mmol) and 10 mL of DMF. The resulting reaction mixture was stirred at room temperature for 5 h until TLC showed the completion of the reaction. Reaction mixture was washed with water and brine. The combined organic layer was then dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (50% EtOAc/petroleum ether) afforded 1.2 g of title compound as a white solid. MS (ES) M+H expected 393.1. found 393.1. 1H NMR (CHLOROFORM-d) δ 7.85 (m, 1H), 4.88-4.97 (m, 0.5H), 4.75 (d, J=13.6 Hz, 0.5H), 4.29-4.48 (m, 2H), 4.11-4.20 (m, 1H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 2H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d, J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).
(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile (7-4) was synthesized by method 1 in step F except using 6-3 as the starting material instead of 6-1. MS (ES) M+H expected 433.1. found 433.3.
(R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile (7-5) was synthesized by method 2 in step F except using 6-3 as the starting material instead of 6-1. MS (ES) M+H expected 415.1. found 415.1.
(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (7-6) was synthesized by method 3 in step F except using 6-3 as the starting material instead of 6-1. MS (ES) M+H expected 419.1. found 419.1. 1H NMR (CHLOROFORM-d) δ 7.85 (m, 1H), 4.87-4.97 (m, 0.5H), 4.77 (d, J=13.6 Hz, 0.5H), 4.29-4.48 (m, 2H), 4.11-4.20 (m, 1H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 2H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 2H), 1.25 (d, 2H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).
(R)-5-bromo-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)nicotinonitrile (7-7) was synthesized by method 1 in step F except using 6-2 as the starting material instead of 6-1. MS (ES) M+H expected 434.1. found 435.1.
(R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)nicotinonitrile (7-8) was synthesized by method 1 in step F except using 6-2 as the starting material instead of 6-1. MS (ES) M+H expected 421.1. found 421.6.
To a solution of (R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl) nicotinonitrile (7-1) (747 mg, 1.8 mmol) in DMF (8 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2 dioxaborolane) (563 mg, 2.2 mmol) and KOAc (538 mg, 5.5 mmol). The resulting mixture was stirred at room temperature for 5 min before addition of PdCl2(dppf).CH2Cl2 (45 mg, 0.03 mmol). After flushing with nitrogen, the reaction mixture was heated at 85° C. for 18 hours. After cooling, the reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was then washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo. Column chromatography (25% EtOAc/petroleum ether) afforded 334 mg of title compound as a white solid. MS (ES) M+H expected 455.3. found 455.2.
1.4 g of (R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl) nicotinonitrile (7-3) (3.3 mmol), 2.12 g of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.34 mmol), 0.7 g of KOAc (7.4 mmol), 154 mg of Xphos (0.32 mmol) and 308 mg of Pd2(dba)3 (0.33 mmol) in 20 mL of dioxane in a round bottom flask was stirred under N2 at 75° C. overnight. Then the mixture was cooled to room temperature. Concentrated, purified by column chromatography (petroleum ether: ethyl acetate from 3:1 to 1:1) to give 670 mg of title compound. MS (ES) M+H expected 441.2. found 441.2.
A mixture of 7-1 (26 mg, 0.06 mmol), thiophen-2-ylboronic acid (14 mg, 0.089 mmol), Pd(PPh3)4 (3 mg, 0.003 mmol), and K2CO3 (16 mg, 0.119 mmol) suspended in 1 mL of DMF was subjected to microwave reaction at 150° C. for 45 min. After the reaction was complete, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to afford 19 mg of title compound as yellowish oil. 1H NMR (CHLOROFORM-d) δ 7.70 (s, 1H), 7.38 (dd, J=3.9, 2.4 Hz, 1H), 7.07-7.14 (m, 2H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.15-4.41 (m, 2.5H), 3.67-3.89 (m, 2.5H), 3.47-3.63 (m, 0.5H), 3.34-3.43 (m, 3H), 3.20-3.33 (m, 1H), 2.99-3.17 (m, 1.5H), 2.63-2.81 (m, 1H), 2.50-2.62 (m, 1H), 2.26-2.36 (m, 1H), 1.37 (d, J=6.3 Hz, 1.5H), 1.27 (d, J=6.8 Hz, 1.5H), 1.10-1.18 (m, 2H), 0.94-1.05 (m, 2H). LC-MS: m/z 411.1 (M+H)+.
To a solution of 8-1 (95 mg, 0.197 mmol), 5-chloro-2-vinylquinazoline (25 mg, 0.131 mmol), Xphos (7 mg, 0.013 mmol), Pd2(dba)3 (6 mg, 0.007 mmol) and K3PO4.H2O (105 mg, 0.393 mmol) was stirred at 100° C. for 16 hours, the mixture was partitioned between EtOAc and water, the organic was washed with water, brine and concentrated to give the crude which was purified by column chromatography to give 25 mg of the product. 1H NMR (CHLOROFORM-d) □δ 9.16 (d, J=3.0 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.5, 7.3 Hz, 1H), 7.66 (s, 1H), 7.45-7.58 (m, 1H), 7.06 (dd, J=17.2, 10.4 Hz, 1H), 6.80 (dd, J=17.3, 1.5 Hz, 1H), 5.80-5.96 (m, 1H), 4.87-5.02 (m, 0.5H), 4.56 (d, J=12.0 Hz, 0.5H), 4.35-4.44 (m, 2.5H), 3.84 (d, J=12.8 Hz, 0.5H), 3.69-3.79 (m, 2H), 3.52-3.65 (m, 0.5H), 3.30-3.43 (m, 4H), 3.05-3.24 (m, 1.5H), 2.65-2.81 (m, 1H), 2.48-2.64 (m, 1H), 1.50-1.59 (m, 1H), 1.30-1.44 (m, 3H), 1.13-1.22 (m, 2H), 0.84-0.89 (m, 2H). LC-MS: m/z 483.2 (M+H)+
General Procedure 2:
To a solution of 6-3 (1 g, 2.24 mmol) in DCM (8 mL) was added (Boc)2O (0.5 g, 2.26 mmol) and Et3N (0.1 mL). The resultant solution was stirred at room temperature for 2 h. The reaction mixture was diluted with water. The organic layer was then washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo to give the title compound as a white solid (1.5 g), which can be used directly for the next step. 1H NMR (CHLOROFORM-d) δ 7.85 (s, 1H), 4.14-4.24 (m, 2H), 3.29-3.34 (m, 1H), 3.12-3.18 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, 1H), 2.12-2.24 (m, 1H), 1.5 (s, 9H), 1.25 (d, 2H), 1.16 (d, 2H), 1.08 (d, 2H), 1.07 (d, 2H).
To a solution of (R)-tert-butyl 4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate (150 mg, 0.33 mmol) in 2 mL of dioxane and 0.5 mL water was added pyridin-3-ylboronic acid (45.6 mg, 0.37 mmol), Pd(dppf)Cl2 (24 mg, 0.033 mmol), CsF (100 mg, 0.66 mmol). The resulting mixture was stirred at 100° C. under N2 atmosphere and microwaved for 1 h. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc/petroleum ether) to afford 100 mg title compound. MS (ES) M+H expected 446.2. found 446.3.
To a solution of (R)-tert-butyl 4-(5-cyano-2-cyclopropyl-[3,3′-bipyridin]-6-yl)-2-cyclopropyl piperazine-1-carboxylate (100 m g, 0.22 mmol) in 3 mL of DCM was added TFA (1 mL). The resulting mixture was stirred at room temperature for 2 h. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and basified with Na2CO3 solution to pH=8. Then the solution was extracted with DCM (10 mL×3). The organic layer was dried and concentrated and purified by Prep-HPLC (5% DCM/MeOH) to get 70 mg title compound. MS (ES) M+H expected 346.2. found 346.2.
To a solution of (R)-2-cyclopropyl-6-(3-cyclopropylpiperazin-1-yl)-[3,3′-bipyridine]-5-carbonitrile (70 mg, 0.2 mmol) in 10 mL DCM was added 3,3,3-trifluoropropanoic acid (31 mg, 0.24 mmol), and triethylamine (1 mL), HOBT (54 mg, 0.4 mmol), EDCI (76.8 mg, 0.4 mmol). The resulting reaction mixture was stirred at r.t. overnight. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by Prep-HPLC (50% EtOAc/petroleum ether) to get 25 mg title compound. 1H NMR (CHLOROFORM-d) δ 8.56-8.77 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 7.65 (s, 1H), 7.44 (dd, J=7.7, 4.9 Hz, 1H), 4.56 (d, J=13.1 Hz, 1H), 4.44 (d, J=13.1 Hz, 1H), 4.12 (br. s., 1H), 3.63-3.86 (m, 2H), 3.32 (d, J=9.3 Hz, 2H), 3.20 (d, J=13.1 Hz, 1H), 3.11 (d, J=11.8 Hz, 1H), 1.99 (td, J=8.0, 3.8 Hz, 1H), 1.11-1.23 (m, 3H), 1.01 (dd, J=7.5, 3.5 Hz, 2H), 0.77-0.95 (m, 2H), 0.66 (br. s., 1H), 0.50 (d, J=5.0 Hz, 2H) LC-MS: m/z 4 456.4 (M+H)+.
General Procedure 3:
To a solution of (R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methyl piperazin-1-yl) nicotinonitrile (50 mg, 0.119 mmol) and 2-chloroacetyl chloride (15 mg, 0.131 mmol) in 2 ml of DCM was added dropwise TEA (24 mg, 0.238 mmol) at 0° C., then the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 20 mg of the product.
1H NMR (CHLOROFORM-d) □δ 8.34 (s, 1H), 7.66-7.75 (m, 1H), 7.62 (s, 1H), 7.50-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.22 (d, J=7.8 Hz, 1H), 4.92 (s, 0.5H), 4.50-4.54 (m, 0.5H), 4.29-4.33 (m, 1H), 4.26 (m, 1H), 4.21-4.25 (m, 0.5H), 3.71-3.84 (m, 2.5H), 3.52-3.57 (m, 0.5H), 3.39 (s, 3H), 3.21-3.32 (m, 1H), 3.13 (d, J=11.3 Hz, 1H), 3.05 (d, J=12.3 Hz, 0.5H), 2.66-2.81 (m, 1H), 2.54-2.65 (m, 1H), 2.07-2.12 (m, 1H), 1.40 (d, J=6.3 Hz, 1H), 1.28-1.31 (m, 2H), 1.14-1.19 (m, 2H), 0.94-1.00 (m, 2H). LC-MS: m/z 496.2 (M+H)+.
To a 25 mL of round-bottom flask was added (R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methyl piperazin-1-yl) nicotinonitrile (50 mg, 0.119 mmol), propionic acid (0.1 mL), HATU (20 mg), DIPEA (0.05 mL) and 10 mL of methylene chloride. The resulting reaction mixture was stirred at room temperature overnight until TLC showed the completion of the reaction. Reaction mixture was with satd. NaHCO3 and brine. The combined organic layer was then dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (30% EtOAc/petroleum ether) afforded 45 mg of title compound as a white solid. 1H NMR (CHLOROFORM-d) □□7.75 (s, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.14-4.35 (m, 2.5H), 3.67-3.85 (m, 2.5H), 3.49-3.62 (m, 0.5H), 3.37 (s, 3H), 3.17-3.32 (m, 1H), 2.93-3.17 (m, 1.5H), 2.63-2.81 (m, 1H), 2.52-2.63 (m, 1H), 2.37-2.49 (m, 2H), 2.05-2.13 (m, 1H), 1.38 (d, J=6.5 Hz, 1H), 1.22-1.31 (m, 5H), 1.14 (dt, J=7.4, 3.6 Hz, 2H), 0.88-1.01 (m, 2H). LC-MS: m/z 476.3 (M+H)+.
General Procedure 4:
To a solution of 4 (2.37 g, 10 mmol) in THF (20 mL) was added TsCl (1.9 g, 11 mmol) and Et3N (1 mL). The reaction was stirred at room temperature for 2 h. The resultant solution was partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated to give the crude which was purified by column chromatography to give 2.6 g of 10. 1H NMR (CHLOROFORM-d) δ 7.86 (s, 1H), 7.35-7.46 (m, 2H), 7.11-7.25 (m, 2H), 1.99-2.17 (m, 1H), 1.21-1.38 (m, 2H), 1.00-1.20 (m, 2H). LC-MS: m/z 393.0 (M+H)+.
A mixture of 10 (2.6 g, 11 mmol), 4-fluorophenylboronic acid (1.4 g, 10 mmol), Pd(PPh3)4 (30 mg), and K2CO3 (16 mg, 0.119 mmol) suspended in 10 mL of DMF was subjected to microwave reaction at 150° C. for 45 min. After the reaction, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to afford 1.9 g of title compound as a yellow solid. LC-MS: m/z 255.0 (M+H)+
3-cyano-6-cyclopropyl-5-(4-fluorophenyl)pyridin-2-yl trifluoromethanesulfonate. 1H NMR (CHLOROFORM-d) δ: 7.87 (s, 1H), 7.32-7.57 (m, 2H), 7.13-7.24 (m, 2H), 1.99-2.17 (m, 1H), 1.21-1.38 (m, 2H), 1.00-1.20 (m, 2H). LC-MS: m/z 387.1 (M+H)+.
The same procedure as General procedure 1, step E except using 12-1 as the starting material instead of 5 and the suitable building blocks described in the “building block” section.
The same procedure as General procedure 1, step G except using the suitable building blocks described in the “building block” section.
General Procedure 5:
To a 25 mL flask was added with 9-1 (1000 mg 2.235 mmol), 2-chloropyridin-4-ylboronic acid (457 mg, 2.906 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), K2CO3 (926 mg, 6.705 mmol), and 4 mL DMF. The resultant mixture was stirred at 150° C. for 5 h. After washing with satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (20% EtOAc/petroleum ether) afforded 640 mg of title compound. 1H NMR (CHLOROFORM-d) δ□□8.48 (d, J=5.0 Hz, 1H), 7.62 (s, 1H), 7.39-7.47 (m, 1H), 7.32 (dd, J=5.1, 1.3 Hz, 1H), 4.59 (d, J=12.9 Hz, 1H), 4.45 (d, J=13.2 Hz, 1H), 4.09 (d, J=13.5 Hz, 1H), 3.50 (d, J=9.1 Hz, 1H), 3.34-3.43 (m, 1H), 3.27 (dd, J=13.2, 3.8 Hz, 1H), 3.11 (td, J=12.5, 3.7 Hz, 1H), 1.94-2.06 (m, 1H), 1.77 (br. s., 2H), 1.50 (s, 9H), 1.34 (br. s., 1H), 1.04 (dd, J=7.9, 3.2 Hz, 2H), 0.56-0.63 (m, 2H), 0.50 (dd, J=8.5, 3.5 Hz, 1H), 0.32-0.42 (m, 1H).
To a flask was added with (R)-tert-butyl 4-(2′-chloro-5-cyano-2-cyclopropyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazine-1-carboxylate (640 mg 1.33 mmol), tributyl(vinyl)stannane (550 mg, 1.73 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), K2CO3 (460 mg, 3.33 mmol), and 4 mL DMF. The resultant mixture was stirred at 150° C. for 5 h. After washing with satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography purification (20% EtOAc/petroleum ether) afforded the compound. LC-MS: m/z 472.2 (M+H)+.
To a flask was added (R)-tert-butyl 4-(5-cyano-2-cyclopropyl-2′-vinyl-3,4′-bipyridin-6-yl)-2-cyclopropylpiperazine-1-carboxylate and 12 mL EtOH/HCl (1M). The resulting reaction mixture was stirred at 0° C. for 30 minutes until TLC showed the completion of the reaction, which was concentrated in vacuo to afford a product as light yellowish solid. 1H NMR (CHLOROFORM-d) δ: 8.65 (d, J=5.0 Hz, 1H), 7.62 (s, 1H), 7.38 (s, 1H), 7.23 (dd, J=5.0, 1.8 Hz, 1H), 6.89 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (dd, J=17.6, 1.2 Hz, 1H), 5.57 (dd, J=10.9, 1.2 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 4.36 (d, J=13.2 Hz, 1H), 3.28 (br. s., 1H), 3.22 (d, J=12.3 Hz, 1H), 3.10 (br. s., 1H), 2.95 (br. s., 1H), 1.96-2.06 (m, 1H), 1.21 (t, J=4.1 Hz, 1H), 0.95-1.07 (m, 3H), 0.92 (br. s., 1H), 0.62 (d, J=7.9 Hz, 2H), 0.40 (d, J=4.7 Hz, 2H).
The same procedure as General procedure 1, step G except using the suitable building blocks described in the “building block” section.
General Procedure 6:
A mixture of CH3ONa (75.65 g, 1.25 mol) and 1-cyclopropylethanone (105.0 g, 1.25 mol) in THF (1000 mL) was stirred at 35° C. for 1 h and followed by addition of ethyl acetate (110.0 g, 1.25 mol) dropwise. After stirring at 50° C. for 4 hrs, the solvent was removed under reduced pressure and the residue was dissolved in H2O 2O (500 mL) and adjusted to pH 3.5 with citric acid. The mixture was extracted by ethyl acetate (500 mL×3). The combined organic layers were concentrated in vacuum to give 1-cyclopropylbutane-1,3-dione (110.0 g, yield 69%) as a yellow oil. 1H NMR (CHLOROFORM-d) δ 0.83-0.95 (m, 2H), 1.06-1.10 (m, 2H), 1.54-1.63 (m, 1H), 2.00 (s, 3H).
A mixture of 1-cyclopropylbutane-1,3-dione (126.0 g, 1.0 mol) and 2-cyanoacetamide (88.0 g, 1.0 mol) and piperidine (60 mL) in EtOH (1500 mL) was stirred at reflux for 4 hrs. The reaction mixture was filtered, washed with PE (200 mL) and dried in vacuum to give 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (90.0 g, 52%) as a white solid. 1H NMR (DMSO-d6) δ 12.36 (br. s., 1H), 5.93 (s, 1H), 2.26 (s, 3H), 1.81-1.91 (m, 1H), 1.06-1.14 (m, 2H), 0.91-0.95 (m, 2H).
A mixture of 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (90.0 g, 0.52 mol) and NBS (100.0 g, 0.57 mol) in DCE (1500 mL) was stirred at reflux temperature for 4 hrs. The reaction mixture was filtered and the residue was washed with DCE (200 mL) and dried in vacuum to give 5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (100.0 g, 76%) as a white solid. MS (ES) M+H expected 253.0. found 253.0. 1H NMR (CHLOROFORM-d) δ 2.68 (s, 3H), 1.79-1.88 (m, 1H), 1.03-1.09 (m, 2H), 0.93-1.01 (m, 2H).
To a solution of 5-bromo-2-hydroxy-6-isopropylnicotinonitrile (40 g, 0.15 mol) in 200 mL of methylene chloride was added DMAP (1.78 g, 14.6 mmol), and triethylamine (25 mL, 175 mmol). The mixture was cooled to 0° C. in an ice-water bath, and trifluoromethanesulfonic anhydride (37 mL, 0.21 mol) was added dropwise by syringe. The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to room temperature and stirred overnight. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc/petroleum ether) to afford 55 g of title compound. 1H NMR (CHLOROFORM-d) □□2.70 (s, 3H), 2.16-2.20 (m, 1H), 1.23-1.25 (m, 2H), 1.19-1.22 (m, 2H)
A mixture of 5-bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yl trifluoromethanesulfonate (50.0 g, 0.13 mol) and (R)-2-methylpiperazine (15.6 g, 0.16 mol) and Et3N (26.0 g, 0.26 mol) in THF (500 mL) was stirred at 80° C. overnight. The resulting mixture concentrated in vacuum to give (R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl) nicotinonitrile (34.8 g, 80%) as a white solid. 1H NMR (CHLOROFORM-d) δ 4.08-4.16 (m, 0.5H), 4.05-4.08 (m, 1H), 4.01-4.04 (m, 0.5H), 2.99-3.08 (m, 1H), 2.97 (d, J=8.8 Hz, 2H), 2.88-2.95 (m, 1H), 2.58-2.65 (m, 1H), 2.55-2.57 (m, 3H), 1.77 (br. s., 1H), 1.12 (s, 1.5H), 1.10 (s, 1.5H), 1.05-1.09 (m, 2H), 1.00-1.05 (m, 2H).
A mixture of (R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methyl piperazin-1-yl)nicotinonitrile (34.8 g, 0.1 mol) and 3-methoxypropanoic acid (16.0 g, 0.15 mol) in pyridine (500 mL) was stirred at 0° C. for 30 min, and followed by addition of POCl3 (28.7 g, 0.19 mol) dropwise. The resulting mixture was stirred at 20° C. for 2 hrs. The reaction mixture was concentrated and purified by chromatography to give (R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile (25.0 g, 59%) as yellow oil. 1H NMR (CHLOROFORM-d) δ 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.22 (br. s., 0.5H), 3.95-4.13 (m, 2H), 3.78 (br. s., 0.5H), 3.74 (t, J=5.9 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H), 3.07-3.24 (m, 1.5H), 2.90-3.06 (m, 1H), 2.65-2.79 (m, 1H), 2.60 (s, 3H), 2.52-2.63 (m, 1H), 2.17-2.21 (m, 1H), 1.37 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=6.3 Hz, 1.5H), 1.09 (s, 2H), 1.05-1.08 (m, 2H).
Step G′ was similar to Step H in general procedure 1.
General Procedure 7:
To a solution of 6-cyclopropyl-2-hydroxynicotinonitrile (20 g, 0.125 mmol) in Ac2O (110 mL) was added dropwise HNO3 (15 mL) at 0° C. 40° C. for 30 mins. After the addition, the reaction mixture was stirred at r.t. for 3 hrs. The mixture was cooled to 0° C. and the solid was collected by filtration. The solid was washed with brine dried under vacuum to give the title compound (15.5 g, 60.4%) as a pale yellow solid. 1H NMR (CHLOROFORM-d) δ10.71 (s, 1H), 8.68 (s, 1H), 3.13 (tt, J=8.6, 5.6 Hz, 1H), 1.57-1.52 (m, 2H), 1.44-1.37 (m, 2H). LC-MS: m/z 205.9 (M+H)+
To a solution of 6-cyclopropyl-2-hydroxy-5-nitronicotinonitrile (7.6 g, 37.7 mmol) in DCM (150 mL) was added DMAP (30.0 mg) and TEA (7.5 g, 74.1 mmol) at r.t. Then Tf2O (15.7 g, 55.6 mmol) was added dropwise to the above solution at −40° C. for 30 min. The reaction mixture was stirred at −40° C. for 2 hs. The mixture was quenched with water at −40° C. The mixture was then extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. The organic phase was filtered and the filtrate was concentrated in vacuum to give the title compound (12.5 g, crude) as a pale yellow solid. LC-MS: m/z 337.5 (M+H)+
To a solution of 3-cyano-6-cyclopropyl-5-nitropyridin-2-yl trifluoromethanesulfonate (10.9 g, 32.3 mmol) and (R)-2-isopropylpiperazine (3.45 g, 27.0 mmol) in CH3CN (100 mL) was added TEA (6.5 g, 64.7 mmol) at r.t. The reaction mixture was heated and stirred at 85° C. for 3 hrs. The mixture was concentrated in vacuo and the residue was extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. The organic phase was filtered and the filtrate was concentrated in vacuum to give the title compound (8.5 g, crude) as a brown solid. LC-MS: m/z 316.6 (M+H)+
To a solution of (R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-nitronicotinonitrile (8.52 g, 26.2 mmol) and Boc anhydride (8.5 g, 39.3 mmol) in DCM (50 mL) was added TEA (3.9 g, 39.3 mmol) at r.t. The reaction mixture was stirred at 30° C. for 3 hrs. The solvent was removed in vacuum and the residue was purified via silica gel column chromatography (DCM:MeOH) to afford the title compound (10.4 g, 95%) as a yellow liquid. 1H NMR (CHLOROFORM-d) δ 8.51 (s, 1H), 4.74 (d, J=13.7 Hz, 1H), 4.55 (d, J=13.1 Hz, 1H), 3.88 (s, 1H), 3.37-3.23 (m, 2H), 3.11 (ddd, J=10.5, 7.7, 5.7 Hz, 2H), 1.86 (tdd, J=13.3, 8.5, 4.9 Hz, 1H), 1.49 (s, 9H), 1.27 (d, J=2.3 Hz, 2H), 1.26-1.17 (m, 4H), 1.01 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H).
To a solution of (R)-tert-butyl 4-(3-cyano-6-cyclopropyl-5-nitropyridin-2-yl)-2-isopropylpiperazine-1-carboxylate (19 g, 45.8 mmol) in EtOH (200 mL) and H2O (100 mL) was added Zinc (30 g, 458 mmol) and NH4Cl (24.5 g, 458 mmol) at r.t. The reaction mixture was stirred at 40° C. overnight. The mixture was filtered through a pad of silica and the filtrate was extracted with EtOAc (100 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. The organic phase was filtered and the filtrate was concentrated in vacuum to give the title compound (13.1 g, 74.3%) as a yellow solid. 1H NMR (CHLOROFORM-d) δ: 7.10 (d, J=2.9 Hz, 1H), 4.02 (t, J=19.0 Hz, 3H), 3.81 (t, J=16.8 Hz, 3H), 3.13 (td, J=12.8, 2.4 Hz, 1H), 2.99-2.86 (m, 2H), 2.25 (tt, J=12.9, 6.5 Hz, 1H), 1.97-1.83 (m, 1H), 1.49 (d, J=2.2 Hz, 9H), 1.13-1.06 (m, 2H), 1.06-1.01 (m, 2H), 0.98 (t, J=9.2 Hz, 3H), 0.87 (t, J=6.6 Hz, 3H).
LC-MS: m/z 386.6 (M+H)+
To a solution of (R)-tert-butyl 4-(5-amino-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-carboxylate (600 mg, 81.6 mmol) and 2-bromo-4-chloropyridine (390.3 mg, 2.03 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (142.7 mg, 0.156 mmol) and Xantphos (135.3 mg, 0.234 mmol) and Cs2CO3 (1.02 g, 3.12 mmol) at r.t. under N2. The resulting mixture was heated and stirred at 115° C. under N2 in microwave for 1 h. The solvent was removed in vacuum and the residue was purified via reverse phase silica gel column chromatography (MeOH: H2O) to afford the title compound (137 mg, 18%) as a pale yellow solid. 1H NMR (CHLOROFORM-d) δ: 8.07 (d, J=5.4 Hz, 1H), 7.72 (d, J=3.3 Hz, 1H), 6.75 (dd, J=5.5, 1.7 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 6.25 (s, 1H), 4.45 (d, J=13.2 Hz, 1H), 4.26 (d, J=9.2 Hz, 1H), 4.21-3.61 (m, 2.5H), 3.11 (dt, J=13.5, 6.8 Hz, 2.5H), 2.22-1.98 (m, 2H), 1.52-1.47 (m, 9H), 1.28 (s, 1H), 1.14 (dt, J=8.1, 4.5 Hz, 1H), 1.08 (dd, J=9.7, 4.7 Hz, 1H), 1.01 (dd, J=10.9, 5.2 Hz, 4H), 0.90 (d, J=6.8 Hz, 3H). LC-MS: m/z 497.6 (M+H)+
To a solution of (R)-tert-butyl 4-(5-((4-chloropyridin-2-yl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-carboxylate (600 mg, 1.21 mmol) in isopropanol (15 mL) and H2O (3 mL) was added Vinyltrifluoroboric acid potassium salt (324.2 mg, 2.42 mmol), Pd(dppf)Cl2 (98.7 mg, 0.121 mmol) and DIPEA (312.2 mg, 2.42 mmol) at r.t. under N2. The reaction mixture was heated and stirred at 125° C. under N2 in microwave for 1.5 h. The solvent was removed in vacuum and the residue was purified via silica gel column chromatography (DCM: MeOH) to afford the title compound (513 mg, 87%) as a yellow solid.
LC-MS: m/z 489.6 (M+H)+
To a solution of (R)-tert-butyl 4-(3-cyano-6-cyclopropyl-5-((4-vinylpyridin-2-yl)amino)pyridin-2-yl)-2-isopropylpiperazine-1-carboxylate (513 mg, 1.05 mmol) in anhydrous DCM (10 mL) was added TFA (5 mL) at r.t. The reaction mixture was stirred at r.t. for 2 hs. The solvent was removed in vacuum and the residue was adjusted to pH>7.0. The residue mixture was extracted with EtOAc (15 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. The organic phase was filtered and the filtrate was concentrated in vacuum to give out the title compound (crude, 406 mg) as a yellow liquid. 1H NMR (CHLOROFORM-d) δ: 7.99 (d, J=6.6 Hz, 1H), 7.72 (s, 1H), 7.04 (dd, J=6.6, 1.3 Hz, 1H), 6.64 (dd, J=17.4, 10.8 Hz, 1H), 6.47 (s, 1H), 6.12 (d, J=17.5 Hz, 1H), 5.81 (d, J=10.8 Hz, 1H), 5.24 (s, 1H), 4.59 (d, J=13.9 Hz, 1H), 4.45 (d, J=14.3 Hz, 1H), 3.63-3.48 (m, 2H), 3.30 (dd, J=14.1, 11.1 Hz, 2H), 3.18 (s, 1H), 2.15-2.01 (m, 2H), 1.28 (d, J=4.8 Hz, 1H), 1.16 (dd, J=10.2, 6.9 Hz, 8H), 1.12-1.09 (m, 1H). LC-MS: m/z 389.5 (M+H)+
To a solution of (R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile (300 mg, 0.77 mmol) in DMF (15 mL) was added sodium 3-hydroxypropanoate (208.8 mg, 1.55 mmol), HATU (442.5 mg, 1.2 mmol) and DIPEA (200 mg, 1.55 mmol) at r.t. The reaction mixture was stirred at r.t. for 3 hs. The solvent was removed in vacuum and the residue was purified via silica gel column chromatography (DCM: MeOH) to afford the title compound (138 mg, 38.8%) as a pale yellow solid. 1H NMR (CHLOROFORM-d) δ: 8.12 (d, J=5.4 Hz, 1H), 7.85 (d, J=5.5 Hz, 1H), 6.84 (d, J=5.4 Hz, 1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 5.91 (d, J=17.5 Hz, 1H), 5.48 (d, J=10.9 Hz, 1H), 4.69 (d, J=10.4 Hz, 0.5H), 4.44 (d, J=12.6 Hz, 1.5H), 4.31-4.23 (m, 1H), 3.93 (s, 2H), 3.75 (d, J=13.5 Hz, 0.5H), 3.51-3.38 (m, 2H), 3.14-2.97 (m, 2H), 2.61 (dt, J=5.7, 4.8 Hz, 2H), 2.36-2.25 (m, 0.5H), 2.19 (ddd, J=12.9, 8.1, 4.9 Hz, 1H), 1.29 (t, J=16.6 Hz, 1H), 1.18-0.97 (m, 7H), 0.95-0.88 (m, 1.5H), 0.86 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 461.6 (M+H)+
General Procedure 8
To a mixture of (R)-tert-butyl 4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate (0.35 g, 1.0 mmol), potassium hydroxide (0.22 g, 4 mmol) in a 50 mL flask was added Pd2(dba)3 (0.092 g, 0.1 mmol), t-Bu-Xphos (0.082 g, 0.2 mol). Then 10 mL 1,4-dioxane and 1.0 mL water was added, the mixture was stirred at 80° C. for 16 hours, cooled and acidified with 2N HCl to pH 6 (temperature held below 25° C.). Then the mixture was extracted with ethyl acetate (15 mL×2), the organic phase was combined and concentrated to give brown oil, which was further purified by silica gel chromatography (PE:EA=3:1), to give 0.16 g of (1) as a white solid (41% yield). LC-MS: m/z 386.0 (M+H)+
A mixture of (R)-tert-butyl 4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropyl piperazine-1-carboxylate (0.16 g, 0.41 mol), 2-chloro-4-iodopyridine (0.15 g, 0.62 mol), 9 mg Cu(I)Br (0.06 mmol) and 12 mg 2,2,6,6-tetramethylheptane-3,5-dione (0.06 mmol), 0.28 g Cs2CO3 was heated under microwave in 4 mL DMSO for 30 min. The mixture was cooled to room temperature and washed with water and purified by silica gel chromatography (DCM:MeOH=20:1) to give 0.10 g of (2) as a yellow solid (52% yield). LC-MS: m/z 486.0 (M+H)+
A mixture of (R)-tert-butyl 4-(5-(2-chloropyridin-4-yloxy)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclo propylpiperazine-1-carboxylate (0.10 g, 0.21 mmol) and TFA (0.35 mL) was stirred in DCM (10 mL) for 2 hrs. The solvent was removed and the residue was basified with NaHCO3 solution and extracted with DCM (10 mL), the organic phase was separated and concentrated to give a yellow solid (3) (0.075 g, 0.19 mmol, crude yield 90%).
LC-MS: m/z 397.1 (M+H)+
A mixture of (R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl) nicotinonitrile (0.35 g, 0.88 mmol), sodium 3-hydroxypropanoate (0.10 g, 0.88 mmol), HATU (0.50 g, 1.32 mmol) and 0.23 g DIEA (1.76 mmol) was stirred in 8 mL DMF for 4 hrs. Then the mixture was quenched by adding 6 mL water and extracted with EA (15 mL×2), the organic phase was combined and concentrated to give a yellow oil, which was further purified by silica gel chromatography (DCM:MeOH=20:1) to give 0.10 g of product as a yellow solid (52% yield). 1H NMR (CHLOROFORM-d) δ: 8.30 (d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H), 6.81 (dt, J=5.6, 2.0 Hz, 2H), 4.70 (s, 1H), 4.41 (d, J=13.0 Hz, 1H), 4.29 (d, J=13.0 Hz, 1H), 4.12 (dd, J=18.6, 7.4 Hz, 1H), 3.93 (s, 2H), 3.84-3.67 (m, 1H), 3.18 (d, J=12.8 Hz, 1H), 3.13-2.99 (m, 1H), 2.61 (s, 2H), 2.32-2.22 (m, 0.5H), 2.02 (t, J=4.6 Hz, 1H), 1.35 (s, 1H), 1.29 (d, J=9.4 Hz, 3H), 1.14 (dd, J=7.4, 3.0 Hz, 2H), 1.04 (dt, J=7.9, 3.1 Hz, 2H), 0.66-0.67 (m, 2H), 0.46-0.51 (m, 2H). LC-MS: m/z 468.1 (M+H)+
A mixture of (R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxy propanoyl) piperazin-1-yl)nicotinonitrile (4) 0.35 g, (0.75 mmol), potassium trifluoro(vinyl)borate (0.15 g, 1.1 mmol), PdCl2dppf (80 mg, 0.075 mmol) and DIEA (0.24 mL, 1.5 mmol) was heated in isopropanol at reflux at 85° C. under nitrogen for 5 hrs. Then mixture was then concentrated under reduced pressure to give a yellow solid which was further purified by silica chromatography (PE/EA/MeOH=150/120/8) to give 0.19 g of product as a white solid (55% yield). 1H NMR (CHLOROFORM-d) δ: 8.47 (d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H), 6.86 (d, J=2.3 Hz, 1H), 6.77 (dd, J=17.4, 10.8 Hz, 1H), 6.66 (dd, J=5.6, 2.4 Hz, 1H), 6.22 (dd, J=17.4, 0.9 Hz, 1H), 5.53 (dd, J=10.8, 0.8 Hz, 1H), 4.68 (d, J=11.7 Hz, 1H), 4.38 (d, J=12.9 Hz, 1H), 4.30-4.22 (m, 1H), 4.15-4.04 (m, 1H), 3.92 (s, 2H), 3.75 (d, J=20.7 Hz, 1H), 3.47 (d, J=21.7 Hz, 1H), 3.25-3.12 (m, 1H), 3.09-2.95 (m, 1H), 2.60 (s, 2H), 2.32-2.22 (m, 0.5H), 2.11-2.05 (m, 1H), 1.37 (d, J=20.5 Hz, 1H), 1.27 (d, J=2.0 Hz, 1H), 1.16-1.10 (m, 2H), 1.01 (ddd, J=10.1, 6.7, 3.3 Hz, 2H), 0.65 (t, J=33.7 Hz, 2H), 0.45-0.48 (m, 2H). LC-MS: m/z 460.1 (M+H)+
General Procedure 9:
Core 7-1 (120 mg, 0.295 mmol) and amine (0.295 mmol) were dissolved in toluene (2 mL). K3PO4 (125.0 mg, 0.590 mmol), Xantphos (cat.) and Pd2(dba)3(cat.) were added to above mixture under N2. The mixture was shaken at 120□ for 16 hrs. The crude product was purified by prep-HPLC.
Step 1:
To a solution of (R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylquinazolin-5-yl)nicotinonitrile (100 g, 0.87 mol) in water (1250 ml), NaHCO3 (175 g, 2.08 mol) was add at room temperature, then a solution of (Boc)2O in THF (1250 mL) was added and the reaction mixture was heated to reflux overnight. Then the resulting mixture was concentrated to remove THF under reduced pressure. EtOAc (1250 mL) was added to the residue and the resulting mixture was cooled to 5° C. and then adjusted to pH 3 with saturated aqueous NaHSO4. The layers were separated and the aqueous was extracted with EtOAc (1000 mL×3). The combined EtOAc layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give (R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (165 g, yield 88%). 1H NMR (MeOD 400 MHz) □□ 3.16-3.14 (d, J=8.8, 1H), 1.11 (s, 9H), 0.73-0.78 (m, 1H), 0.28-0.2 (m, 3H), 0.18-0.15 (m, 1H) 100 ee %.
Step 2:
Isobutyl chloroformate (81.6 g, 0.6 moL) was added over 1 hr to a stirred mixture of (R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (129 g, 0.6 moL) and Et3N (67 g, 0.66 moL) in DCM (1000 mL) at 0° C.-5° C. and the reaction mixture was stirred 1 hr at 0° C.-5° C. In a separate flask, a mixture of glycine methyl ester hydrochloride (82.8 g, 0.66 moL), Et3N (73 g, 0.72 moL) and DCM (1000 mL) was stirred for 1 hr and the mixture was then added to the flask over 2 hrs. After the addition was complete, the mixture was stirred overnight at room temperature for 40 hrs and then washed with water and brine, dried with Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatography to give (R)-methyl 2-(2-(tert-butoxycarbonylamino)-2-cyclopropyl acetamido)acetate (100 g, yield 58%) as white solid. 100 ee %. 1H NMR (DMSO 400 MHz) □δ 8.2-8.16 (t, J=5.6, 1H), 6.66-6.86 (d, J=8.8, 9H), 3.71-3.92 (m, 2H), 3.62 (s, 3H), 3.46-3.51 (t, J=8.4, 1H), 1.36 (s, 9H), 0.97-1.01 (m, 1H), 0.38-0.44 (m, 3H), 0.25-0.28 (m, 1H).
Step 3:
To a solution of (R)-methyl 2-(2-(tert-butoxycarbonylamino)-2-cyclopropylacetamido) acetate (290 g, 1.014 mol) in DCM (1740 mL), TFA (870 mL) was added dropwise at 0° C. The reaction solution was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure to give (R)-methyl 2-(2-amino-2-cyclopropylacetamido) acetate (511 g crude).
Step 4:
To a solution (R)-methyl 2-(2-amino-2-cyclopropylacetamido)acetate (255.5 g crude, 0.507 mol) in MeOH (1250 ml), Et3N (750 ml, 10.78 mol) was added was added dropwise at 0° C. Then the reaction solution was stirred two days at room temperature. The resulting mixture was filtered and the precipitate was washed with MTBE and dried by high vacuum to give (R)-3-cyclopropylpiperazine-2,5-dione (60 g, yield 76.9%). 1H NMR (DMSO 400 MHz) δ 7.98 (s, 1H), 7.74 (s, 1H), 3.68-6.64 (d, J=17.6, 1H), 3.30-3.36 (m, 1H), 2.9-2.93 (dd, J=3.2, 1H), 0.87-0.92 (m, 1H), 0.21-0.27 (m, 3H), 0.18-0.21 (m, 1H).
Step 5:
To a suspension mixture of (R)-3-cyclopropylpiperazine-2,5-dione (30 g, 0.195 mmol) in THF (1000 mL), AlLiH4 (45 g, 1.184 mol) was added in portions over 1.5 hrs at 0° C. Then the reaction mixture was heated to 70° C. overnight. After cooling, water (45 mL) was added dropwise at 0° C. and then a solution of KOH (45 mL, 1%) was added dropwise at 0° C. The resulting mixture was filtered and the residue was washed with EtOAc and MeOH (3:1) and the filtrate was concentrated under reduced pressure to give crude product. Then the crude product was washed with DCM and the filtrate was concentrated under reduced pressure to give (R)-2-cyclopropylpiperazine (18.5 g, yield 75.5%). 99.5 ee %. 1H NMR (MeOD 400 MHz) δ 2.9-2.96 (m, 1H), 2.8-2.88 (m, 1H), 2.7-2.8 (m, 1H), 2.55-2.68 (m, 2H), 2.4-2.5 (q, J=10.4, 1H), 1.65-1.73 (m, 1H), 0.55-0.67 (m, 1H), 0.35-0.45 (m, 2H), 0.05-0.25 (m, 2H).
Step 1:
To a solution of 2-amino-4,4,4-trifluorobutanoic acid (450 m g, 3 mmol) in 5 mL H2O and 5 mL THF was added NaHCO3 (504 mg, 6 mmol), followed by a solution of di-tert-butyl dicarbonate (650 mg, 3 mmol) in THF (3 mL). The resulting mixture was stirred at 80° C. overnight. After removal of THF, poured into water and extracted with methylene chloride. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. 723 mg of 2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid was obtained as a crude product and used in subsequent reaction without further purification. MS (ES) M+H expected 258. found 258. 1H NMR (CHLOROFORM-d) δ □ 5.25 (d, J=7.8 Hz, 1H), 4.40-4.67 (m, 1H), 2.60-2.90 (m, 2H), 1.46 (s, 9H).
Step 2:
To a 25 mL of round-bottom flask was added 2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (723 mg, 2.8 mmol), Et3N (560 mg, 5.6 mmol), isobutyl carbonochloridate (380 g, 2.8 mmol) in 5 mL methylene chloride. The resulting reaction mixture was stirred at 0° C. for 0.5 hours. And methyl 2-aminoacetate (352 mg, 2.8 mmol) was added. The resulting mixture was stirred at room temperature overnight. After washing with Satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. 900 mg of methyl 2-(2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanamido)acetate was obtained as a crude product and used in subsequent reaction without further purification. MS (ES) M+H expected 329.1. found 329.0. 1H NMR (CHLOROFORM-d) δ 7.11 (br. s., 1H), 5.28 (br. s., 1H), 4.44-4.67 (m, 1H), 3.84-4.07 (m, 2H), 3.69-3.83 (s, 3H), 2.72-2.95 (m, 1H), 2.42-2.64 (m, 1H), 1.38-1.50 (m, 9H).
Step 3:
A mixture of methyl 2-(2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanamido)acetate (900 mg, 2.7 mmol) in 5 mL 1,2-dichlorobenzene was heated to 180° C. overnight. The mixture was cooled down and was added MTBE (5 mL). A brown yellowish precipitate was formed. The filter cake was washed with MTBE and air-dried to give 200 mg of 3-(2,2,2-trifluoroethyl)piperazine-2,5-dione. 1H NMR (DMSO-d6) δ 8.28 (d, J=9.3 Hz, 2H), 4.00-4.26 (m, 1H), 3.68-3.87 (m, 2H), 2.66-2.88 (m, 2H).
Step 4:
To a flask was added 3-(2,2,2-trifluoroethyl)piperazine-2,5-dione (200 mg, 1 mmol) in THF (5 mL), and LAH (2.5 mL, 6 mmol) was added dropwise under N2 at 0° C. And the mixture was heated to 65° C. overnight. After reaction, the mixture was cooled down. And 0.23 mL H2O was added followed by 0.2×3 mL 10% NaOH and 0.46 mL H2O, and the mixture was filtered. The cake washed with EtOAc. The organic phase was concentrated to give 2-(2,2,2-trifluoroethyl)piperazine 140 mg, which was used without further purification. 1H NMR (CHLOROFORM-d) δ 2.75-3.02 (m, 7H), 2.52 (dd, J=11.7, 9.9 Hz, 1H), 2.10-2.17 (m, 2H).
To a solution of 1,4-dibenzyl-2-(difluoromethyl)piperazine (synthesized according to Synthetic Communications, 2011, vol. 41, #14, 2031-2035)(80 mg, 0.253 mmol) in 40 mL of EtOH was added Pd(OH)2/C (15 mg). The resulting mixture was hydrogenated under 50 Psi at r.t. for two days. The reaction mixture was filtered, and the filtrate was concentrated to afford 2-(difluoromethyl)piperazine, which was used directly without further purification. LC-MS: m/z 137.1 (M+H)+
Step 1:
To a solution of 1,4-ditosyl-1,4-diazepan-6-ol (synthesized according to Synthesis, 2003, 2, 223-226) (200 mg, 0.47 mmol) in 5 mL of DCM was added DAST (190 mg, 1.18 mmol). The resulting mixture was stirred at r.t. overnight. The reaction mixture was quenched with aq NaHCO3. The aqueous layer was extracted with DCM and the combined organic phases were dried and concentrated. The residue was purified by prep-TLC to afford 6-fluoro-1,4-ditosyl-1,4-diazepane (120 mg). 1H NMR (CHLOROFORM-d) δ 7.66-7.71 (m, 4H), 7.34 (d, J=8.0 Hz, 4H), 5.02-4.92 (m, 1H), 3.60 (dd, J=18.1, 5.3 Hz, 4H), 3.34-3.53 (m, 4H), 2.46 (s, 6H).
Step 2:
A suspension of 6-fluoro-1,4-ditosyl-1,4-diazepane (82 mg, 0.19 mmol) in HOAc—HBr (3 mL, 30 wt %) was heated to 100° C. for 3 mins in a pressure tube using microwave irradiation. The solvent was removed in vacuum and the residue triturated with Et2O, washed with Et2O to give 6-fluoro-1,4-diazepane, which was used directly without further purification. LC-MS: m/z 119.1 (M+H)+
Step 1:
6-fluoro-2-methyl-1,4-ditosyl-1,4-diazepane (120 mg) was obtained from 2-methyl-1,4-ditosyl-1,4-diazepan-6-ol (synthesized according to Synthesis, 2003, 2, 223-226) (200 mg, 0.47 mmol) (200 mg) by the method similar to 6-fluoro-1,4-ditosyl-1,4-diazepane. 1H NMR (CHLOROFORM-d) δ 7.62-7.75 (m, 4H), 7.30-7.37 (m, 4H), 5.00-4.84 (m, 1H), 4.09-4.37 (m, 2H), 3.73-3.95 (m, 1H), 3.37-3.62 (m, 2H), 3.12-3.32 (m, 1H), 3.05 (ddd, J=13.6, 7.2, 4.0 Hz, 1H), 2.43-2.46 (m, 6H), 1.05-1.14 (m, 3H).
Step 2:
6-fluoro-2-methyl-1,4-diazepane was obtained from 6-fluoro-2-methyl-1,4-ditosyl-1,4-diazepane by the method similar to 6-fluoro-1,4-ditosyl-1,4-diazepane. LC-MS: m/z 133.1 (M+H)+
Step 1:
A mixture of 3-buten-1-ol (18.03 g, 0.25 mol), TEA (2.4 mL, 0.02 mol) and sodium hydroxide (15 g, 0.38 mol) in hexane (200 mL) was stirred at 50° C. for 0.5 h. Benzyl bromide (32.7 mL, 0.27 mol) in hexane (50 mL) was added dropwise over a period of 0.5 h. Afterwards, the resulting mixture was heated to reflux overnight (oil temperature: 85° C.). The precipitate was removed via filtration and washed with ethyl acetate twice. The combined organic phase was washed with brine and dried over sodium sulfate. Such obtained product was pure enough for the next reaction step. Yield: 38.21 g, 94.2%, colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.46-7.29 (m, 6H), 5.89 (ddt, J=17.0, 10.1, 6.7 Hz, 1H), 5.21-5.03 (m, 2H), 4.56 (s, 2H), 3.57 (t, J=6.8 Hz, 2H), 2.43 (qd, J=6.7, 1.1 Hz, 2H).
Step 2:
To solution of ((but-3-en-1-yloxy)methyl)benzene (38.21 g, 0.24 mol) in dichloromethane (400 mL) was added mCPBA (77.15 g, 0.38 mol) at −20° C. as solid in portions. Afterwards, the resulting suspension was allowed to warm to rt and stirred overnight. The precipitate was filtered off and washed with dichloromethane. Afterwards, the combined organic phase was washed with saturated NaHCO3 and Na2SO3 and brine. The white precipitate was occurred while removing solvents under reduced pressure. More n-hexane was added and the most appeared white solid was filtered off. This procedure was repeated third times. The crude product was subjected to column chromatography on silica gel using a mixture of ethyl acetate with petroleum ether as eluent (EtOAc:PE=1/50 to 1/5) to afford the title compound. Yield: 35.26 g, 84.0%, pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 5H), 4.56 (s, 2H), 3.73-3.59 (m, 2H), 3.15-3.06 (m, 1H), 2.85-2.77 (m, 1H), 2.55 (dd, J=5.0, 2.7 Hz, 1H), 1.95 (dddd, J=13.4, 7.2, 6.2, 4.7 Hz, 1H), 1.81 (dq, J=14.3, 5.9 Hz, 1H). LC-MS: m/z 220.0 (M+CH3CN)+.
Step 3:
To a round bottom flask charged with HOAc (60.1 mg, 1.0 mol %) in toluene (20 mL) was added Jacobsen salen Co(II) catalyst (0.30 g, 0.5 mol %) at rt and the resulting solution was stirred at rt for 0.5 h while the flask is open to air in order to absorb oxygen. The volatiles were removed under reduced pressure to give rise to a dark solid. Racemic epoxide (17.82 g, 100 mmol) was added neat, followed by the addition of distilled water (1.0 mL, 56 mmol) dropwise at 0° C. The resulting reaction mixture was allowed to warm to rt slowly and stirred at rt overnight. The reaction mixture was diluted with n-hexane and then passed through a pad of celite. Epoxide was obtained by using petroleum ether and diol was obtained by using a mixture of methanol with dichloromethane (1/30). The obtained epoxide (red oil) was distilled and the desired product was obtained at 145-165° C. (oil temperature); similarly, the diol was obtained at 185-205° C. (oil temperature). Yield of epoxide: 7.83 g, 43.9%, pale yellow oil; Yield of diol: 8.46 g, 43.1%, bright yellow oil. For chiral epoxide: 1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 5H), 4.56 (s, 2H), 3.73-3.59 (m, 2H), 3.15-3.06 (m, 1H), 2.85-2.77 (m, 1H), 2.55 (dd, J=5.0, 2.7 Hz, 1H), 1.95 (dddd, J=13.4, 7.2, 6.2, 4.7 Hz, 1H), 1.81 (dq, J=14.3, 5.9 Hz, 1H). LC-MS: m/z 220.0 (M+CH3CN)+. For chiral diol: 1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 5H), 4.53 (s, 2H), 3.94 (s, 1H), 3.86-3.41 (m, 5H), 3.18 (s, 1H), 1.91-1.66 (m, 2H). LC-MS: m/z 219.0 (M+Na)+. ee>99%.
Step 4:
A mixture of potassium tert-butoxide (1.68 g, 15 mmol) and trimethyloxosulphonium iodide (3.30 g, 15 mmol) in tert-butoxide (35 mL) was stirred at 50° C. for 1 h. A solution of chiral epoxide (0.89 g, 5 mmol) in tert-butoxide (15 mL) was added dropwise while keeping the temperature around 50° C. Afterwards, the resulting reaction mixture was stirred at 50° C. overnight. The precipitate was removed via filtration and washed with ethyl acetate. The combined organic phase was dried under reduced pressure and diluted with ethyl acetate. The diluted solution was washed with brine and dried over sodium sulfate. The crude product was subjected to column chromatography on silica gel using EtOAc:PE=1/10 as eluent to afford the title compound. Yield: 0.55 g, 57.7%; colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 5H), 5.09-4.94 (m, 1H), 4.70 (dd, J=14.0, 7.8 Hz, 1H), 4.62-4.38 (m, 3H), 3.67-3.51 (m, 2H), 2.72 (dq, J=13.9, 7.8 Hz, 1H), 2.43 (dt, J=10.7, 7.6 Hz, 1H), 2.16 (td, J=13.3, 5.8 Hz, 1H), 2.02 (td, J=13.6, 6.0 Hz, 1H). LC-MS: m/z 234.1 (M+CH3CN)+. ee>99%.
Step 5:
A mixture of (R)-2-(2-(benzyloxy)ethyl)oxetane (4.35 g, 22.63 mmol) and palladium hydroxide on carbon (20%, with 50% of water, 0.80 g, 2.5 mol %) in methanol (50 mL) and dichloromethane (15 mL) was stirred at rt overnight with an input of hydrogen gas. The precipitate was removed via filtration through a pad of celite and washed with dichloromethane. The combined organic phase was dried using water pump at 30° C. and was confirmed pure enough for the next reaction. Yield: 2.28 g, 98.7%; colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.09 (qd, J=7.5, 4.6 Hz, 1H), 4.70 (td, J=8.0, 6.0 Hz, 1H), 4.57 (dt, J=9.1, 5.9 Hz, 1H), 3.82 (ddd, J=11.8, 7.3, 4.6 Hz, 1H), 3.74 (ddd, J=11.1, 6.5, 4.9 Hz, 1H), 3.11-2.77 (m, 1H), 2.77-2.62 (m, 1H), 2.45 (ddt, J=11.0, 9.1, 7.4 Hz, 1H), 2.13-1.98 (m, 1H), 1.91 (ddt, J=14.3, 7.3, 4.7 Hz, 1H). ee>99%.
Step 6:
To a mixture of oxetane (3.10 g, 30.48 mmol), sodium periodate (19.56 g, 91.44 mmol), water (30 mL), acetonitrile (60 mL) and carbon tetrachloride (30 mL) was added ruthenium trichloride plus three water (79.7 mg, 1 mol %) at 0-5° C. Afterwards, the resulting mixture was allowed to warm to rt and stirred at this temperature for 2 h. The precipitate was removed via filtration through a pad of celite and washed with diethyl ether (around 100 mL×5). The combined organic phase was washed with brine (50 mL×3) and then dried using water pump at 35° C. and was confirmed pure enough for the next reaction. Yield: 2.26 g, 63.8%; light yellow oil. 1H NMR (400 MHz, methanol-d4) δ 5.26-5.15 (m, 1H), 4.69 (ddd, J=8.3, 7.8, 5.9 Hz, 1H), 4.58 (dt, J=9.2, 5.9 Hz, 1H), 2.88-2.70 (m, 3H), 2.51 (ddt, J=11.2, 9.1, 7.3 Hz, 1H). ee>99%.
To a solution of 5-bromoisoquinoline (1.5 g, 7.2 mmol) in dichloromethane (20 mL) was added mCPBA (1.5 g, 8.6 mmol) at room temperature all at once. The reaction mixture was stirred at room temperature for 2 h. Then the mixture was washed with water (20 mL) and brine (20 mL), dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography over silica gel (EtOAc) to give 0.97 g of title compound as a pale yellow solid.
1H NMR (CHLOROFORM-d) δ 8.71-8.80 (m, 1H), 8.22 (dd, J=7.3, 1.5 Hz, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.81-7.91 (m, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.43-7.54 (m, 1H). LC-MS: m/z 222.9 (M+H)+
To a solution of 5-bromoisoquinoline 2-oxide (0.4 g, 2.4 mmol) in CHCl3 (10 mL) was added POCl3 (0.7 mL, 3 eq). Then the mixture was refluxed for 2 h. After cooling to room temperature, the reaction mixture was poured into ice-water, neutralized with saturated NaHCO3 (aq), extracted with EtOAc. The solvent was removed and 0.45 g crude product was obtained which was used in next step with further purification. 1H NMR (CHLOROFORM-d) δ 8.33-8.44 (m, 2H), 8.02-8.08 (m, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.52-7.61 (m, 1H). LC-MS: m/z 242.9 (M+H)+.
To a solution of 5-bromo-1-chloroisoquinoline (1.2 g, 5.0 mmol) in methanol (10 mL) was added NaOMe (324 mg, 6.0 mmol). The mixture was refluxed for 2 h. The solvent was removed and the residue was purified by column chromatography over silica gel (10-20% EtOAc/petroleum ether) to obtain 600 mg of title compound as a white solid. 1H NMR (DMSO-d6) δ 8.26 (d, J=8.3 Hz, 1H), 8.12 (d, J=6.0 Hz, 1H), 7.95 (dd, J=7.5, 1.0 Hz, 1H), 7.58 (d, J=6.0 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 4.17 (s, 3H). LC-MS: m/z 237.0 (M+H)+
To a suspension of 5-bromo-1-chloroisoquinoline (300 mg, 1.2 mmol) in water (10 mL) was added NaOH (240 mg, 6 mmol). The mixture was refluxed for 2 h. After cooling to room temperature, the pH of the mixture was adjusted to 7 with 2N HCl. The precipitate was filtered and dried to get 205 mg crude product as a white solid which was used directly in next step. LC-MS: m/z 222.9 (M+H)+
A mixture of 5-bromoisoquinoline 2-oxide (224 mg, 1.0 mmol), diethyl phosphorocyanidate (489 mg, 3.0 mmol) and Et3N (101 mg, 1.0 mmol) in CH3CN (5 mL) was heated at 150° C. for 1.5 h in a microwave oven. After cooling to room temperature, the precipitate was filtered and dried to obtain 110 mg product as a yellow solid. 1H NMR (CHLOROFORM-d) δ 8.79 (d, J=5.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.29 (d, J=5.8 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H). LC-MS: m/z 231.9 (M+H)+
Step 1:
To a solution of 1,3-dichloroisoquinoline (4 g, 20.2 mmol) in CH3CN (100 mL) was added H2SO4 (4 mL), followed by NBS (4.4 g, 24.2 mmol). The mixture was stirred at room temperature for 90 h. Then the precipitate was collected by filtration, washed with water, dried to afford 3.4 g of 5-bromo-1,3-dichloroisoquinoline as a pale yellow solid. 1H NMR (CHLOROFORM-d) δ 8.33 (d, J=8.5 Hz, 1H), 8.03-8.10 (m, 2H), 7.56 (dd, J=8.4, 7.7 Hz, 1H). LC-MS: m/z 276.9 (M+H)+
Step 2:
To a suspension of 5-bromo-1,3-dichloroisoquinoline (3 g, 10.8 mmol) in AcOH (30 mL) and conc. HCl (6 mL) was added Sn powder (3.86 g, 32.4 mmol). The mixture was stirred at 60° C. for 20 min. After cooling to room temperature, the mixture was neutralized with NaOH (aq), filtered through celite. The filtrate was extracted with EtOAc (2×30 mL). The solvent was removed and the residue was purified by column chromatography over silica gel (5-10% EtOAc/petroleum ether) to afford 0.8 g of 5-bromo-3-chloroisoquinoline as a white solid. 1H NMR (CHLOROFORM-d) δ 9.04 (s, 1H), 8.04 (s, 1H), 7.90-8.02 (m, 2H), 7.47 (t, J=7.9 Hz, 1H).
Step 1:
To a stirred solution of ethyl-2-aminonicotinate (1 g, 6.02 mmol) and ethyl acetate (13 g, 147.7 mmol) in 15 mL of anhydrous THF was added sodium tert-butoxide (1.45 g, 15.1 mmol) portionwise over 1 min. The resulting mixture was stirred at room temperature for 40 mins and at 100° C. for 4 hours. After this time the reaction was cooled to r.t. and evaporated in vacuo. The resulting solid was dissolved in water (20 mL) and neutralized to pH 7 with 1.0M aqueous HCl. The resulting solid was filtered and dried under vacuum overnight to give ethyl 3-(3-acetamidoisonicotinamido)isonicotinate as a tan solid (0.58 g, 59%). LC-MS: m/z 329.1 (M+H)+ 1H NMR (CHLOROFORM-d) δ: 11.96 (s, 1H), 10.74 (br. s., 1H), 10.12 (s, 1H), 9.99 (s, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.59 (d, J=5.0 Hz, 1H), 7.89-7.96 (m, 1H), 7.66 (d, J=5.3 Hz, 1H), 4.51 (q, J=7.0 Hz, 2H), 2.24-2.33 (m, 3H), 2.19 (s, 2H), 1.43-1.54 (t, 3H).
Step 2:
A stirred solution of ethyl 3-(3-acetamidoisonicotinamido)isonicotinate (400 mg, 2.47 mmol) in phosphorus oxychloride (2.5 mL) was heated to 120° C. for 3 hours. After this time the reaction was cooled to r.t. and evaporated in vacuo. The resulting residue was carefully basified to pH>10 with an aqueous solution of Na2CO3 and the resulting solid was filtered, washed with water and dried under vacuum to give 2,4-dichloro-1,7-naphthyridine (200 mg, 83%). 1H NMR (CHLOROFORM-d) δ: 9.48 (s, 1H), 8.79 (d, J=5.9 Hz, 1H), 8.01 (d, J=5.9 Hz, 1H), 7.74 (s, 1H). LC-MS: m/z 200 (M+H)+
Step 3:
To 5 mg PdCl2(dppf).CH2Cl2 in a reaction tube under nitrogen were added 3 mL isopropanol, 1 mL water, 93.6 mg (0.8 mmol) DIPEA, 52 mg (0.39 mmol) potassium vinyl trifluoroborate and 78 mg (0.39 mmol) 4-chloro-2-vinyl-1,7-naphthyridine. The reaction solution was heated to 100° C. for half hour under microwave irradiation. The reaction mixture was extracted into ethyl acetate, washed several times with water and purified by prepTLC (petrol:ethyl acetate=1:1) to give 4-chloro-2-vinyl-1,7-naphthyridine 50 mg (66.8%). 1H NMR (CHLOROFORM-d) δ: 9.51 (d, J=0.6 Hz, 1H), 8.70 (d, J=5.6 Hz, 1H), 7.98-8.04 (m, 1H), 7.89 (s, 1H), 7.02 (dd, J=17.6, 10.9 Hz, 1H), 6.41 (d, J=17.6 Hz, 1H), 5.83 (d, J=11.2 Hz, 1H). LC-MS: m/z 191.6 (M+H)+
Step 1:
To a solution of 5-chloroquinoxaline (1.4 g, 8.54 mmol) in 50 mL of dichloromethane was added mCPBA (1.62 g, 9.39 mmol). The resulting mixture was stirred at room temperature overnight. After removal of dichloromethane, the crude product obtained was purified by doing column chromatography (100% DCM) to afford 1.5 g of 5-chloroquinoxaline 1-oxide as a white solid.
Step 2:
To a solution of 5-chloroquinoxaline 1-oxide (450 mg, 2.5 mmol) in 5 mL of chloroform was added POCl3 (1.9 g, 12.5 mmol) slowly. The resulting mixture was heated to 80° C. and held stirring at 80° C. overnight. After removal of chloroform and excess POCl3, the crude product obtained was purified by doing column chromatography (5% PE/EA) to afford 240 mg of 2,5-dichloroquinoxaline as a white solid. MS (ES) M+H expected 198. found 199. 1H NMR (CHLOROFORM-d) δ: 8.89 (s, 1H), 7.98 (d, 1H), 7.92 (d, 1H), 7.76 (t, 1H).
Step 3:
To a flask was added 2,5-dichloroquinoxaline (315 mg, 1.59 mmol), potassium trifluoro(vinyl)borate (234 mg, 1.75 mmol), PdCl2DPPF (130 mg, 0.16 mmol), K2CO3 (442 mg, 3.18 mmol), propan-2-ol (4 mL), and H2O (1 mL), the mixture was degassed with N2, then heated to 90° C. with stirring for about 3 hrs. TLC (5% PE/EA) showed the consumption of the starting material and new spot appeared. The mixture was then filtered through celite, the cake was washed with ethyl acetate. The filtrate was concentrated in vacuo, the residue was purified by column chromatography (1-5% PE/EA) to afford 256 mg of 5-chloro-2-vinylquinoxaline as a white solid. 1H NMR (CHLOROFORM-d) δ: 9.10 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.71 (t, 1H), 7.09 (q, 1H), 6.57 (d, 1H), 5.89 (d, 1H). MS (ES) M+H expected 190. found 191.
Step 1:
A mixture of 7-2 (500 mg, 1.28 mmol), Potassium vinyltrifluoroborate (258 mg, 1.93 mmol), TEA (650 mg, 6.4 mmol) and Pd(dppf)Cl2 (52 mg, 0.064 mmol) in i-PrOH and water was heated at 100° C. under microwave irradiation for 0.5 hr. The reaction mixture was concentrated and the residue was purified by column chromatography (50% PE/EA) to afford 420 mg of title compound. 1H NMR (CHLOROFORM-d) δ 7.80 (s, 1H), 6.99 (dd, J=17.3, 10.8 Hz, 1H), 5.58 (dd, J=17.3, 0.8 Hz, 1H), 5.36 (dd, J=11.0, 0.8 Hz, 1H), 4.86 (br. s., 0.5H), 4.53 (br. s., 0.5H), 4.44 (br. s., 0.5H), 4.09-4.29 (m, 2.5H), 3.65 (br. s., 0.5H), 3.41 (br. s., 0.5H), 3.12-3.24 (m, 2H), 2.14-2.26 (m, 1H), 1.76 (br. s., 1H), 1.25-1.42 (m, 3H), 1.10-1.17 (m, 2H), 0.96-1.10 (m, 4H), 0.82 (dd, J=7.8, 1.8 Hz, 2H).
Step 2:
A mixture of (R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-vinylnicotinonitrile (200 mg, 0.59 mmol), N-(2-hydroxyethyl)-4-nitrobenzenesulfonamide (174 mg, 0.71 mmol, synthesized in accordance with Organic Letters, 2011, 13, #4, p. 728-731), and NIS (159 mg, 0.71 mmol) suspended in 10 mL of MeCN was stirred at r.t. for 2 hrs. After the mixture was concentrated in vacuo, the residue was purified by column chromatography (50% PE/EA) to afford 100 mg of N-(2-(1-(5-cyano-6-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl pyridin-3-yl)-2-iodoethoxy)ethyl)-4-nitrobenzenesulfonamide as a light yellowish solid. 1H NMR (CHLOROFORM-d) □δ 8.36-8.45 (m, J=8.8 Hz, 2H), 8.08-8.17 (m, J=8.8 Hz, 2H), 7.60 (s, 1H), 5.57 (br. s., 1H), 4.83 (br. s., 0.5H), 4.60-4.71 (m, 1H), 4.53 (br. s., 0.5H), 4.40 (br. s., 0.5H), 4.19-4.34 (m, 2.5H), 3.54-3.72 (m, 1H), 3.15-3.48 (m, 8H), 1.88-1.98 (m, 1H), 1.75 (br. s., 1H), 1.34-1.40 (m, 3H), 1.00-1.18 (m, 6H), 0.81 (d, J=7.8 Hz, 2H).
Step 3:
A mixture of N-(2-(1-(5-cyano-6-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)-2-iodoethoxy)ethyl)-4-nitrobenzenesulfonamide (100 mg, 0.14 mmol), K2CO3 (97 mg, 0.71 mmol) in 10 mL of MeCN was stirred at r.t. overnight. After the mixture was filtered, the filtrate was concentrated and the residue was purified by column chromatography (50% PE/EA) to afford 66 mg of 2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(4-((4-nitrophenyl)sulfonyl)morpholin-2-yl)nicotinonitrile as a light yellowish solid. 1H NMR (CHLOROFORM-d) δ 8.39-8.49 (m, J=8.5 Hz, 2H), 7.90-8.02 (m, J=8.3 Hz, 2H), 7.70 (s, 1H), 4.91 (dd, J=10.2, 2.1 Hz, 1H), 4.84 (br. s., 0.5H), 4.52 (br. s., 0.5H), 4.42 (br. s., 0.5H), 4.16 (dd, J=11.8, 2.5 Hz, 4H), 3.86-4.00 (m, 2H), 3.76 (d, J=11.5 Hz, 1H), 3.61 (br. s., 0.5H), 3.14-3.38 (m, 3H), 2.52-2.69 (m, 1H), 1.97-2.09 (m, 1H), 1.74 (br. s., 1H), 1.28-1.48 (m, 3H), 1.19-1.25 (m, 2H), 1.11-1.19 (m, 2H), 1.04-1.11 (m, 2H), 0.81 (d, J=7.5 Hz, 2H).
Step 4:
A mixture of 2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(4-((4-nitrophenyl)sulfonyl)morpholin-2-yl)nicotinonitrile (50 mg, 0.075 mmol), butane-1-thiol (3 d) and LiOH.H2O (20 mg) in 10 mL of MeCN was stirred at r.t. overnight. After the mixture was filtered, the filtrate was concentrated and the residue was purified by column chromatography (10% DCM/MeOH) to afford 21 mg of 2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(morpholin-2-yl)nicotinonitrile. 1H NMR (CHLOROFORM-d) □ δ 7.81 (br. s., 1H), 4.96 (br. s., 1H), 4.34-4.63 (m, 1H), 4.14 (br. s., 3H), 3.97 (br. s., 1H), 3.46 (br. s., 3H), 3.32 (br. s., 2H), 3.09 (br. s., 3H), 2.75 (br. s., 1H), 2.09 (br. s., 1H), 1.74 (br. s., 1H), 1.26 (br. s., 5H), 1.03 (br. s., 4H), 0.80 (br. s., 2H).
Step 1:
To a solution of 1-chloro-2-methyl-3-nitrobenzene (10.0 g, 58.3 mmol) in 150 mL of anhydrous DMF was added 1,1-dimethoxy-N,N-dimethylmethanamine (21.0 g, 175 mmol). The resulting mixture was stirred at 140° C. for 16 hours. After cooling to 0° C., the mixture was added slowly a solution of NaIO4 (37.4 g, 175 mmol) in H2O and DMF. The mixture was stirred for another 6 hours. The mixture was filtered and partitioned between EtOAc and water. The organic layer was washed with water and dried over Na2SO4 and concentrated to give the crude which was purified by column to afford 6.5 g of 2-chloro-6-nitrobenzaldehyde. 1H NMR (CHLOROFORM-d) δ 10.39 (s, 1H), 7.95-8.04 (m, 1H), 7.74-7.80 (m, 1H), 7.64 (t, J=8.0 Hz, 1H). LC-MS: m/z 186.0 (M+H)+
Step 2:
To a solution of 2-chloro-6-nitrobenzaldehyde (1 g, 0.0054 mmol) in ethanol was added Fe (1.8 g, 0.032 mmol), AcOH (10 ml) and 2N aqueous HCl (5 mL). The resulting mixture was stirred at 25° C. for 2 hours. The mixture was filtered and the filtrate was partitioned between DCM and water, the organic layer was washed with water and brine, concentrated to give 2-amino-6-chlorobenzaldehyde under 25° C. which was without purification for next step. LC-MS: m/z 156.01 (M+H).
Step 3:
The mixture of compound 2-amino-6-chlorobenzaldehyde (2.8 g, 0.018 mol), guanidine (3.43 g, 0.36 mol) and Na2CO3 (3.82 g, 0.36 mol) in naphthalene was stirred at 180° C. for 2 hours. After cooling to room temperature, the mixture was filtered and the solid was washed with water and DCM to give the yellow solid 5-chloroquinazolin-2-amine which was used without purification for next step. 1H NMR (DMSO-d6) δ□9.28 (s, 1H), 7.65 (dd, J=8.5, 7.8 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.16 (s, 2H). LC-MS: m/z 180.0 (M+H).
Step 4:
The mixture of 5-chloroquinazolin-2-amine (2.2 g, 12.2 mmol), isoamyl nitrite (4.30 g, 36.7 mmol), CuI (1.17 g, 6.12 mmol) and CH2I2 (16.4 g, 61.2 mmol) in THF was stirred at 60° C. for 72 hours. After cooling to room temperature, the mixture was filtered and the filtrate was partitioned between EtOAc and water, the organic layer was washed with water and brine, dried over Na2SO4. Then the organic layer was concentrate to give the crude which was purified by column to give 5-chloro-2-iodoquinazoline as yellow solid. 1H NMR (CHLOROFORM-d) δ□9.46 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.86 (dd, J=8.5, 7.5 Hz, 1H), 7.72 (dd, J=7.4, 1.1 Hz, 1H). LC-MS: m/z 291.1 (M+H).
Step 5:
The mixture of 5-chloro-2-iodoquinazoline (1.3 g, 4.48 mmol), potassium vinyltrifluoroborate (600 mg, 4.48 mmol), Pd(dppf)Cl2 (165 mg, 0.224 mmol) and CsF (2.04 g, 13.4 mmol) in dioxane/H2O was stirred at 80° C. for 16 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine and dried over Na2SO4, concentrated to give the crude which was purified by column to give 500 mg of 5-chloro-2-vinylquinazoline as yellow solid. 1H NMR (CHLOROFORM-d) δ 9.75 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.06 (dd, J=17.2, 10.4 Hz, 1H), 6.85 (dd, J=17.3, 1.8 Hz, 1H), 5.90 (dd, J=10.5, 1.5 Hz, 1H). LC-MS: m/z 191.0 (M+H).
Step 1:
A mixture of 25 g of 2-aminonicotinic acid (0.18 mol), 25 g of K2CO3 (0.18 mol) in 250 mL of DMF was stirred at 140° C. for 30 minutes, then cooled to 10° C. in ice/H2O, 11 mL of MeI (0.18 mol) was added at 10° C. dropwise, the mixture was stirred at room temperature overnight. The mixture was filtered, the filtrate was concentrated, residue was dissolved in EtOAc, and filtered again through a pad of silica gel, the filtrate was concentrated to give 15 g of methyl 2-aminonicotinate. 1H NMR (400 MHz, CHLOROFORM-d) δ: 7.67 (d, J=7.0 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.60-7.44 (m, 1H), 3.54 (br. s., 3H).
Step 2:
To methyl 2-aminonicotinate (7.48 g, 49 mmol) in EtOAc/THF (150 mL/150 mL) was added 13.8 g of KtOBu (123 mmol) in portions slowly at room temperature, and the mixture was stirred at room temperature for 50 minutes before it was refluxed for 4 hours. After cooling to room temperature, the mixture was concentrated, the residue was dissolved in 200 mL of H2O, pH was adjusted to pH=7 with 1N HCl with vigorous stirring, the resulting suspension was filtered, the solid obtained was dried in vacuum to give 7 g of 1,8-naphthyridine-2,4-diol. Step 3: A mixture of 8.0 g of 1,8-naphthyridine-2,4-diol (49 mmol) in 80 mL of POCl3 was refluxed for 1.5 hour, excessive POCl3 was removed under reduced pressure, the residue was poured into satd NaHCO3 slowly with vigorous stirring, the mixture was extracted with EtOAc, and the organic layers were dried over Na2SO4, concentrated to give 2 g of 2,4-dichloro-1,8-naphthyridine, which was used in the subsequent reaction without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ: 9.21-9.12 (m, 1H), 8.59 (dd, J=1.8, 8.3 Hz, 1H), 7.67-7.58 (m, 2H).
Step 4:
100 mg of 2,4-dichloro-1,8-naphthyridine (0.5 mmol), 68 mg of potassium vinyltrifluoroborate (0.5 mmol), 130 mg of DIPEA (1 mmol) in iPrOH/H2O (3 mL/1 mL) was added Pd(dppf)2Cl2, then the mixture was stirred at 105° C. in a sealed tube for 1 hour. When TLC (Petroleum ether: Ethyl acetate=3:1) indicated the completion of the reaction, the mixture was cooled to room temperature, filtered through a pad of celite, the filtrate was concentrated to give 120 mg of crude 4-chloro-2-vinyl-1,8-naphthyridine, and was used in the subsequent reaction without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ: 9.17 (dd, J=1.8, 4.3 Hz, 1H), 8.58 (dd, J=1.9, 8.4 Hz, 1H), 7.62-7.49 (m, 2H), 7.13-6.94 (m, 1H), 6.52 (d, J=17.6 Hz, 1H), 5.81 (d, J=10.8 Hz, 1H).
The mixture of 5-chloropyridazin-3-ol (500 mg, 3.36 mmol), potassium vinyltrifluoroborate (450 mg, 3.36 mmol), Pd(dppf)Cl2 (124 mg, 0.168 mmol) and CsF (1.5 g, 10.07 mmol) in dioxane/H2O (8 mL/2 mL) was stirred at 100° C. for 16 hours. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was partitioned between EtOAc (50 mL) and water (30 mL), the organic layer was washed with water (30 mL), brine and dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 200 mg of the product.
1H NMR (CHLOROFORM-d) δ 9.06 (d, J=2.3 Hz, 1H), 7.60 (d, J=2.3 Hz, 1H), 7.02 (dd, J=17.8, 11.0 Hz, 1H), 6.32 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H). LC-MS: m/z 141.0 (M+H)+
The mixture of 3,5-dichloropyridazine (400 mg, 2.68 mmol), BocNH2 (314 mg, 2.68 mmol), Pd(dppf)Cl2 (99 mg, 0.134 mmol), Xantphos (155 mg, 0.268 mmol) and Cs2CO3 (2.61 g, 8.05 mmol) in toluene was stirred at 80° C. for 16 hours. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was partitioned between EtOAc (50 mL) and water (30 mL), the organic layer was washed with water (30 mL), brine and dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 150 mg of the product 19 and 120 mg of 20. tert-butyl 6-chloropyridazin-4-ylcarbamate 1H NMR (CHLOROFORM-d) δ 8.86 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.3 Hz, 1H), 8.12 (br. s., 1H), 1.56 (s, 9H). LC-MS: m/z 230.1 (M+H)+ tert-butyl 5-chloropyridazin-3-ylcarbamate 1H NMR (CHLOROFORM-d) δ 8.94 (s, 1H), 8.04 (s, 1H), 7.37 (br. s., 1H), 1.48-1.63 (s, 9H). LC-MS: m/z 230.1 (M+H)+
To a solution of 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine (20 mg, 0.1 mmol), potassium vinyl trifluoroborate (13 mg, 0.1 mmol), 5 mg PdCl2(dppf).CH2Cl2 and CsF (45 mg, 0.3 mmol) in dioxane/H2O (5:1) 3 mL was stirred at 100° C. for 1 hours. Then the mixture was partitioned between EtOAc and water, the organic was washed with water, brine and concentrated to give the crude which was purified by column to give 14 mg of the product. 1H NMR (CHLOROFORM-d) δ: 11.19 (br. s., 1H), 7.39 (br. s., 1H), 7.28 (s, 2H), 6.91 (dd, J=17.3, 10.9 Hz, 1H), 6.62 (br. s., 1H), 6.21 (d, J=17.3 Hz, 1H), 5.55 (d, J=10.9 Hz, 1H). LC-MS: m/z 179.6 (M+H)+
Step 1:
To a suspension of 5-(4-methoxybenzyloxy)-1,7-naphthyridin-2-ol (180 mg, 0.64 mmol) in DMF (5 mL) was added POCl3 (293 mg, 1.92 mmol). The mixture was heated at 45° C. for 6 h. After cooling to room temperature, the reaction mixture was poured into ice-water, neutralized with NaHCO3, extracted with EtOAc (3×20 mL). The organic layer washed with water (20 mL) and brine (20 mL). The solvent was removed and 150 mg crude product was obtained which was used in next step without further purification. LC-MS: m/z 300 (M+H)+
Step 2:
To a solution of 2-chloro-5-(4-methoxybenzyloxy)-1,7-naphthyridine (150 mg, 0.5 mmol) in EtOH (10 mL) was added 1N HCl (2.5 mL). Then the mixture was heated at 90° C. for 2 h. After cooling to room temperature, 190 mg of K2CO3 was added and followed 10 mL of methanol. The mixture was stirred vigorously for 1 h at which time silica gel was added. The solvent was removed and the residue was purified by column chromatography (5% methanol/dichloromethane) to give 70 mg of title compound (83%). LC-MS: m/z 180 (M+H)+
Step 3:
A mixture of 2-chloro-1,7-naphthyridin-5-ol (70 mg, 0.39 mmol), Potassium vinyltrifluorobrate (104 mg, 0.78 mmol), Pd(dppf)Cl2 (32 mg, 0.039 mmol) and CsF (119 mg, 0.78 mmol) in dioxane:H2O=5:1 (5 ml+1 ml) was purged with N2 for three times. Then the mixture was heated at 100° C. for 2 h. The solvent was removed and the residue was purified by column chromatography (5% methanol/dichloromethane) to give 30 mg of title compound (45%).
LC-MS: m/z 173 (M+H)+
Step 4:
To a solution of 2-vinyl-1,7-naphthyridin-5-ol (30 mg, 0.17 mmol) and Et3N (35 mg, 0.34 mmol) in dichloromethane (3 mL) was added Tf2O (59 mg, 0.21 mmol) at 0° C. Then the temperature was raised to room temperature and stirred for 2 h. The solvent was removed and the residue was purified by prep. TLC (EtOAc/petroleum ether=3/7) to give 10 mg of title compound (20%). LC-MS: m/z 305 (M+H)+
A mixture of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.8 g, 4.0 mmol), Potassium vinyltrifluorobrate (540 mg, 4.0 mmol), Pd(dppf)Cl2 (98 mg, 0.12 mmol) and CsF (1.22 g, 8 mmol) in dioxane:H2O=5:1 (10 mL+2 mL) was purged with N2 three times. Then the mixture was heated at 100° C. for 2 h. The solvent was removed and the residue was purified by column chromatography (30% EtOAc/petroleum ether) to give 500 mg of title compound (65%). 1H NMR (CHLOROFORM-d) δ 8.03 (s, 1H), 7.24 (s, 1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.36 (d, J=17.3 Hz, 1H), 5.64 (d, J=10.9 Hz, 1H), 4.16 (s, 3H). LC-MS: m/z 193 (M+H)+
Step 1:
7-bromoquinoline 1-oxide: to a solution of 7-bromoquinoline (1.04 g, 5 mmol) in 20 mL of DCM was added m-Chloroperbenzoic acid (1.01 g, 5 mmol) at room temperature. The reaction mixture was then stirred at room temperature overnight. After LC-MS showed the completion of reaction, the mixture was poured into water and extracted with methylene chloride. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (hexane/ethyl acetate=3/1) afforded 1.0 g of title compound as a white solid.
LC-MS: m/z 225.1 (M+H)+
Step 2:
7-bromo-2-chloroquinoline: to a solution of 7-bromoquinoline 1-oxide (1.0 g, 4.5 mmol) in 20 mL of chloroform was added Phosphorus oxychloride (3.42 g, 22 mmol) at room temperature. The reaction mixture was then heated at reflux for 3 hours. After LC-MS showed the completion of reaction, the mixture was poured into water and extracted with methylene chloride. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (hexane/ethyl acetate=3/1) afforded 0.75 g of title compound as a white solid. LC-MS: m/z 244.1 (M+H)+
Step 3:
7-bromo-2-vinylquinoline: to a solution of 7-bromo-2-chloroquinoline (0.75 g, 3 mmol) in 1,4-dioxane (10 mL) was added Potassium vinyltrifluoroborate (0.42 g, 3 mmol), dichlorobis (triphenylphosphine) palladium (II) (143 mg) and Cesium fluoride (1.40 g, 9 mmol), and the mixture was stirred at 100° C. for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) afforded 0.42 g of title compound as a white solid. LC-MS: m/z 234.9 (M+H)+
Step 1:
(R)-2-(2-(benzyloxy)ethyl)tetrahydrofuran: to a well stirred suspension of 1.28 g (52 mmol) of NaH in dry diglyme (15 mL) was added 6.86 g (31.2 mmol) of trimethylsulfoxonium iodide at room temperature. The mixture was gently heated to 120° C., and compound 1 (Step 4 product in building block 6 scheme) (1 g, 5.2 mmol) in diglyme (3 mL) was added in one portion. The reaction mixture was stirred at 120° for 4 hours, cooled, carefully quenched with water, and extracted three times with n-hexane. The combined extracts were washed with water and brine and dried over Na2SO4. Removal of solvent and purification by chromatography on silica gel gave the compound 2 (0.5 g, 46%). 1H NMR (CHLOROFORM-d) δ 7.34-7.42 (m, 4H), 7.26-7.34 (m, 1H), 4.43-4.63 (m, 2H), 3.91-4.05 (m, 1H), 3.83-3.91 (m, 1H), 3.74 (td, J=7.9, 6.5 Hz, 1H), 3.62 (t, J=6.6 Hz, 2H), 1.96-2.05 (m, 1H), 1.73-1.95 (m, 4H), 1.52 (dd, J=11.9, 8.7 Hz, 1H).
Step 2:
(R)-2-(tetrahydrofuran-2-yl)ethanol: to a solution of compound 2 (0.3 g, 1.45 mmol) in MeOH (15 mL) was added 10% Pd(OH)2/C (20 mg). The reaction mixture was purged with hydrogen and stirred under an atmosphere of hydrogen for 2 d. The black suspension was passed through a plug of celite eluting with MeOH, then the solution was concentrated to yield the desired product as colorless oil (0.15 g, 89%). 1H NMR (CHLOROFORM-d, 400 MHz): δ 4.00-4.08 (m, 1H), 3.86-4.00 (m, 1H), 3.66-3.86 (m, 3H), 2.87 (br. s., 1H), 1.98-2.10 (m, 1H), 1.84-1.98 (m, 2H), 1.70-1.84 (m, 2H), 1.46-1.63 ppm (m, 1H).
Step 3:
(R)-2-(tetrahydrofuran-2-yl)acetic acid: to a mixture of compound 3 (0.15 g, 1.3 mmol), sodium periodate (0.72 G, 2.6 mmol), water (10 mL), acetonitrile (20 mL) and carbon tetrachloride (20 mL) was added ruthenium trichloride (29 mg, 10 mol %) at 0-5° C. Afterwards, the resulting mixture was allowed to warm to rt and stirred at this temperature for 2 h. The precipitate was removed via filtration through a pad of celite and washed with diethylether (around 100 mL×5). The combined organic phase was washed with brine (50 mL×3) and then dried under reduced pressure to get the compound 4 (60 mg, contain about 8% of the byproduct).
1H NMR (CHLOROFORM-d, 400 MHz): δ 4.19-4.33 (m, 1H), 3.89-4.06 (m, 1H), 3.83 (td, J=7.8, 6.5 Hz, 1H), 2.62 (dd, J=6.5, 1.5 Hz, 2H), 2.07-2.23 (m, 1H), 1.89-2.06 (m, 2H), 1.54-1.72 (m, 1H).
1H NMR (CHLOROFORM-d) δ 7.76-7.82 (m, 1H), 7.69 (td, J=7.7, 1.4 Hz, 1H), 7.58-7.63 (m, 1H), 7.52 (td, J=7.7, 1.1 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 4.56-4.79 (m, 1.5H), 4.44 (t, J=10.3 Hz, 1.5H), 3.86 (d, J=13.8 Hz, 0.5H), 3.70-3.79 (m, 2H), 3.51-3.65 (m, 0.5H), 3.34-3.49 (m, 3.5H), 3.03-3.24 (m, 2H), 2.87-3.00 (m, 0.5H), 2.53-2.82 (m, 2H), 2.05-2.29 (m, 1H), 1.63-1.77 (m, 1H), 1.26 (br. s., 1H), 0.93-1.23 (m, 7H), 0.87-0.92 (m, 1.5H), 0.84 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 458.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.58 (d, J=2.5 Hz, 1H), 7.39 (td, J=7.9, 1.8 Hz, 1H), 7.18-7.25 (m, 1H), 7.04 (td, J=7.4, 1.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.69 (d, J=12.8 Hz, 0.5H), 4.49-4.60 (m, 1H), 4.44 (d, J=10.5 Hz, 0.5H), 4.25-4.38 (m, 1H), 3.79-3.89 (m, 4H), 3.68-3.78 (m, 2H), 3.51-3.63 (m, 0.5H), 3.34-3.42 (m, 3H), 2.90-3.16 (m, 2.5H), 2.53-2.82 (m, 2H), 2.09-2.36 (m, 1H), 1.75-1.88 (m, 1H), 1.02-1.18 (m, 5H), 0.79-0.96 (m, 5H). LC-MS: m/z 463.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.54 (d, J=2.0 Hz, 1H), 7.43-7.48 (m, 1H), 7.33-7.41 (m, 3H), 4.69 (d, J=13.3 Hz, 0.5H), 4.60 (t, J=13.3 Hz, 1H), 4.41 (dd, J=16.8, 13.3 Hz, 1.5H), 3.85 (d, J=13.3 Hz, 0.5H), 3.70-3.79 (m, 2H), 3.52-3.62 (m, 0.5H), 3.35-3.49 (m, 3.5H), 3.03-3.23 (m, 2H), 2.89-3.02 (m, 0.5H), 2.53-2.82 (m, 2H), 1.67-1.78 (m, 1H), 1.04-1.12 (m, 5H), 0.77-0.98 (m, 6H). LC-MS: m/z 517.2 (M+H)+
To a solution of N′-hydroxyacetimidamide (221 mg, 2 mmol) hydrochloride in 10 mL anhydrous THF was added NaH (48 mg, 2 mmol). The reaction mixture was heated reflux for 0.5 h and (R)-methyl 6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinate (455 mg, 1 mmol) was added to this solution. The reaction was continued reflux for 2 h. The reaction was cooled down to RT and filtered. The filtrate was concentrated to dryness and 120 mg product was obtained by prep-TLC. 1H NMR (CHLOROFORM-d) δ 7.99 (s, 1H), 7.33-7.49 (m, 2H), 7.05-7.23 (m, 2H), 4.85 (br. s., 0.5H), 4.42 (d, J=13.1 Hz, 0.5H), 4.17 (br. s., 0.5H), 3.77-3.93 (m, 2H), 3.47-3.77 (m, 6H), 3.37 (s, 4H), 3.06-3.26 (m, 2H), 2.81-3.06 (m, 1H), 2.51-2.80 (m, 3H), 2.31-2.49 (m, 3H), 1.87-2.11 (m, 1H), 1.28-1.43 (m, 1.5H), 1.15-1.28 (m, 3.5H), 1.12 (br. s., 1H), 0.80-1.06 (m, 2H).
1H NMR (CHLOROFORM-d) δ 7.66-7.71 (m, 2H), 7.62-7.65 (m, 1H), 7.55-7.60 (m, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 4.18-4.40 (m, 2.5H), 3.67-3.88 (m, 2.5H), 3.46-3.62 (m, 0.5H), 3.38 (s, 3H), 3.24-3.35 (m, 1H), 2.99-3.20 (m, 1.5H), 2.64-2.81 (m, 1H), 2.49-2.63 (m, 1H), 1.85-1.97 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=6.5 Hz, 1.5H), 1.14-1.21 (m, 2H), 0.94-1.04 (m, 2H). LC-MS: m/z 430.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.57-7.60 (m, 1H), 7.22 (t, J=7.8 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.68-6.74 (m, 2H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.09-4.31 (m, 2.5H), 3.67-3.81 (m, 2.5H), 3.47-3.60 (m, 0.5H), 3.37 (s, 3H), 3.18-3.29 (m, 1H), 2.95-3.16 (m, 1.5H), 2.63-2.78 (m, 1H), 2.52-2.61 (m, 1H), 2.09-2.17 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.06-1.16 (m, 2H), 0.88-0.99 (m, 2H). LC-MS: m/z 420.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.34 (s, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.68-7.75 (m, 1H), 7.61-7.68 (m, 2H), 7.43 (t, J=5.6 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d, J=13.1 Hz, 0.5H), 4.18-4.47 (m, 2.5H), 3.69-3.86 (m, 2.5H), 3.54-3.67 (m, 0.5H), 3.37-3.44 (m, 3H), 3.34 (dd, J=13.1, 6.3 Hz, 1H), 3.04-3.25 (m, 1.5H), 2.67-2.78 (m, 1H), 2.54-2.67 (m, 1H), 1.48-1.58 (m, 1H), 1.39-1.47 (m, 1.5H), 1.29-1.39 (m, 1.5H), 1.09-1.21 (m, 2H), 0.75-0.89 (m, 2H). LC-MS: m/z 456.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.40 (br. s., 1H), 7.74 (s, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.24-7.29 (m, 1H), 7.02-7.10 (m, 1H), 6.37-6.45 (m, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.6 Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.71-3.86 (m, 2.5H), 3.51-3.65 (m, 0.5H), 3.35-3.44 (m, 3H), 3.20-3.32 (m, 1H), 2.98-3.17 (m, 1.5H), 2.66-2.81 (m, 1H), 2.54-2.64 (m, 1H), 1.94-2.04 (m, 1H), 1.40-1.46 (m, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.08-1.17 (m, 2H), 0.80-0.91 (m, 2H). LC-MS: m/z 444.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.97 (dd, J=4.1, 1.6 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.94-8.05 (m, 1H), 7.82 (dd, J=8.5, 7.0 Hz, 1H), 7.61-7.66 (m, 1H), 7.48-7.55 (m, 1H), 7.40-7.48 (m, 1H), 4.83-5.06 (m, 0.5H), 4.56 (d, J=13.1 Hz, 0.5H), 4.15-4.43 (m, 2.5H), 3.69-3.91 (m, 2.5H), 3.57 (d, J=10.5 Hz, 0.5H), 3.36-3.45 (m, 3H), 3.33 (dd, J=13.1, 3.5 Hz, 1H), 3.01-3.26 (m, 1.5H), 2.65-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.48-1.56 (m, 1H), 1.39-1.47 (m, 1.5H), 1.29-1.38 (m, 1.5H), 1.07-1.18 (m, 2H), 0.74-0.91 (m, 2H). LC-MS: m/z 456.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.41 (br. s., 1H), 7.69 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.39 (s, 1H), 7.27-7.30 (m, 1H), 7.13 (dd, J=8.0, 1.5 Hz, 1H), 6.60 (t, J=2.1 Hz, 1H), 4.91 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.13-4.32 (m, 2.5H), 3.68-3.84 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s, 3H), 3.17-3.31 (m, 1H), 2.93-3.16 (m, 1.5H), 2.64-2.82 (m, 1H), 2.53-2.63 (m, 1H), 2.13-2.23 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.09-1.17 (m, 2H), 0.84-0.98 (m, 2H). LC-MS: m/z 444.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.19 (d, J=8.0 Hz, 1H), 7.50-7.65 (m, 4H), 7.30-7.37 (m, 1H), 7.22 (dd, J=10.2, 7.9 Hz, 1H), 4.93 (br. s., 0.5H), 4.56 (d, J=13.3 Hz, 0.5H), 4.15-4.42 (m, 2.5H), 3.69-3.90 (m, 2.5H), 3.50-3.68 (m, 0.5H), 3.36-3.43 (m, 3H), 3.24-3.34 (m, 1H), 3.00-3.23 (m, 1.5H), 2.65-2.85 (m, 1H), 2.55-2.64 (m, 1H), 1.54-1.61 (m, 1H), 1.40-1.48 (m, 1.5H), 1.33 (dd, J=6.3, 3.5 Hz, 1.5H), 1.07-1.18 (m, 2H), 0.72-0.85 (m, 2H). LC-MS: m/z 473.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.36-7.45 (m, 1H), 7.25-7.34 (m, 3H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1 Hz, 0.5H), 4.26 (t, J=12.5 Hz, 2.5H), 3.64-3.85 (m, 7H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H), 3.19-3.30 (m, 1H), 2.93-3.18 (m, 2H), 2.63-2.81 (m, 1H), 2.49-2.63 (m, 1H), 2.02-2.12 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.10-1.20 (m, 2H), 0.89-1.00 (m, 2H). LC-MS: m/z 477.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.14 (br. s., 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.42 (dd, J=8.7, 1.4 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.12-4.39 (m, 2.5H), 3.69-3.89 (m, 2.5H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.20-3.33 (m, 1H), 2.97-3.20 (m, 1.5H), 2.66-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.99-2.14 (m, 1H), 1.36-1.46 (m, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.13-1.21 (m, 2H), 0.90-0.99 (m, 2H). LC-MS: m/z 445.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.84-7.96 (m, J=8.5 Hz, 2H), 7.57-7.66 (m, 1H), 7.45-7.56 (m, 2H), 6.27 (br. s., 1H), 5.99 (br. s., 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.14-4.38 (m, 2.5H), 3.70-3.87 (m, 2.5H), 3.47-3.62 (m, 0.5H), 3.33-3.43 (m, 3H), 3.27 (t, J=10.3 Hz, 1H), 2.99-3.21 (m, 1.5H), 2.64-2.83 (m, 1H), 2.50-2.64 (m, 1H), 1.95-2.09 (m, 1H), 1.38 (d, J=6.3 Hz, 1.5H), 1.25-1.31 (m, 1.5H), 1.13-1.21 (m, 2H), 0.92-1.02 (m, 2H). LC-MS: m/z 448.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.35-7.42 (m, 1H), 7.23-7.27 (m, 3H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.14-4.31 (m, 2.5H), 3.91 (t, J=6.7 Hz, 2H), 3.68-3.83 (m, 2.5H), 3.49-3.61 (m, 0.5H), 3.37 (s, 3H), 3.19-3.29 (m, 1H), 2.97-3.18 (m, 1.5H), 2.91-2.97 (m, 2H), 2.64-2.81 (m, 1H), 2.52-2.62 (m, 1H), 2.02-2.14 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H), 1.27-1.32 (m, 1.5H), 1.08-1.19 (m, 2H), 0.89-1.02 (m, 2H). LC-MS: m/z 449.6 (M+H)+
1H NMR (METHANOL-d4) δ 7.96 (t, J=1.5 Hz, 1H), 7.91 (dt, J=7.7, 1.6 Hz, 1H), 7.81 (s, 1H), 7.62-7.67 (m, 1H), 7.56-7.62 (m, 1H), 4.82 (br. s., 0.5H), 4.38-4.48 (m, 1H), 4.16-4.29 (m, 2H), 3.97 (d, J=13.6 Hz, 0.5H), 3.68-3.76 (m, 2H), 3.54-3.67 (m, 0.5H), 3.36 (s, 4H), 3.05-3.26 (m, 1.5H), 2.72-2.89 (m, 1H), 2.57-2.70 (m, 1H), 1.99-2.10 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 1.20 (dq, J=4.4, 3.1 Hz, 2H), 0.93-1.04 (m, 2H). LC-MS: m/z 448.3 (M+H)+
1H NMR (METHANOL-d4) δ 7.71 (br. s., 1H), 7.37-7.48 (m, 3H), 7.32 (d, J=7.5 Hz, 1H), 4.80 (br. s., 1H), 4.68 (s, 3H), 4.36-4.51 (m, 1H), 4.13-4.30 (m, 2H), 3.95 (d, J=13.6 Hz, 0.5H), 3.67-3.78 (m, 2H), 3.50-3.65 (m, 0.5H), 3.27-3.35 (m, 2.5H), 2.99-3.20 (m, 1.5H), 2.70-2.84 (m, 1H), 2.61-2.67 (m, 1H), 2.06-2.13 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.12-1.24 (m, 2H), 0.96 (dd, J=7.3, 3.5 Hz, 2H). LC-MS: m/z 435.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.40 (s, 1H), 7.53-7.64 (m, 1H), 7.29 (d, J=7.8 Hz, 1H), 6.98-7.07 (m, 1H), 6.87-6.93 (m, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.4 Hz, 0.5H), 4.13-4.37 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.49-3.65 (m, 2.5H), 3.34-3.43 (m, 3H), 3.20-3.31 (m, 1H), 2.95-3.18 (m, 1.5H), 2.51-2.81 (m, 2H), 2.02-2.15 (m, 1H), 1.38-1.40 (m, 1.5H), 1.26-1.31 (m, 1.5H), 1.07-1.20 (m, 2H), 0.90-1.04 (m, 2H). LC-MS: m/z 460.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.10 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.44-7.50 (m, 1H), 6.55-6.64 (m, 1H), 4.89 (br. s., 0.5H), 4.72 (br. s., 2H), 4.52 (d, J=13.3 Hz, 0.5H), 4.15-4.31 (m, 2.5H), 3.69-3.85 (m, 2.5H), 3.49-3.63 (m, 0.5H), 3.34-3.43 (m, 3H), 3.19-3.31 (m, 1H), 2.96-3.17 (m, 1.5H), 2.51-2.81 (m, 2H), 1.99-2.08 (m, 1H), 1.23-1.41 (m, 3H), 1.11-1.18 (m, 2H), 0.90-0.99 (m, 2H). LC-MS: m/z 421.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.99 (d, J=4.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.61-7.71 (m, 2H), 7.53-7.61 (m, 1H), 7.36 (d, J=4.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.56 (d, J=12.5 Hz, 0.5H), 4.25-4.45 (m, 2.5H), 3.68-3.91 (m, 2.5H), 3.57 (d, J=9.3 Hz, 0.5H), 3.29-3.45 (m, 4H), 3.01-3.27 (m, 1.5H), 2.65-2.84 (m, 1H), 2.51-2.65 (m, 1H), 1.54 (td, J=8.2, 4.1 Hz, 1H), 1.42 (d, J=5.5 Hz, 1.5H), 1.32 (t, J=5.0 Hz, 1.5H), 1.05-1.21 (m, 2H), 0.74-0.92 (m, 2H). LC-MS: m/z 456.0 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.51-7.57 (m, 1H), 7.30-7.38 (m, 1H), 6.65 (d, J=8.3 Hz, 2H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.11-4.34 (m, 2.5H), 3.67-3.84 (m, 8.5H), 3.47-3.62 (m, 0.5H), 3.32-3.43 (m, 3H), 2.95-3.24 (m, 2.5H), 2.63-2.84 (m, 1H), 2.51-2.63 (m, 1H), 1.65-1.72 (m, 1H), 1.41 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.00-1.12 (m, 2H), 0.75-0.86 (m, 2H). LC-MS: m/z 465.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.44 (s, 1H), 8.10-8.18 (m, 1H), 7.67 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.69-3.88 (m, 2.5H), 3.52-3.69 (m, 0.5H), 3.35-3.45 (m, 3H), 3.22-3.35 (m, 1H), 2.98-3.20 (m, 1.5H), 2.54-2.82 (m, 2H), 2.04-2.13 (m, 1H), 1.38-1.47 (m, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H), 1.14-1.19 (m, 2H), 0.90-0.97 (m, 2H). LC-MS: m/z 540.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.94 (dd, J=4.1, 1.6 Hz, 1H), 8.23 (dd, J=8.3, 1.8 Hz, 1H), 7.90 (dd, J=8.2, 1.4 Hz, 1H), 7.73 (s, 1H), 7.66-7.71 (m, 1H), 7.59-7.66 (m, 1H), 7.45 (dd, J=8.3, 4.3 Hz, 1H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.13-4.38 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.24 (t, J=12.8 Hz, 1H), 2.96-3.17 (m, 1.5H), 2.52-2.82 (m, 2H), 1.59-1.68 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H), 1.07 (br. s., 2H), 0.78 (br. s., 2H)
1H NMR (CHLOROFORM-d) δ 7.64 (s, 1H), 7.58 (s, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.11-4.36 (m, 2.5H), 3.67-3.86 (m, 2.5H), 3.54 (t, J=10.9 Hz, 0.5H), 3.33-3.43 (m, 3H), 3.18-3.31 (m, 1H), 2.94-3.17 (m, 1.5H), 2.63-2.79 (m, 1H), 2.51-2.63 (m, 1H), 2.17-2.28 (m, 3H), 2.06-2.14 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=7.0 Hz, 1.5H), 1.08-1.17 (m, 2H), 0.91-1.00 (m, 2H). LC-MS: m/z 462.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.70-7.79 (m, 2H), 7.54-7.63 (m, 2H), 7.41 (t, J=7.9 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.48 (dd, J=16.8, 1.0 Hz, 1H), 6.31 (dd, J=16.8, 10.0 Hz, 1H), 5.81 (dd, J=10.2, 1.1 Hz, 1H), 4.91 (br. s., 1H), 4.54 (d, J=13.1 Hz, 0.5H), 4.12-4.36 (m, 2.5H), 3.69-3.88 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s, 3H), 3.20-3.33 (m, 1H), 2.96-3.17 (m, 1.5H), 2.54-2.81 (m, 2H), 2.07-2.16 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.25-1.35 (m, 1.5H), 1.15 (quin, J=3.6 Hz, 2H), 0.89-1.02 (m, 2H). LC-MS: m/z 474.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.64-7.76 (m, 2H), 7.60-7.63 (m, 1H), 7.49-7.53 (m, 1H), 7.37-7.44 (m, 1H), 7.30-7.35 (m, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.95-7.10 (m, 1H), 5.99 (dd, J=15.1, 1.8 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=12.8 Hz, 0.5H), 4.20-4.32 (m, 2.5H), 3.76 (t, J=6.3 Hz, 2H), 3.50-3.62 (m, 0.5H), 3.39 (s, 3H), 3.18-3.34 (m, 1.5H), 2.97-3.16 (m, 1.5H), 2.65-2.80 (m, 1H), 2.53-2.65 (m, 1H), 2.09-2.16 (m, 1H), 1.95 (dd, J=6.8, 1.5 Hz, 3H), 1.40 (d, J=6.3 Hz, 1H), 1.29-1.31 (m, 2H), 1.12-1.19 (m, 2H), 0.92-1.01 (m, 2H)
LC-MS: m/z 487.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.38-7.66 (m, 4H), 7.32 (dd, J=3.9, 1.9 Hz, 1H), 7.12-7.25 (m, 1H), 4.89 (s, 0.5H), 4.52 (d, J=10.8 Hz, 0.5H), 4.22-4.34 (m, 2H), 4.10-4.22 (m, 0.5H), 3.66-3.85 (m, 2.5H), 3.55 (d, J=3.5 Hz, 0.5H), 3.39 (d, J=1.5 Hz, 3H), 3.20-3.31 (m, 1H), 3.10-3.14 (m, 1.5H), 2.97-3.09 (m, 1H), 2.66-2.80 (m, 1H), 2.53-2.64 (m, 1H), 1.97-2.07 (m, 1H), 1.55-1.58 (m, 3H), 1.35-1.42 (m, 2H), 1.10-1.17 (m, 1H), 1.05-1.10 (m, 1H), 0.73-0.96 (m, 4H). LC-MS: m/z 490.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.34 (s, 1H), 7.66-7.75 (m, 1H), 7.62 (s, 1H), 7.50-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.22 (d, J=7.8 Hz, 1H), 4.92 (s, 0.5H), 4.50-4.54 (m, 0.5H), 4.29-4.33 (m, 1H), 4.26 (m, 1H), 4.21-4.25 (m, 0.5H), 3.71-3.84 (m, 2.5H), 3.52-3.57 (m, 0.5H), 3.39 (s, 3H), 3.21-3.32 (m, 1H), 3.13 (d, J=11.3 Hz, 1H), 3.05 (d, J=12.3 Hz, 0.5H), 2.66-2.81 (m, 1H), 2.54-2.65 (m, 1H), 2.07-2.12 (m, 1H), 1.40 (d, J=6.3 Hz, 1H), 1.28-1.31 (m, 2H), 1.14-1.19 (m, 2H), 0.94-1.00 (m, 2H). LC-MS: m/z 495.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.44-7.52 (m, 1H), 7.36-7.41 (m, 1H), 7.29-7.36 (m, 2H), 7.11 (br. s., 1H), 4.92 (s, 1H), 4.45-4.63 (m, 2.5H), 4.18-4.40 (m, 2.5H), 3.66-3.89 (m, 2.5H), 3.50-3.57 (m, 0.5H), 3.39 (s, 3H), 3.29 (t, J=10.2 Hz, 1H), 2.99-3.20 (m, 1.5H), 2.65-2.83 (m, 1H), 2.52-2.64 (m, 1H), 1.99-2.06 (m, 1H), 1.40 (d, J=6.3 Hz, 1H), 1.30 (s, 2H), 1.15-1.22 (m, 2H), 0.96-1.03 (m, 2H). LC-MS: m/z 531.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.54 (s, 1H), 7.67-7.73 (m, 1H), 7.60 (s, 1H), 7.49-7.57 (m, 1H), 7.38-7.45 (m, 1H), 7.14-7.22 (m, 1H), 4.90 (br. s., 0.5H), 4.44-4.64 (m, 1.5H), 4.16-4.37 (m, 2.5H), 3.68-3.86 (m, 2.5H), 3.50-3.63 (m, 0.5H), 3.37 (s, 3H), 3.19-3.32 (m, 1H), 2.96-3.17 (m, 1.5H), 2.53-2.78 (m, 2H), 2.05-2.12 (m, 1H), 1.83 (d, J=7.0 Hz, 3H), 1.39 (d, J=6.5 Hz, 1.5H), 1.28 (dd, J=6.9, 2.6 Hz, 1.5H), 1.10-1.19 (m, 2H), 0.90-1.02 (m, 2H). LC-MS: m/z 510.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.55-7.67 (m, 3H), 7.31-7.44 (m, 3H), 4.91 (s, 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.14-4.33 (m, 2.5H), 3.65-3.93 (m, 2.5H), 3.46-3.65 (m, 0.5H), 3.39 (s, 3H), 3.20-3.30 (m, 1H), 2.98-3.19 (m, 1.5H), 2.51-2.81 (m, 1H), 2.16-2.31 (m, 3H), 1.98-2.13 (m, 1H), 1.24-1.44 (m, 4H), 1.08-1.18 (m, 2H), 0.84-0.99 (m, 2H). LC-MS: m/z 462.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.14-4.35 (m, 2.5H), 3.67-3.85 (m, 2.5H), 3.49-3.62 (m, 0.5H), 3.37 (s, 3H), 3.17-3.32 (m, 1H), 2.93-3.17 (m, 1.5H), 2.63-2.81 (m, 1H), 2.52-2.63 (m, 1H), 2.37-2.49 (m, 2H), 2.05-2.13 (m, 1H), 1.38 (d, J=6.5 Hz, 1H), 1.22-1.31 (m, 5H), 1.14 (dt, J=7.4, 3.6 Hz, 2H), 0.88-1.01 (m, 2H). LC-MS: m/z 476.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.11 (s, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.42-7.50 (m, 2H), 7.19-7.25 (m, 1H), 4.92 (s, 0.5H), 4.55 (d, J=12.3 Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.71-3.76 (m, 2.5H), 3.55-3.58 (m, 0.5H), 3.36-3.46 (m, 3H), 3.21-3.33 (m, 1H), 3.14 (d, J=13.3 Hz, 1.5H), 3.05 (d, J=12.0 Hz, 1H), 2.63-3.75 (s, 1H), 2.61-3.63 (m, 1H), 2.02-2.12 (m, 1H), 1.81-1.91 (m, 2H), 1.66 (q, J=4.5 Hz, 2H), 1.40 (d, J=5.5 Hz, 1H), 1.25-1.33 (m, 2H), 1.12-1.20 (m, 2H), 0.92-1.01 (m, 2H). LC-MS: m/z 513.2 (M+H)+
1H NMR (CHLOROFORM-d) δ □7.62 (s, 1H), 7.47-7.56 (m, 1H), 7.35-7.44 (m, 1H), 7.18-7.25 (m, 2H), 6.42 (dd, J=16.8, 2.0 Hz, 1H), 6.16 (dd, J=16.6, 10.3 Hz, 1H), 5.57 (dd, J=10.2, 1.6 Hz, 1H), 4.92 (d, J=12.8 Hz, 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.13-4.41 (m, 3H), 3.69-3.90 (m, 3H), 3.58 (d, J=9.3 Hz, 1H), 3.39 (s, 3H), 3.42 (s, 3H), 3.29 (t, J=9.5 Hz, 1H), 3.01-3.21 (m, 2H), 2.65-2.80 (m, 1H), 2.47-2.65 (m, 1H), 1.88-2.07 (m, 1H), 1.65 (br. s., 3H), 1.35-1.44 (m, 2H), 1.25-1.35 (m, 2H), 1.09-1.25 (m, 2H), 0.92-1.09 (m, 2H). LC-MS: m/z 488.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.63-7.69 (m, 2H), 7.61 (s, 1H), 7.41-7.50 (m, 2H), 7.20 (d, J=7.3 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=11.8 Hz, 0.5H), 4.12-4.40 (m, 2.5H), 3.72-3.79 (m, 2.5H), 3.51-3.57 (m, 0.5H), 3.40 (s, 3H), 3.23-3.32 (m, 1H), 3.14 (d, J=13.1 Hz, 1H), 3.05 (d, J=11.0 Hz, 1H), 2.99 (s, 1H), 2.65-2.81 (m, 1H), 2.54-2.65 (m, 1H), 2.05-2.13 (m, 1H), 1.40 (d, J=6.5 Hz, 1H), 1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H), 0.88-0.93 (m, 2H).
LC-MS: m/z 472.2 (M+H)+
To a solution of (R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (20 mg, 0.048 mmol) and 2-chloroethanesulfonyl chloride (8.6 mg, 0.052 mmol) in 5 ml of DCM was added dropwised TEA (15 mg, 0.143 mmol) at 0° C., then the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 15 mg of the product.
1H NMR (CHLOROFORM-d) δ 7.55-7.61 (m, 1H), 7.37-7.46 (m, 1H), 7.15-7.26 (m, 3H), 6.70 (d, J=12.8 Hz, 1H), 6.62 (dd, J=16.4, 9.9 Hz, 1H), 6.34 (d, J=16.3 Hz, 1H), 6.02 (d, J=9.8 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.19-4.37 (m, 2.5H), 3.73-3.79 (m, 3H), 3.52-3.61 (m, 0.5H), 3.39 (s, 3H), 3.28 (t, J=10.4 Hz, 1H), 3.02-3.14 (m, 1H), 2.65-2.80 (m, 1H), 2.55-2.64 (m, 1H), 1.98-2.07 (m, 1H), 1.27 (s, 3H), 1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H).
1H NMR (CHLOROFORM-d) δ 8.19 (d, J=4.5 Hz, 1H), 7.75 (s, 1H), 7.61 (s, 1H), 7.57 (dd, J=8.0, 1.3 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.16-7.23 (m, 1H), 5.84 (dd, J=18.0 Hz, J=3.3 Hz, 0.5H), 5.21-5.35 (m, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.10-4.38 (m, 2.5H), 3.66-3.86 (m, 2.5H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.19-3.33 (m, 1H), 2.95-3.18 (m, 1.5H), 2.56-2.78 (m, 2H), 2.04-2.16 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.11-1.22 (m, 2H), 0.91-1.03 (m, 2H). LC-MS: m/z 492.7 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.79 (br. s., 1H), 7.77 (s, 1H), 7.55-7.65 (m, 2H), 7.44 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 6.05 (t, J=56.0 Hz, 1H), 4.89 (br. s., 0.5H), 4.51 (d, J=13.3 Hz, 0.5H), 4.08-4.37 (m, 2.5H), 3.66-3.88 (m, 2.5H), 3.49-3.63 (m, 0.5H), 3.36 (s, 3H), 2.96-3.25 (m, 2.5H), 2.81 (s, 6H), 2.50-2.79 (m, 2H), 2.03-2.13 (m, 1H), 1.32-1.45 (m, 1.5H), 1.27 (d, J=6.8 Hz, 1.5H), 1.10-1.17 (m, 2H), 0.91-1.02 (m, 2H)
LC-MS: m/z 498.8 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.53-7.62 (m, 1H), 7.11-7.21 (m, 2H), 6.70-6.83 (m, 2H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.04-4.28 (m, 2.5H), 3.64-3.88 (m, 4.5H), 3.47-3.64 (m, 0.5H), 3.30-3.43 (m, 3H), 3.14-3.27 (m, 1H), 2.92-3.14 (m, 1.5H), 2.50-2.79 (m, 2H), 2.08-2.15 (m, 1H), 1.34-1.43 (m, 1.5H), 1.28-1.30 (m, 1.5H), 1.06-1.15 (m, 2H), 0.84-0.95 (m, 2H). LC-MS: m/z 420.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.22 (s, 1H), 7.50-7.64 (m, 1H), 7.21-7.26 (m, 2H), 6.85-7.03 (m, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.10-4.37 (m, 2.5H), 3.68-3.86 (m, 2.5H), 3.48-3.64 (m, 2.5H), 3.35-3.44 (m, 3H), 3.19-3.31 (m, 1H), 2.94-3.17 (m, 1.5H), 2.52-2.82 (m, 2H), 1.99-2.09 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.09-1.20 (m, 2H), 0.91-0.99 (m, 2H). LC-MS: m/z 460.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.14 (br. s., 1H), 7.82 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.16-7.24 (m, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=12.5 Hz, 0.5H), 4.16-4.39 (m, 2.5H), 3.69-3.85 (m, 2.5H), 3.50-3.65 (m, 0.5H), 3.38 (s, 3H), 3.20-3.32 (m, 1H), 2.98-3.14 (m, 1.5H), 2.52-2.82 (m, 2H), 2.04-2.13 (m, 1H), 1.28-1.43 (m, 3H), 0.91-0.98 (m, 2H), 0.81-0.89 (m, 2H).
LC-MS: m/z 445.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.30-9.40 (m, 1H), 8.49-8.58 (m, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.67-7.75 (m, 1H), 7.62-7.67 (m, 2H), 7.36-7.45 (m, 1H), 4.95 (br. s., 0.5H), 4.58-4.61 (m, 0.5H), 4.27-4.49 (m, 2H), 4.14 (br. s., 0.5H), 3.59-3.73 (m, 1H), 3.11-3.39 (m, 4.5H), 1.45-1.55 (m, 2.5H), 1.37 (dd, J=6.4, 4.4 Hz, 1.5H), 1.07-1.19 (m, 2H), 0.77-0.87 (m, 2H). LC-MS: m/z 480.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.40 (br. s., 1H), 8.56 (d, J=4.5 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.72-7.78 (m, 1H), 7.64-7.71 (m, 2H), 7.46 (dd, J=12.5, 5.8 Hz, 1H), 4.58 (dt, J=13.1, 2.1 Hz, 1H), 4.47 (d, J=12.0 Hz, 1H), 4.09-4.26 (m, 0.5H), 3.80-3.86 (m, 1.5H), 3.08-3.44 (m, 5H), 1.49-1.57 (m, 1H), 1.33 (br. s., 1H), 1.08-1.22 (m, 2H), 0.82-0.91 (m, 2H), 0.41-0.72 (m, 4H).
LC-MS: m/z 506.7 (M+H)+
A mixture of 7-1 (410 mg, 1.01 mmol), 2-chloropyridin-4-ylboronic acid (237 mg, 0.95 mmol), K2CO3 (414 mg, 3.03 mmol) and Pd(PPh3)4 (40 mg, 0.035 mmol) in DMF (2 mL) was stirred at 150° C. in the microwave reactor for 1 h. The resultant mixture was partitioned between EtOAc and water, the organic phase was washed with water, brine and concentrated and purified by prepTLC (PE:EA=1:1) to give 375 mg of (R)-2′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4′-bipyridine-5-carbonitrile. 1H NMR (CHLOROFORM-d) □ δ 8.34-8.61 (m, 1H), 7.60 (s, 1H), 7.39 (d, J=1.0 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=11.8 Hz, 0.5H), 4.21-4.41 (m, 2.5H), 3.68-3.91 (m, 2.5H), 3.54 (d, J=4.0 Hz, 1H), 3.25-3.45 (m, 4H), 2.95-3.25 (m, 1H), 2.63-2.92 (m, 1H), 2.42-2.63 (m, 1H), 1.87-2.07 (m, 1H), 1.36 (d, J=6.5 Hz, 1.5H), 1.11-1.31 (m, 3.5H), 0.81-1.11 (m, 2H). LC-MS: m/z 440.1 (M+H)+
A mixture of (R)-2′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4′-bipyridine-5-carbonitrile (40 mg, 0.09 mmol), vinyl tributyl stananne (30 mg, 0.09 mmol), KOAc (10 mg) and Pd(PPh3)4 (5 mg) in DMF (2 mL) was stirred at 120° C. in the microwave reactor for 20 min. The resulting mixture was concentrated and purified by prepTLC (PE:EA=1:1) to give 25 mg of the title product. 1H NMR (CHLOROFORM-d) δ 8.64 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.31-7.45 (m, 1H), 7.22 (dd, J=5.0, 1.8 Hz, 1H), 6.87 (dd, J=17.6, 10.8 Hz, 1H), 6.27 (dd, J=17.6, 1.0 Hz, 1H), 5.41-5.71 (m, 1H), 4.90 (m, 0.5H), 5.51 (m, 0.5H), 4.16-4.44 (m, 3H), 3.74 (t, J=6.1 Hz, 3H), 3.38 (s, 4H), 3.31 (d, J=4.0 Hz, 1H), 3.14 (br. s., 2H), 2.59 (t, J=6.0 Hz, 2H), 1.86-2.06 (m, 1H), 1.38 (d, J=6.3 Hz, 1.5H), 1.24-1.33 (m, 1.5H), 1.10-1.24 (m, 2H), 0.83-1.10 (m, 2H). LC-MS: m/z 432.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.34-8.61 (m, 1H), 7.60 (s, 1H), 7.39 (d, J=1.0 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=11.8 Hz, 0.5H), 4.21-4.41 (m, 2.5H), 3.68-3.91 (m, 2.5H), 3.54 (d, J=4.0 Hz, 1H), 3.25-3.45 (m, 4H), 2.95-3.25 (m, 1H), 2.63-2.92 (m, 1H), 2.42-2.63 (m, 1H), 1.87-2.07 (m, 1H), 1.36 (d, J=6.5 Hz, 1.5H), 1.11-1.31 (m, 3.5H), 0.81-1.11 (m, 2H). LC-MS: m/z 440.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.41 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.68-7.81 (m, 2H), 7.61-7.67 (m, 1H), 7.45-7.56 (m, 1H), 4.58 (d, J=11.5 Hz, 1H), 4.46 (d, J=13.1 Hz, 1H), 3.49-4.23 (m, 2.5H), 3.16-3.33 (m, 2.5H), 1.58-1.69 (m, 1H), 1.42-1.54 (m, 1H), 1.17 (t, J=4.9 Hz, 2H), 1.00-1.10 (m, 3H), 0.76-0.87 (m, 4H), 0.69 (br. s., 1H), 0.41-0.62 (m, 3H); LC-MS: m/z 464.2 (M+H)
Step 1:
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile (2 g, 6.3 mmol) was dissolved in MeOH (5 mL) and NaOH (20% wt aq, 10 mL) and the reaction solution was heated to reflux overnight. The resultant solution was concentrated and then dissolved in MeOH (10 mL), treated with SOCl2 (0.1 ml) and then heated to reflux for 2 h. The resulting solution was concentrated, washed with brine and exacted with EA (50 mL). The organic phase was dried, concentrated and purified with flash column (EA:PE=1:3) to give (R)-methyl 5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinate as a white solid (804 mg, 50% yield).
Step 2:
Following the same procedure as General procedure 1, step F, method 1.
Step 3:
Following the same procedure as General procedure 1, step H.
Step 4:
(R)-methyl6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl) nicotinate (500 mg, 1.1 mmol) and 2 mL hydrazine hydrate was dissolved in 10 mL ethanol. The reaction mixture was heated reflux overnight and cooled down to rt. The mixture was filtered and the residue was washed with cold ethanol. 200 mg title compound was obtained without further purification.
Step 5:
(R)-6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl) nicotine-hydrazide (200 mg, 0.44 mmol) was dissolved in trimethoxymethane (25 mL). The reaction mixture was heated to reflux overnight. The rest of trimethoxymethane was removed under reduced pressure and purified by prep-TLC to give 50 mg of title compound. 1H NMR (CHLOROFORM-d) δ 9.33 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.62-7.89 (m, 2H), 7.27 (s, 1H), 4.63-4.78 (m, 2H), 4.47-4.63 (m, 1H), 3.55-3.84 (m, 3H), 3.39 (s, 4H), 3.19 (dd, J=13.3, 3.5 Hz, 1H), 2.91-3.12 (m, 2H), 2.66-2.88 (m, 3H), 2.44-2.66 (m, 2H), 1.28-1.43 (m, 1.5H), 1.15-1.28 (m, 3.5H), 1.12 (br. s., 1H), 0.80-1.06 (m, 2H); LC-MS: m/z 466.2 (M+H).
1H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (t, J=6.4 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.60-7.76 (m, 3H), 7.35-7.49 (m, 1H), 5.39 (br. s., 0.5H), 4.28-4.86 (m, 3.5H), 3.70-3.97 (m, 1H), 3.44 (d, J=14.3 Hz, 1H), 3.23-3.39 (m, 1H), 1.68-1.91 (m, 1H), 1.53 (td, J=7.8, 3.5 Hz, 1H), 1.08-1.23 (m, 3H), 0.77-1.07 (m, 5H). LC-MS: m/z 492.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (br. s., 1H), 8.55 (t, J=6.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.60-7.80 (m, 3H), 7.42 (dd, J=19.3, 5.5 Hz, 1H), 5.29-5.48 (m, 0.5H), 4.71-4.92 (m, 1.5H), 4.44-4.62 (m, 1H), 4.02 (d, J=13.3 Hz, 0.5H), 3.63-3.86 (m, 2.5H), 3.33-3.51 (m, 3.5H), 3.19-3.32 (m, 2H), 2.75-2.94 (m, 1H), 2.52-2.75 (m, 1H), 2.06 (br. s., 1H), 1.52 (tq, J=8.0, 4.1 Hz, 1H), 1.10-1.22 (m, 2H), 0.76-0.93 (m, 2H). LC-MS: m/z 510.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (t, J=6.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.55-7.80 (m, 3H), 7.32-7.45 (m, 1H), 5.26-5.49 (m, 0.5H), 4.45-5.03 (m, 2.5H), 3.72-3.95 (m, 2H), 3.22-3.52 (m, 5H), 1.54 (tq, J=8.0, 4.2 Hz, 1H), 1.10-1.22 (m, 2H), 0.78-0.94 (m, 3H). LC-MS: m/z 534.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.36 (br. s., 1H), 8.55 (d, J=5.8 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.52-7.77 (m, 3H), 7.44 (t, J=6.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.25-4.48 (m, 2.5H), 4.21 (br. s., 0.5H), 3.95 (br. s., 2H), 3.66-3.86 (m, 1.5H), 3.56-3.66 (m, 1H), 3.28-3.47 (m, 1H), 2.99-3.28 (m, 2H), 2.49-2.77 (m, 1H), 1.40-1.57 (m, 3H), 1.11-1.40 (m, 2H), 0.75-1.04 (m, 2H); LC-MS: m/z 442.2 (M+H).
1H NMR (CHLOROFORM-d) δ 7.61-7.69 (m, 1H), 7.29-7.34 (m, 1H), 6.65-6.83 (m, 3H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.14-4.34 (m, 2.5H), 3.70-3.87 (m, 2.5H), 3.56 (t, J=11.2 Hz, 0.5H), 3.34-3.46 (m, 3H), 3.00-3.28 (m, 8.5H), 2.54-2.83 (m, 2H), 2.14-2.23 (m, 1H), 1.29-1.43 (m, 3H), 1.07-1.20 (m, 2H), 0.84-1.01 (m, 2H). LC-MS: m/z 448.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.63 (s, 1H), 7.23-7.27 (m, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.62-6.68 (m, 1H), 6.56-6.62 (m, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.15-4.33 (m, 2.5H), 3.70-3.88 (m, 2.5H), 3.52-3.62 (m, 0.5H), 3.39 (s, 3H), 3.00-3.28 (m, 2.5H), 2.89 (s, 3H), 2.65-2.83 (m, 1H), 2.51-2.65 (m, 1H), 2.14-2.21 (m, 1H), 1.30-1.47 (m, 3H), 1.10-1.19 (m, 2H), 0.89-0.98 (m, 2H). LC-MS: m/z 434.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.36 (br. s., 1H), 8.54 (d, J=4.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.60-7.84 (m, 3H), 7.44 (dd, J=12.3, 6.0 Hz, 1H), 4.71-4.73 (m, 0.5H), 4.56 (d, J=11.8 Hz, 1H), 4.38-4.50 (m, 1H), 4.07-4.19 (m, 0.5H), 3.91 (d, J=11.0 Hz, 0.5H), 3.69-3.83 (m, 3H), 3.51 (s, 3H), 3.20-3.29 (m, 1.5H), 3.13 (br. s., 1H), 2.61-2.70 (m, 2H), 1.52 (ddd, J=12.0, 7.9, 4.6 Hz, 1H), 1.40 (br. s., 1H), 1.12-1.20 (m, 2H), 0.80-0.90 (m, 2H), 0.48-0.77 (m, 4H). LC-MS: m/z 482.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.40 (br. s., 1H), 8.48-8.69 (m, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.63-7.86 (m, 3H), 7.44-7.55 (m, 1H), 4.70-4.73 (m, 0.5H), 4.57 (dd, J=13.1, 2.0 Hz, 1H), 4.41-4.52 (m, 1H), 4.13 (d, J=7.8 Hz, 0.5H), 3.94 (br. s., 2H), 3.69-3.82 (m, 1H), 3.13-3.26 (m, 3H), 2.50-2.71 (m, 2H), 1.48-1.57 (m, 1H), 1.39-1.48 (m, 1H), 1.12-1.21 (m, 2H), 0.86-0.91 (m, 2H), 0.42-0.69 (m, 4H). LC-MS: m/z 468.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.88 (br. s., 1H), 8.15 (d, J=6.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.63 (s, 1H), 7.52-7.58 (m, 1H), 7.44-7.52 (m, 1H), 4.94 (br. s., 0.5H), 4.55-4.59 (m, 0.5H), 4.21-4.44 (m, 2.5H), 3.57-3.86 (m, 3H), 3.34-3.40 (m, 4H), 3.19-3.22 (m, 1.5H), 2.58-2.86 (m, 2H), 1.47-1.55 (m, 1H), 1.30-1.38 (m, 3H), 1.09-1.21 (m, 2H), 0.78-0.95 (m, 2H). LC-MS: m/z 472.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (br. s., 1H), 8.53 (d, J=5.0 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.68-7.75 (m, 1H), 7.60-7.67 (m, 2H), 7.42 (d, J=5.8 Hz, 1H), 3.39-3.85 (m, 10H), 3.38 (s, 3H), 2.63-2.75 (m, 2H), 1.46-1.55 (m, 1H), 1.08-1.18 (m, 2H), 0.75-0.85 (m, 2H). LC-MS: m/z 442.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.37 (br. s., 1H), 8.56 (br. s., 1H), 8.09 (d, J=8.0 Hz, 1H), 7.60-7.79 (m, 3H), 7.43 (d, J=10.3 Hz, 1H), 6.09 (br. s., 1H), 4.97-5.45 (m, 4H), 3.12-3.89 (m, 3H), 1.98-2.08 (m, 1H), 1.80-1.87 (m, 1H), 1.00-1.21 (m, 4H), 0.83-0.92 (m, 4H). LC-MS: m/z 474.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.55 (dd, J=5.8, 3.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.59-7.81 (m, 3H), 7.33-7.50 (m, 1H), 5.24 (br. s., 0.5H), 4.34 (d, J=13.1 Hz, 1H), 4.26-4.50 (m, 2.5H), 3.69 (br. s., 0.5H), 3.20-3.45 (m, 2H), 3.13 (br. s., 0.51H), 2.58-2.75 (m, 2H), 1.77 (br. s., 1H), 1.47-1.61 (m, 1H), 1.09-1.24 (m, 4H), 0.77-0.93 (m, 4H). LC-MS: m/z 506.5 (M+H)+
Compound 390 (18 mg) in EtOH was treated with Pd/C and hydrogenated at room temperature and normal pressure to give the title compound as a white solid. 1H NMR (CHLOROFORM-d) δ 8.63 (d, J=4.8 Hz, 1H), 7.63 (s, 1H), 7.23 (d, J=4.5 Hz, 2H), 4.92 (br. s., 1H), 4.55 (d, J=12.8 Hz, 1H), 4.14-4.43 (m, 3H), 3.64-3.89 (m, 3H), 3.57 (br. s., 1H), 3.40 (s, 3H), 3.32 (d, J=11.8 Hz, 1H), 3.14 (d, J=14.3 Hz, 1H), 2.94 (q, J=7.4 Hz, 2H), 2.65-2.83 (m, 1H), 2.39-2.65 (m, 1H), 2.03 (td, J=8.0, 3.9 Hz, 2H), 1.25-1.42 (m, 8H), 1.11-1.25 (m, 3H), 1.01 (dd, J=7.8, 3.0 Hz, 2H). LC-MS: m/z 434.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.41 (dd, J=7.9, 1.4 Hz, 1H), 8.14 (s, 1H), 7.72-7.84 (m, 1H), 7.57-7.71 (m, 2H), 4.93 (d, J=13.3 Hz, 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.14-4.43 (m, 3H), 3.69-3.90 (m, 3H), 3.53-3.68 (m, 1H), 3.34-3.46 (m, 3H), 3.27 (t, J=11.2 Hz, 1H), 2.97-3.22 (m, 2H), 2.54-2.84 (m, 2H), 1.55-1.80 (m, 2H), 1.43 (d, J=6.5 Hz, 2H), 1.18-1.38 (m, 3H), 1.09 (br. s., 1H), 0.70-0.99 (m, 2H).
LC-MS: m/z 473.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.23 (s, 1H), 7.93-8.03 (m, 1H), 7.50-7.66 (m, 3H), 7.21 (d, J=6.0 Hz, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.19-4.42 (m, 2.5H), 3.83 (d, J=12.3 Hz, 0.5H), 3.65-3.78 (m, 2H), 3.56 (d, J=16.8 Hz, 0.5H), 3.37 (s, 3H), 3.31 (d, J=13.1 Hz, 1H), 2.98-3.25 (m, 1.5H), 2.68-2.84 (m, 1H), 2.53-2.68 (m, 5H), 1.47-1.57 (m, 1H), 1.43 (d, J=6.3 Hz, 1.5H), 1.29-1.36 (m, 1.5H), 1.13 (dd, J=6.5, 4.0 Hz, 2H), 0.76-0.84 (m, 2H). LC-MS: m/z 470.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.32 (dd, J=7.5, 1.3 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H), 7.52-7.65 (m, 3H), 6.94 (t, J=5.9 Hz, 1H), 4.85 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.20-4.40 (m, 2.5H), 4.15 (s, 3H), 3.66-3.89 (m, 3H), 3.38 (s, 3H), 3.31 (d, J=8.3 Hz, 1H), 3.17 (d, J=13.3 Hz, 1.5H), 2.65-2.84 (m, 1H), 2.51-2.65 (m, 1H), 1.48-1.60 (m, 1H), 1.42 (m, 1.5H), 1.29-1.36 (m, 1.5H), 1.03-1.19 (m, 2H), 0.81 (dd, J=8.0, 3.0 Hz, 2H). LC-MS: m/z 486.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.34 (s, 1H), 8.53 (d, J=5.8 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.62-7.80 (m, 3H), 7.42 (t, J=5.9 Hz, 1H), 4.87 (br. s., 0.5H), 4.38-4.65 (m, 1.5H), 4.33 (d, J=12.0 Hz, 2H), 4.19 (q, J=7.0 Hz, 2H), 3.62-3.85 (m, 0.5H), 3.46 (d, J=13.1 Hz, 0.5H), 3.10-3.40 (m, 2H), 2.36 (br. s., 1H), 2.17-2.31 (m, 1H), 2.09 (br. s., 1H), 1.38-1.45 (m, 2H), 1.22-1.37 (m, 6H), 1.03-1.22 (m, 2H), 0.69-0.94 (m, 2H). LC-MS: m/z 461.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.87 (br. s., 1H), 8.06-8.26 (m, 1H), 7.70-7.83 (m, 2H), 7.61-7.69 (m, 1H), 7.54 (br. s., 2H), 4.59 (d, J=7.0 Hz, 1H), 4.47 (d, J=12.5 Hz, 1H), 3.51-4.30 (m, 3H), 3.32 (br. s., 1H), 3.17 (br. s., 1H), 1.96-2.10 (m, 1H), 1.75 (br. s., 1H), 1.43-1.54 (m, 1H), 1.14-1.23 (m, 2H), 1.00-1.12 (m, 2H), 0.81-0.94 (m, 4H), 0.38-0.73 (m, 4H). LC-MS: m/z 480.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60-7.64 (m, 1H), 7.50-7.56 (m, 2H), 7.29-7.37 (m, 3H), 7.01-7.16 (m, 2H), 6.26-6.40 (m, 2H), 6.11-6.25 (m, 2H), 4.92 (s, 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.19-4.37 (m, 2.5H), 3.73-3.79 (m, 3H), 3.52-3.61 (m, 0.5H), 3.39 (s, 3H), 3.28 (t, J=10.4 Hz, 1H), 3.02-3.14 (m, 1H), 2.65-2.80 (m, 1H), 2.55-2.64 (m, 1H), 1.98-2.07 (m, 1H), 1.27 (s, 3H), 1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H). LC-MS: m/z 600.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.68 (s, 1H), 7.53-7.60 (m, 1H), 7.41-7.53 (m, 1H), 7.31 (s, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.86 (s, 1H), 6.61 (d, J=15.3 Hz, 1H), 4.83 (s, 0.5H), 4.46 (d, J=11.0 Hz, 0.5H), 4.22 (d, J=9.8 Hz, 2.5H), 3.90 (s, 1.5H), 3.67-3.81 (m, 2.5H), 3.52 (s, 0.5H), 3.28-3.41 (m, 3H), 3.24 (s, 1H), 3.04-3.15 (m, 1H), 2.94-3.04 (m, 1H), 2.88 (s, 2H), 2.82 (s, 6H), 2.57 (d, J=15.8 Hz, 1H), 1.97-2.08 (m, 1H), 1.33-1.40 (m, 2H), 1.18-1.30 (m, 2H), 1.02-1.15 (m, 2H), 0.89 (s, 2H). LC-MS: m/z 531.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.88 (d, J=9.5 Hz, 1H), 7.63-7.70 (m, 1H), 7.43-7.63 (m, 3H), 6.80 (d, J=9.5 Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (d, J=13.1 Hz, 0.5H), 4.15-4.45 (m, 3H), 3.66-3.87 (m, 2H), 3.40 (s, 2H), 3.29 (t, J=9.7 Hz, 1H), 3.11-3.22 (m, 1H), 2.66-2.88 (m, 1H), 2.48-2.66 (m, 1H), 1.96-2.10 (m, 1H), 1.36-1.56 (m, 1.5H), 1.08-1.36 (m, 3.5H), 0.97 (dd, J=7.8, 3.0 Hz, 2H). LC-MS: m/z 472.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.3 Hz, 1H), 7.59-7.67 (m, 1H), 7.35-7.45 (m, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.89 (dd, J=17.3, 10.8 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.58 (d, J=10.8 Hz, 1H), 4.87 (br. s., 1H), 4.56 (br. s., 1H), 4.30 (d, J=13.3 Hz, 1H), 4.13 (br. s., 1H), 3.58-3.88 (m, 1H), 3.33 (d, J=10.0 Hz, 1H), 3.20 (br. s., 2H), 1.91-2.09 (m, 1H), 1.38-1.51 (m, 1.5H), 1.11-1.38 (m, 2.5H), 0.87-1.08 (m, 6H), 0.79-0.87 (m, 2H). LC-MS: m/z 414.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.59-7.69 (m, 1H), 7.34-7.43 (m, 1H), 7.15-7.27 (m, 1H), 6.89 (dd, J=17.6, 10.8 Hz, 1H), 6.23-6.37 (m, 1H), 5.58 (d, J=11.5 Hz, 1H), 4.94 (br. s., 1H), 4.20-4.48 (m, 2H), 3.51-3.79 (m, 1H), 3.37 (d, J=5.5 Hz, 1H), 3.05-3.34 (m, 4H), 1.87-2.07 (m, 1H), 1.42-1.51 (m, 2H), 1.13-1.42 (m, 3H), 0.95-1.08 (m, 2H). LC-MS: m/z 456.8 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.77 (br. s., 1H), 7.96 (br. s., 1H), 7.80-7.92 (m, 2H), 7.12-7.27 (m, 1H), 6.82 (d, J=17.6 Hz, 1H), 6.06 (d, J=10.8 Hz, 1H), 4.67 (d, J=12.3 Hz, 1H), 4.54 (d, J=11.5 Hz, 2H), 4.24 (br. s., 1H), 3.67 (br. s., 1H), 3.33 (br. s., 1H), 3.18 (br. s., 1H), 1.93 (br. s., 1H), 1.67 (br. s., 1H), 1.25 (br. s., 2H), 1.04-1.23 (m, 3H), 0.89-1.04 (m, 3H), 0.47 (d, J=4.8 Hz, 2H), 0.39 (br. s., 2H). LC-MS: m/z 440.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.7 Hz, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.23 (d, J=4.1 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H), 4.55 (d, J=13.2 Hz, 1H), 4.43 (d, J=12.6 Hz, 1H), 4.03-4.16 (m, 1H), 3.91 (br. s., 2H), 3.65-3.82 (m, 1H), 3.40-3.53 (m, 1H), 3.02-3.32 (m, 3H), 2.49-2.69 (m, 2H), 1.98-2.10 (m, 1H), 1.13-1.38 (m, 3H), 1.01 (dd, J=7.5, 3.4 Hz, 2H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.32-0.51 (m, 2H). LC-MS: m/z 444.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.54-8.72 (m, 1H), 7.57-7.74 (m, 1H), 7.38 (d, J=1.0 Hz, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.88 (dd, J=17.3, 10.8 Hz, 1H), 6.28 (dd, J=17.4, 1.1 Hz, 1H), 5.48-5.63 (m, 1H), 4.56 (dd, J=13.2, 1.9 Hz, 1H), 4.45 (d, J=13.1 Hz, 1H), 4.11 (br. s., 1H), 3.65-3.88 (m, 2H), 3.32 (q, J=9.6 Hz, 2H), 3.20 (d, J=12.0 Hz, 1H), 2.98-3.15 (m, 1H), 2.04 (tt, J=8.0, 4.7 Hz, 1H), 1.30-1.39 (m, 1H), 1.14-1.25 (m, 2H), 0.96-1.07 (m, 2H), 0.65 (br. s., 1H), 0.56 (br. s., 1H), 0.41-0.54 (m, 2H). LC-MS: m/z 482.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.60-7.71 (m, 1H), 7.41 (s, 1H), 7.26 (dd, J=5.0, 1.3 Hz, 1H), 6.90 (dd, J=17.4, 10.9 Hz, 1H), 6.31 (d, J=17.1 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H), 4.72-4.99 (m, 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.22-4.49 (m, 2H), 3.74 (d, J=13.6 Hz, 1H), 3.56 (br. s., 1H), 3.40 (br. s., 1H), 3.32 (td, J=8.6, 3.9 Hz, 1H), 2.95-3.25 (m, 2H), 2.68 (br. s., 1H), 2.44-2.65 (m, 2H), 2.00-2.19 (m, 1H), 1.16-1.45 (m, 3H), 0.95-1.12 (m, 3H), 0.90 (t, J=6.8 Hz, 1H). LC-MS: m/z 418.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.64 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.38 (s, 1H), 7.23 (dd, J=5.0, 1.5 Hz, 1H), 6.81-6.93 (m, 1H), 6.28 (d, J=11.0 Hz, 1H), 5.56 (d, J=11.0 Hz, 1H), 4.88 (s, 0.5H), 4.24-4.53 (m, 1.5H), 4.24-4.36 (m, 2.5H), 3.78 (d, 0.5H), 3.54 (t, 0.5H), 3.27-3.37 (m, 4H), 3.02-3.18 (m, 1.5H), 2.35-2.56 (m, 2H), 1.92-2.06 (m, 4H), 1.38 (d, 1.5H), 1.28 (d, 1.5H), 1.18-1.21 (m, 2H), 0.99-1.02 (m, 2H). LC-MS: m/z 476.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.90 (s, 1H), 8.65 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.24 (d, J=5.0 Hz, 1H), 6.88 (q, 1H), 6.28 (d, 1H), 5.56 (d, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J=12.8 Hz, 0.5H), 4.25-4.37 (m, 2.5H), 3.80 (br. s., 0.5H), 3.60 (br. s., 0.5H), 3.03-3.38 (m, 3H), 2.62-2.89 (m, 4.5H), 2.03 (m, 1H), 1.42 (d, 1.5H), 1.28 (d, 1.5H), 1.18-1.21 (m, 2H), 0.99-1.10 (m, 2H). LC-MS: m/z 430.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.62-7.73 (m, 1H), 7.39 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.56 (d, J=13.1 Hz, 1H), 4.43 (d, J=11.3 Hz, 1.5H), 4.09 (d, J=8.8 Hz, 0.5H), 3.93 (d, J=5.0 Hz, 2H), 3.75-3.82 (m, 1.5H), 3.43 (br. s., 1H), 3.16-3.32 (m, 1.5H), 3.02-3.16 (m, 1H), 2.43-2.71 (m, 2H), 2.00-2.09 (m, 1H), 1.67 (s, 1H), 1.16-1.25 (m, 2H), 0.95-1.08 (m, 2H), 0.40-0.80 (m, 4H). LC-MS: m/z 444.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.90 (d, J=3.0 Hz, 2H), 8.05-8.34 (m, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 4.92 (br. s., 0.5H), 4.26-4.56 (m, 3H), 3.57-3.84 (m, 3H), 3.31-3.38 (m, 4H), 3.13-3.16 (m, 1.5H), 2.27-2.78 (m, 2H), 2.04-2.16 (m, 1H), 1.41 (d, J=5.8 Hz, 1.5H), 1.30 (d, J=6.0 Hz, 1.5H), 1.22 (br. s., 2H), 0.94-1.06 (m, 2H). LC-MS: m/z 457.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.58-7.67 (m, 1H), 7.38-7.50 (m, 2H), 7.32 (dd, J=7.7, 1.6 Hz, 2H), 6.49 (dd, J=16.6, 10.0 Hz, 1H), 6.25 (d, J=16.6 Hz, 1H), 6.06 (d, J=10.0 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.13-4.41 (m, 3H), 3.71-3.87 (m, 2H), 3.49-3.63 (m, 1H), 3.39 (s, 3H), 3.21-3.34 (m, 4H), 2.95-3.21 (m, 2H), 2.51-2.81 (m, 2H), 1.91-2.17 (m, 1H), 1.73 (br. s., 2H), 1.23-1.50 (m, 5H), 0.94-1.23 (m, 4H). LC-MS: m/z 524.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.57 (s, 1H), 7.70 (s, 1H), 7.57-7.64 (m, 1H), 7.47-7.56 (m, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 4.90 (br. s., 0.5H), 4.47-4.65 (m, 1.5H), 4.18-4.30 (m, 2.5H), 3.73-3.81 (m, 2.5H), 3.48-3.64 (m, 0.5H), 3.37 (s, 3H), 3.21-3.31 (m, 1H), 2.95-3.18 (m, 1.5H), 2.53-2.79 (m, 2H), 2.04-2.12 (m, 1H), 1.83 (d, J=7.0 Hz, 3H), 1.38 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.11-1.18 (m, 2H), 0.89-1.03 (m, 2H). LC-MS: m/z 510.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.38-7.49 (m, 2H), 7.30-7.34 (m, 1H), 7.26 (dd, J=8.0, 1.3 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.13-4.40 (m, 2.5H), 3.67-3.93 (m, 2.5H), 3.51-3.66 (m, 0.5H), 3.38 (s, 3H), 3.02-3.32 (m, 4.5H), 2.55-2.84 (m, 2H), 2.00-2.11 (m, 1H), 1.38-1.44 (m, 4H), 1.24-1.31 (m, 2H), 1.12-1.21 (m, 2H), 0.90-1.03 (m, 2H). LC-MS: m/z 512.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.83 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.51-7.57 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 5.83 (s, 1H), 5.43-5.54 (m, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.13-4.36 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.55 (t, J=11.3 Hz, 0.5H), 3.35-3.46 (m, 3H), 3.20-3.31 (m, 1H), 2.96-3.17 (m, 1.5H), 2.81 (s, 2H), 2.51-2.77 (m, 2H), 2.03-2.19 (m, 4H), 1.38 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.10-1.18 (m, 2H), 0.88-1.02 (m, 2H). LC-MS: m/z 488.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.35-7.47 (m, 1H), 7.28 (s, 1H), 7.23-7.27 (m, 1H), 7.15-7.22 (m, 2H), 6.63 (dd, J=16.6, 9.8 Hz, 1H), 6.26-6.39 (m, 1H), 6.01 (d, J=9.8 Hz, 1H), 4.52 (d, J=12.5 Hz, 1H), 4.40 (d, J=12.3 Hz, 1H), 4.07-4.24 (m, 1H), 3.65-3.90 (m, 1H), 3.22-3.52 (m, 1.5H), 3.10 (s, 1.5H), 2.03-2.10 (m, 1H), 1.29-1.36 (m, 1H), 1.14-1.21 (m, 2H), 0.93-1.12 (m, 4H), 0.85-0.92 (m, 1H), 0.76-0.85 (m, 2H), 0.60-0.71 (m, 1H), 0.38-0.60 (m, 3H). LC-MS: m/z 518.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.63 (s, 1H), 7.49-7.58 (m, 2H), 7.33-7.36 (m, 1H), 7.31 (dt, J=6.7, 2.3 Hz, 1H), 7.07 (d, J=9.8 Hz, 1H), 7.10-7.13 (m, 1H), 6.28-6.38 (m, 2H), 6.14-6.22 (m, 2H), 4.41-4.62 (m, 2.5H), 3.98-4.18 (m, 1H), 3.75-3.90 (m, 1H), 3.09-3.33 (2.5, 1H), 2.00-2.07 (m, 1H), 1.15-1.25 (m, 3H), 0.97-1.11 (m, 4H), 0.86-0.92 (m, 1H), 0.82 (dd, J=7.8, 2.3 Hz, 2H), 0.39-0.67 (m, 4H). LC-MS: m/z 608.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.43-7.54 (m, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.17-7.26 (m, 2H), 5.44 (d, J=3.3 Hz, 1H), 5.18-5.38 (m, 1H), 4.82-5.11 (m, 2H), 4.54 (d, J=12.3 Hz, 1H), 4.10-4.40 (m, 3H), 3.75 (br. s., 2H), 3.57 (d, J=7.8 Hz, 1H), 3.35-3.48 (m, 6H), 3.28 (br. s., 1H), 3.14 (d, J=10.5 Hz, 1H), 2.94-3.10 (m, 1H), 2.73 (br. s., 1H), 2.60 (br. s., 1H), 2.19 (s, 1H), 1.90-2.10 (m, 1H), 1.78 (br. s., 1H), 1.23-1.51 (m, 8H), 1.06-1.23 (m, 2H), 0.78-1.06 (m, 3H). LC-MS: m/z 506.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.73-7.80 (m, 2H), 7.63 (s, 1H), 7.51-7.59 (m, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.40-6.54 (m, 1H), 6.31 (dd, J=16.8, 10.3 Hz, 1H), 5.81 (d, J=10.3 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.39 (d, J=12.3 Hz, 1H), 3.92-4.27 (m, 1H), 3.51-3.94 (m, 1H), 3.25 (m, 1H), 2.85-3.42 (m, 3H), 2.08-2.15 (m, 1H), 1.29-1.36 (m, 1H), 1.13-1.20 (m, 2H), 0.94-1.11 (m, 4H), 0.86-0.93 (m, 1H), 0.75-0.85 (m, 2H), 0.68 (d, J=12.5 Hz, 1H), 0.40-0.54 (m, 3H). LC-MS: m/z 482.2 (M+H)+
1H NMR (CHLOROFORM-d) δ □ 7.61 (s, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.31-7.36 (m, 1H), 5.87 (s, 1H), 4.83-5.04 (m, 1H), 4.19-4.42 (m, 3H), 3.76 (br. s., 2H), 3.56 (br. s., 1H), 3.36-3.49 (m, 6H), 3.30 (br. s., 1H), 2.91-3.20 (m, 4H), 2.74 (br. s., 1H), 2.68 (br. s., 1H), 2.61 (br. s., 1H), 1.93-2.02 (m, 1H), 1.15-1.45 (m, 16H), 0.99 (dd, J=7.8, 2.8 Hz, 2H), 0.76-0.94 (m, 2H). LC-MS: m/z 512.2 (M+H)+
1H NMR (CHLOROFORM-d) δ □7.61 (s, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.29-7.37 (m, 2H), 4.10-4.39 (m, 3H), 3.70-3.90 (m, 2H), 3.66 (s, 1H), 3.49 (s, 1H), 3.38 (s, 5H), 3.30 (d, J=14.8 Hz, 1H), 3.14 (br. s., 2H), 2.71-2.91 (m, 2H), 2.48-2.71 (m, 2H), 2.05 (dt, J=7.8, 4.0 Hz, 2H), 1.13-1.42 (m, 8H), 0.91-1.08 (m, 2H). LC-MS: m/z 486.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 10.93 (s, 1H), 8.51 (dd, J=6.8, 2.3 Hz, 1H), 7.51-7.67 (m, 3H), 6.32 (s, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.18-4.41 (m, 2.5H), 3.53-3.92 (m, 3.5H), 3.40 (s, 1H), 3.16-3.38 (m, 2.5H), 2.51-2.83 (m, 2H), 1.61 (br. s., 1H), 1.39-1.49 (m, 1.5H), 1.31-1.39 (m, 1.5H), 1.14 (dd, J=8.3, 4.8 Hz, 2H), 0.79-0.93 (m, 2H). LC-MS: m/z 472.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.25 (s, 1H), 8.00 (dd, J=7.2, 1.6 Hz, 1H), 7.54-7.67 (m, 3H), 7.16-7.27 (m, 1H), 4.57 (d, J=12.5 Hz, 1H), 4.46 (d, J=12.5 Hz, 1H), 3.62-4.63 (m, 2H), 3.10-3.40 (m, 2.5H), 2.67 (d, J=4.5 Hz, 3H), 2.25-2.49 (m, 0.5H), 1.74 (br. s., 1H), 1.54 (dtd, J=12.7, 3.9, 1.9 Hz, 2H), 1.13-1.23 (m, 2H), 0.95-1.13 (m, 2H), 0.77-0.91 (m, 4H), 0.70 (br. s., 1H), 0.39-0.60 (m, 3H). LC-MS: m/z 478.2 (M+H)+
A mixture of (R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (300 mg), pentane-2,4-dione (100 mg) and TFA (1 drop) in cyclohexane was refluxed for 3 h. After evaporation, the residue was dissolved in CH3CN and some Na2SO4 was added followed by select-F-TEDA-BF4 (800 mg). The mixture was refluxed for overnight. After evaporation, the residue was purified by pre-TLC to give the title compound (75 mg). 1H NMR (CHLOROFORM-d) δ 7.86 (s, 1H), 7.58-7.75 (m, 2H), 7.47 (t, J=8.0 Hz, 1H), 7.10-7.26 (m, 2H), 6.33 (dt, J=6.0, 1.8 Hz, 1H), 4.91 (br. s., 0.5H), 4.42-4.63 (m, 2.5H), 4.13-4.40 (m, 2.5H), 3.65-3.95 (m, 2.5H), 3.39 (s, 3H), 3.21-3.32 (m, 1H), 2.99-3.20 (m, 2H), 2.52-2.81 (m, 2H), 2.00-2.29 (m, 1H), 1.35-1.53 (m, 1.5H), 1.23-1.35 (m, 1.5H), 1.07-1.23 (m, 2H), 0.92-1.07 (m, 2H). LC-MS: m/z 486.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.93-7.88 (m, 1H), 7.61-7.55 (m, 2H), 7.45 (dd, J=7.5, 0.9 Hz, 1H), 4.97 (ddd, J=13.1, 10.1, 1.5 Hz, 1H), 4.42-4.15 (m, 5H), 3.90-3.49 (m, 3H), 3.39 (d, J=5.2 Hz, 3H), 3.32 (dd, J=13.1, 3.6 Hz, 1H), 3.26-3.09 (m, 4H), 2.85-2.53 (m, 2H), 2.12-1.88 (m, 1H), 1.17 (dd, J=7.5, 3.1 Hz, 3H), 0.96 (dd, J=7.9, 3.2 Hz, 2H), 0.90 (t, J=6.8 Hz, 3H).
LC-MS: m/z 474.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ=7.93 (d, J=7.5 Hz, 1H), 7.64-7.57 (m, 2H), 7.53-7.47 (m, 1H), 7.44 (s, 1H), 4.93-4.21 (m, 6H), 4.21-2.84 (m, 6H), 1.82-1.65 (m, 2H), 1.55-1.29 (m, 4H), 1.17 (dd, J=7.0, 3.8 Hz, 2H), 1.10-0.97 (m, 2H), 0.95 (dd, J=7.8, 3.2 Hz, 2H), 0.84-0.75 (m, 2H). LC-MS: m/z 458.6.3 (M+H)+
1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J=7.6, 0.8 Hz, 1H), 7.64-7.59 (m, 2H), 7.51 (dd, J=5.4, 2.1 Hz, 1H), 6.76 (s, 1H), 5.07-4.24 (m, 6H), 3.22 (d, J=59.5 Hz, 2H), 2.05 (dt, J=15.3, 7.7 Hz, 1H), 1.31 (s, 2H), 1.19 (dd, J=4.4, 3.2 Hz, 2H), 0.96 (dd, J=7.9, 3.2 Hz, 2H), 0.90 (t, J=6.8 Hz, 3H), 0.82 (dd, J=7.9, 2.4 Hz, 2H), 0.49 (ddd, J=18.9, 9.9, 4.8 Hz, 3H). LC-MS: m/z 468.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ=7.90 (d, J=7.6 Hz, 1H), 7.61-7.54 (m, 2H), 7.45 (d, J=7.5 Hz, 1H), 5.04-3.99 (m, 6H), 3.78-3.06 (m, 6H), 2.13-1.83 (m, 1H), 1.31 (d, J=5.5 Hz, 4H), 1.20-1.14 (m, 2H), 1.09-0.99 (m, 2H), 0.95 (dd, J=7.9, 3.2 Hz, 2H), 0.83 (dd, J=7.9, 1.3 Hz, 2H).
LC-MS: m/z 466.6 (M+H)+
A mixture of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (103.9 mg, 0.25 mol), 7-bromoisatin (67.8 mg, 0.30 mmol), Pd(PPh3)4 (29 mg, 0.03 mmol), and K2CO3 (86.3 mg, 0.63 mmol) suspended in 5 mL of 1,4-dioxane was subjected to microwave reaction at 120° C. for 1 h. After the reaction, the reaction mixture was concentrated in vacuo, residue was purified by column chromatography to afford the title compound. Yield: 14.1 mg (11.7%). 1H NMR (400 MHz, CDCl3) δ 7.75-7.65 (m, 2H), 7.64 (s, 1H), 7.53 (dd, J=7.8, 1.2 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 4.62 (d, J=13.4 Hz, 1H), 4.49 (d, J=12.2 Hz, 1H), 4.24 (m, 1H), 3.77 (m, 1H), 3.26 (m, 2H), 1.88-1.77 (m, 1H), 1.73 (s, 2H), 1.30-1.16 (m, 3H), 1.16-0.96 (m, 4H), 0.83 (dd, J=7.9, 2.5 Hz, 2H), 0.52 (dd, J=17.5, 12.8 Hz, 3H). LC-MS: m/z 482.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.18 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J=1.0 Hz, 1H), 7.43 (dd, J=8.2, 1.6 Hz, 1H), 4.55 (d, J=12.5 Hz, 1H), 4.43 (d, J=12.5 Hz, 1H), 4.18-4.34 (m, 1H), 3.91-4.18 (m, 1H), 3.73 (br. s., 1H), 3.28 (br. s., 1H), 3.12 (br. s., 1H), 2.00-2.12 (m, 1H), 1.73 (br. s., 1H), 1.44 (br. s., 1H), 1.18-1.24 (m, 2H), 0.94-1.12 (m, 4H), 0.77-0.87 (m, 2H), 0.68 (br. s., 1H), 0.40-0.61 (m, 3H). LC-MS: m/z 454.5 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.15-8.21 (m, 1H), 7.84-7.90 (m, 1H), 7.67 (s, 1H), 7.61-7.66 (m, 1H), 7.39-7.47 (m, 1H), 4.59 (br. s., 1H), 4.21-4.46 (m, 3H), 3.43-3.61 (m, 1H), 3.39 (br. s., 1H), 3.18 (br. s., 1H), 2.00-2.10 (m, 1H), 1.78 (br. s., 1H), 1.25-1.32 (m, 3H), 1.16-1.24 (m, 2H), 1.00-1.11 (m, 2H), 0.93-1.00 (m, 2H), 0.83 (dd, J=7.8, 1.8 Hz, 2H). LC-MS: m/z 428.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.26 (s, 1H), 7.96-8.06 (m, 1H), 7.55-7.69 (m, 3H), 7.21 (d, J=15.1 Hz, 1H), 4.57 (dt, J=13.1, 2.3 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 4.15 (br. s., 0.5H), 3.69-3.95 (m, 1.5H), 3.21-3.45 (m, 3H), 3.04-3.21 (m, 2H), 2.67 (d, J=4.5 Hz, 3H), 1.40-1.61 (m, 2H), 1.24-1.31 (m, 1H), 1.07-1.21 (m, 2H), 0.77-0.91 (m, 2H), 0.70 (br. s., 1H), 0.43-0.56 (m, 2H). LC-MS: m/z 520.2 (M+H)+
To a solution of (R)-5-(3-aminophenyl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile (30 mg, 0.07 mmol) in DCM was added propiolic acid (5 mg, 0.07 mmol) and DCC (18 mg, 0.084 mmol). The mixture was stirred at 25° C. for 16 hours. TLC and LC-MS showed product and the mixture was purified by prep-TLC to give 15 mg of the compound. 1H NMR (CHLOROFORM-d) □ δ 8.19 (s, 1H), 7.66-7.77 (m, 1H), 7.62 (s, 1H), 7.47-7.56 (m, 1H), 7.36-7.47 (m, 1H), 7.19 (d, J=7.8 Hz, 1H), 4.51 (d, J=12.0 Hz, 1.5H), 4.29-4.45 (m, 1.5H), 4.08-4.29 (m, 1H), 3.42-3.87 (m, 1H), 3.13-3.42 (m, 1H), 2.99-3.13 (m, 1H), 2.98 (s, 1H), 2.05-2.14 (m, 1H), 1.68-1.77 (m, 1H), 1.11-1.21 (m, 3H), 1.04-1.11 (m, 1H), 0.93-1.04 (m, 3H), 0.76-0.86 (m, 2H), 0.66 (s, 1H), 0.38-0.60 (m, 3H). LC-MS: m/z 480.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.89 (d, J=9.5 Hz, 1H), 7.67 (s, 1H), 7.52-7.64 (m, 3H), 6.81 (d, J=9.5 Hz, 1H), 4.53 (d, J=12.5 Hz, 2H), 4.41 (d, J=12.3 Hz, 2H), 3.28 (br. s., 2H), 3.11 (br. s., 1H), 1.96-2.07 (m, 2H), 1.14-1.32 (m, 2H), 0.93-1.11 (m, 4H), 0.76-0.92 (m, 2H), 0.67 (br. s., 1H), 0.31-0.60 (m, 3H). LC-MS: m/z 490.2 (M+H)
Step 1:
To a solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(2-hydroxyquinolin-5-yl)nicotinonitrile (50 mg, 0.104 mmol), Et3N (12 mg, 0.12 mmol) in DCM (2 mL) was added dropwise Tf2O (30.3 mg, 0.107 mmol) at 0° C. and stirred at r.t. for 3 h. Water was added and the organic layer was combined, dried, concentrated to give 50 mg product after prep-TLC.
Step 2:
To a solution of (R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)quinolin-2-yl trifluoromethanesulfonate (50 mg, 0.082 mmol), tributyl(vinyl)stannane (27 mg, 0.086 mmol), LiCl (5.2 mg, 0.123 mmol) in THF (2 mL) was added Pd(PPh3)4 (4.7 mg, 0.0041 mmol) under N2 and the reaction mixture was heated to 85° C. for 2 h. The mixture was cooled and the solvent was removed. Product (9 mg) was obtained by prep-TLC. 1H NMR (CHLOROFORM-d) δ 8.16 (t, J=9.3 Hz, 2H), 7.72-7.86 (m, 3H), 7.68 (d, J=8.5 Hz, 1H), 7.04-7.14 (m, 2H), 6.34 (d, J=17.6 Hz, 1H), 5.73 (d, J=11.0 Hz, 1H), 4.53 (d, J=12.5 Hz, 2H), 4.41 (d, J=12.3 Hz, 2H), 3.28 (br. s., 2H), 3.11 (br. s., 1H), 1.67 (br. s., 2H), 0.95-1.16 (m, 6H), 0.77-0.95 (m, 6H). LC-MS: m/z 490.2 (M+H).
1H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.48-8.65 (m, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.69 (m, 2H), 7.42 (d, J=6.0 Hz, 1H), 4.99 (br. s., 0.5H), 4.84 (br. s., 0.5H), 4.72 (br. s., 1.5H), 4.60 (br. s., 1H), 4.49 (d, J=13.8 Hz, 1H), 4.17-4.39 (m, 2H), 3.76 (br. s., 0.5H), 3.32-3.57 (m, 2H), 3.22 (br. s., 1H), 1.70 (br. s., 1H), 1.54 (br. s., 1H), 1.14-1.20 (m, 2H), 1.04-1.12 (m, 2H), 0.83-0.90 (m, 4H). LC-MS: m/z 456.1 (M+H)
1H NMR (CHLOROFORM-d) δ 7.70-7.81 (m, 2H), 7.65 (S, 1H), 4.49 (d, J=13.1 Hz, 1H), 4.37 (d, J=12.3 Hz, 1H), 4.13 (d, J=14.8 Hz, 1H), 3.79 (s, 1H), 3.25 (s, 1.5H), 3.08 (s, 1.5H), 2.19-2.28 (m, 1H), 1.64-1.80 (m, 1H), 1.15-1.22 (m, 2H), 0.95-1.11 (m, 4H), 0.86-0.93 (m, 1H), 0.81 (dd, J=7.8, 2.3 Hz, 2H), 0.66 (s, 1H), 0.38-0.59 (m, 3H). LC-MS: m/z 442.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (dd, J=6.0, 1.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.65-7.74 (m, 3H), 7.43 (dd, J=6.0 Hz, 1H), 4.58 (br. s., 0.5H), 4.46 (d, J=11.8 Hz, 1H), 4.26 (br. s., 0.5H), 4.09 (br. s., 0.5H), 3.83 (br. s., 0.5H), 3.68 (br. s., 0.5H), 3.52 (dd, J=10.3, 5.3 Hz, 1H), 3.29-3.41 (m, 4H), 3.23 (br. s., 2H), 1.67-1.75 (m, 2H), 1.39-1.59 (m, 2H), 1.26-1.36 (m, 3H), 1.16-1.19 (m, 2H), 0.82-0.85 (m, 3H), 0.55 (br. s., 2H), 0.48 (br. s., 2H). LC-MS: m/z 508.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.38 (br. s., 1H), 8.55 (d, J=5.3 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.66-7.75 (m, 3H), 7.44-7.47 (m, 1H), 4.45-4.59 (m, 2.5H), 4.09-4.19 (m, 1H), 3.86 (s, 0.5H), 3.57-3.68 (m, 3.5H), 3.05-3.45 (m, 2.5H), 1.93 (br. s., 1H), 1.51-1.54 (m, 1H), 1.18-1.25 (m, 6H), 0.83-0.91 (m, 4H), 0.49-0.68 (m, 4H). LC-MS: m/z 508.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.16 (s, 1H), 7.85 (dd, J=7.8, 1.0 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.42 (dd, J=7.5, 1.0 Hz, 1H), 4.58 (br. s., 1H), 4.32 (d, J=13.1 Hz, 2H), 3.49-3.62 (m, 1H), 3.46 (br. s., 1H), 3.21 (br. s., 2H), 1.85-1.93 (m, 1H), 1.78 (br. s., 1H), 1.31-1.45 (m, 3H), 1.18-1.25 (m, 2H), 1.00-1.11 (m, 2H), 0.89-0.99 (m, 2H), 0.84 (d, J=6.8 Hz, 2H). LC-MS: m/z 428.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.16 (s, 1H), 7.82-7.87 (m, 1H), 7.79 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.42 (dd, J=7.5, 1.0 Hz, 1H), 4.59 (d, J=12.8 Hz, 1H), 4.47 (d, J=12.0 Hz, 1H), 3.95-4.20 (m, 2H), 3.79 (br. s., 1H), 3.30 (br. s., 1H), 3.15 (br. s., 1H), 1.85-1.97 (m, 1H), 1.61 (br. s., 2H), 1.19-1.25 (m, 2H), 1.06 (d, J=16.8 Hz, 2H), 0.91-0.98 (m, 2H), 0.82 (d, J=6.5 Hz, 2H), 0.68 (br. s., 1H), 0.40-0.61 (m, 3H). LC-MS: m/z 454.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.40 (br. s., 1H), 8.56 (br. s., 1H), 8.12 (d, J=8.0 Hz, 1H), 7.69-7.81 (m, 2H), 7.68 (d, J=1.0 Hz, 1H), 7.47-7.54 (m, 1H), 4.54-4.98 (m, 6H), 3.25-3.44 (m, 1H), 3.17 (br. s., 1H), 1.77-1.89 (m, 1H), 1.49-1.54 (m, 1H), 1.25-1.30 (m, 3H), 1.19-1.23 (m, 2H), 1.10 (br. s., 2H), 0.84-0.91 (m, 4H). LC-MS: m/z 470.2 (M+H)
To a solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile (60 mg, 0.149 mmol) in DMF was added K2CO3 (42 mg, 0.298 mmol) and 2-bromoacetonitrile (27 mg, 0.224 mmol). The resulting mixture was stirred for 16 hours. Then the mixture was partitioned between EtOAc and water, the organic layer was washed with water, brine and dried over Na2SO4, concentrated to give the crude which was purified by prep-TLC to give 25 mg of the product. 1H NMR (CHLOROFORM-d) δ 7.72 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 5.17 (s, 2H), 4.32-4.52 (m, 2.5H), 3.65-3.89 (m, 1H), 4.01-4.22 (m, 1H), 3.55-4.92 (m, 1H), 2.89-3.33 (m, 2.5H), 2.10-2.23 (m, 1H), 1.72 (s, 1H), 1.31-1.47 (m, 1H), 1.14-1.22 (m, 2H), 0.92-1.09 (m, 4H), 0.75-0.86 (m, 2H), 0.39-0.63 (m, 4H). LC-MS: m/z 442.2 (M+H)+
Step 1:
To a solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile (100 mg, 0.248 mmol) in CH2Cl2 was added cyclopent-2-enone (51 mg, 0.621 mmol) and ScCl3 (338 mg, 2.24 mmol). The mixture was stirred for 16 hours at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine and dried over Na2SO4, concentrated to give the crude which was purified by prep-TLC to give 50 mg of the product. LC-MS: m/z 485.3 (M+H)+
Step 2:
To a solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile (40 mg, 0.0825 mmol) in MeOH was added NaBH4, the mixture was stirred for 2 hours at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine and dried over Na2SO4, concentrated to give the crude which was purified by prep-TLC to give 15 mg of the product. 1H NMR (CHLOROFORM-d) δ 7.56-7.70 (m, 3H), 4.85 (br. s., 1H), 4.25-4.70 (m, 4H), 4.00-4.25 (m, 1H), 3.50-3.90 (m, 1H), 2.95-3.41 (m, 3H), 2.12-2.41 (m, 6H), 1.90-2.03 (m, 1H), 1.37-1.54 (m, 1H), 1.23-1.37 (m, 1H), 1.17-1.28 (m, 2H), 0.94-1.09 (m, 4H), 0.76-0.85 (m, 2H), 0.39-0.64 (m, 4H). LC-MS: m/z 487.3 (M+H)+
To a solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile (30 mg, 0.074 mmol) in DCM was added TEA (15 mg, 0.149 mmol) and methanesulfonyl chloride (9.4 mg, 0.082 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with H2O, brine and dried over Na2SO4, concentrated to give the crude which was purified by prep-TLC to give 15 mg of the product. 1H NMR (CHLOROFORM-d) δ 8.16 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 4.40-4.60 (m, 2.5H), 4.09-4.25 (m, 1H), 3.53-3.90 (m, 1H), 3.45 (s, 3H), 3.05-3.41 (m, 2.5H), 2.06-2.19 (m, 1H), 1.12-1.26 (m, 3H), 0.95-1.12 (m, 4H), 0.89 (t, J=6.8 Hz, 1H), 0.75-0.85 (m, 2H), 0.36-0.64 (m, 4H). LC-MS: m/z 481.2 (M+H)+
To a solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile (30 mg, 0.0745 mmol) in DMF was added K2CO3 (21 mg, 0.149 mmol) and 2-bromoacetamide (12 mg, 0.082 mmol). The mixture was stirred for 16 hours at room temperature, then the mixture was partitioned between EtOAc and water. The organic layer was partitioned between EtOAc and water, the organic layer was washed with water, brine and dried over Na2SO4 concentrated to give 25 mg of the product. 1H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.57-7.69 (m, 2H), 6.43 (br. s., 1H), 6.04 (br. s., 1H), 4.88 (s, 2H), 4.30-4.60 (m, 2.5H), 3.84-4.23 (m, 1H), 3.50-3.80 (m, 1H), 3.00-3.45 (m, 2.5H), 2.13-2.25 (m, 1H), 1.92 (s, 1H), 1.71 (s, 1H), 1.12-1.21 (m, 2H), 0.94-1.10 (m, 4H), 0.72-0.84 (m, 2H), 0.35-0.63 (m, 4H). LC-MS: m/z 460.2 (M+H)+
To a solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(1H-pyrazol-4-yl)nicotinonitrile (50 mg, 0.124 mmol) in DMF was added NaH (10 mg, 0.248 mmol) and (chloromethyl)(methyl)sulfane (24 mg, 0.248 mmol). The mixture was stirred for 2 hours at room temperature. The mixture was partitioned between EtOAc and water, the organic layer was washed with water, brine and dried over Na2SO4, concentrated to give the crude which was purified by prep-TLC to give 15 mg of the product. 1H NMR (CHLOROFORM-d) □ δ 7.73 (s, 1H), 7.59-7.68 (m, 2H), 5.20 (s, 2H), 4.28-4.48 (m, 2.5H), 4.26-4.30 (m, 1H), 3.50-3.80 (m, 1H), 2.99-3.40 (m, 2.5H), 2.22-2.28 (m, 1H), 2.21 (s, 3H), 1.73 (s, 1H), 1.30-1.48 (m, 1H), 1.14-1.23 (m, 2H), 0.94-1.10 (m, 4H), 0.75-0.85 (m, 2H), 0.39-0.64 (m, 4H). LC-MS: m/z 463.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.66 (s, 1H), 7.58-7.64 (m, 2H), 4.47 (d, J=12.3 Hz, 1H), 4.25-4.41 (m, 3H), 3.97-4.18 (m, 3H), 3.77 (s, 1H), 3.23 (s, 2H), 3.07 (s, 1H), 2.16-2.30 (m, 1H), 1.23-1.35 (m, 2H), 1.12-1.21 (m, 2H), 0.95-1.09 (m, 4H), 0.74-0.87 (m, 2H), 0.38-0.64 (m, 4H). LC-MS: m/z 446.2M+H)+
1H NMR (CHLOROFORM-d) δ 9.07 (s, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.68-7.73 (m, 1H), 7.58 (dd, J=8.4, 1.6 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.43 (d, J=12.3 Hz, 1H), 3.50 (d, J=9.0 Hz, 2H), 3.29 (br. s., 2H), 3.13 (br. s., 1H), 2.04-2.12 (m, 1H), 1.29-1.40 (m, 2H), 1.18-1.25 (m, 2H), 0.94-1.12 (m, 4H), 0.77-0.86 (m, 2H), 0.68 (br. s., 1H), 0.40-0.61 (m, 3H); LC-MS: m/z 470.2 (M+H).
1H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.55 (dd, J=5.8, 2.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.64-7.79 (m, 4H), 7.41-7.50 (m, 2H), 6.59 (s, 1H), 4.61 (dd, J=13.1, 2.0 Hz, 1H), 4.43 (br. s., 2H), 3.98 (br. s., 1H), 3.73 (br. s., 1H), 3.22-3.36 (m, 1H), 3.07-3.22 (m, 1H), 1.50-1.57 (m, 2H), 1.12-1.21 (m, 2H), 0.81-0.89 (m, 2H), 0.65-0.78 (m, 1H), 0.53-0.62 (m, 1H), 0.47 (br. s., 2H). LC-MS: m/z 490.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.37 (br. s., 1H), 8.55 (br. s., 1H), 8.08 (d, J=8.0 Hz, 1H), 7.70-7.77 (m, 1H), 7.60-7.70 (m, 2H), 7.46 (dd, J=12.0, 5.8 Hz, 1H), 4.50-4.60 (m, 1H), 4.37-4.47 (m, 1H), 4.17 (d, J=12.5 Hz, 1H), 3.76 (s, 3H), 3.45-3.59 (m, 2H), 3.29 (ddd, J=12.9, 6.4, 3.8 Hz, 1H), 3.13 (tdd, J=12.5, 7.2, 3.5 Hz, 1H), 1.47-1.57 (m, 1H), 1.34-1.47 (m, 1H), 1.18 (dd, J=7.3, 4.0 Hz, 2H), 0.85-0.93 (m, 2H), 0.60-0.72 (m, 1H), 0.48-0.60 (m, 2H), 0.36-0.48 (m, 1H). LC-MS: m/z 454.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.92 (br. s., 2H), 7.99-8.07 (m, 1H), 7.63 (s, 1H), 4.63 (d, J=12.8 Hz, 1H), 4.50 (d, J=12.3 Hz, 1H), 3.33 (br. s., 1H), 3.17 (m, 2H), 1.80-1.90 (m, 2H), 1.73 (m., 1H), 1.19-1.31 (m, 4H), 0.94-1.12 (m, 4H), 0.76-0.88 (m, 2H), 0.36-0.60 (m, 4H). LC-MS: m/z 439.5 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.28 (d, J=2.0 Hz, 1H), 8.66 (d, J=8.5 Hz, 1H), 7.88-7.97 (m, 1H), 7.72-7.85 (m, 2H), 7.66-7.72 (m, 2H), 4.60-4.74 (m, 1.5H), 4.43-4.60 (m, 1.5H), 3.60-3.89 (m, 1H), 3.35 (br. s., 1H), 3.22 (br. s., 1H), 1.49-1.58 (m, 1H), 1.16-1.36 (m, 4H), 0.99-1.16 (m, 2H), 0.78-0.99 (m, 4H), 0.63-0.78 (m, 1H), 0.42-0.63 (m, 3H). LC-MS: m/z 465.6 (M+H)+
The procedure was similar to the synthesis of Compound 390. 1H NMR (CHLOROFORM-d) δ 8.67-8.84 (m, 1H), 8.07 (s, 1H), 7.43 (d, J=5.0 Hz, 1H), 6.87-7.03 (m, 1H), 6.74 (dd, J=17.4, 1.6 Hz, 1H), 5.76-5.88 (m, 1H), 4.68 (d, J=13.1 Hz, 1H), 4.55 (d, J=13.3 Hz, 1H), 4.07 (br. s., 1H), 3.88 (s, 1H), 3.66 (br. s., 1H), 3.33 (br. s., 1H), 3.17 (br. s., 1H), 2.34-2.47 (m, 1H), 1.96-2.08 (m, 2H), 1.30-1.42 (m, 2H), 1.00-1.11 (m, 3H), 0.85-0.93 (m, 1H), 0.82 (dd, J=8.0, 2.5 Hz, 2H), 0.65 (br. s., 1H), 0.39-0.59 (m, 3H). LC-MS: m/z 441.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.40 (dd, J=6.0, 2.0 Hz, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.68-7.76 (m, 1H), 7.31 (d, J=6.5 Hz, 2H), 4.58 (d, J=10.5 Hz, 1H), 4.46 (d, J=12.5 Hz, 1H), 4.23 (br. s., 1H), 3.82 (br. s., 1H), 3.67 (br. s., 1H), 3.32 (br. s., 1H), 3.17 (br. s., 1H), 2.93-3.12 (m, 3H), 1.74 (br. s., 1H), 1.47-1.57 (m, 2H), 1.14-1.22 (m, 2H), 1.00-1.12 (m, 2H), 0.83 (dd, J=6.7, 4.6 Hz, 4H), 0.70 (br. s., 1H), 0.41-0.63 (m, 3H). LC-MS: m/z 478.3 (M+H)+
The procedure was similar to the synthesis of Compound 390. 1H NMR (CHLOROFORM-d) δ 7.95 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.39-7.45 (m, 1H), 7.32-7.37 (m, 1H), 6.82-6.96 (m, 1H), 6.31 (dd, J=17.6, 1.3 Hz, 1H), 5.49-5.59 (m, 1H), 4.58 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.5 Hz, 1H), 4.19 (br. s., 0.5H), 4.06 (br. s., 0.5H), 3.78 (br. s., 0.5H), 3.60 (br. s., 0.5H), 3.28 (br. s., 2H), 3.11 (br. s., 1H), 2.29-2.39 (m, 1H), 1.67-1.79 (m, 1H), 1.32-1.45 (m, 1H), 1.18-1.25 (m, 2H), 0.96-1.12 (m, 4H), 0.74-0.87 (m, 2H), 0.65 (br. s., 1H), 0.35-0.58 (m, 3H). LC-MS: m/z 440.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ=9.20 (s, 1H), 7.89 (dd, J=25.5, 17.4 Hz, 3H), 7.73 (s, 1H), 4.66 (d, J=12.8 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 3.49 (s, 4H), 3.36-3.10 (m, 2H), 2.15-1.83 (m, 3H), 1.53 (m, 1H), 1.08-0.95 (m, 4H), 0.84 (m, 3H), 0.61-0.40 (m, 3H). LC-MS: m/z 454.1 (M+H)+
1H NMR (400 MHz, CDCl3) δ=8.38 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 5.48-5.23 (m, 1H), 4.98 (m, 1H), 3.38-3.05 (m, 2H), 2.14-1.88 (m, 4H), 1.01 (dd, J=7.9, 3.4 Hz, 3H), 0.90 (dd, J=9.0, 4.7 Hz, 5H), 0.86-0.77 (m, 3H), 0.57-0.40 (m, 3H). LC-MS: m/z 482.2 (M+H)+
A mixture of 2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(morpholin-2-yl)nicotinonitrile (13 mg, 0.03 mmol), acryloyl chloride (1 drop) and TEA (1 drop) in 10 mL of DCM was stirred at r.t. for 10 mins. After the mixture was quenched and worked up, the filtrate was concentrated and the residue was purified by column chromatography (50% PE/EA) to afford 11 mg of title compound. 1H NMR (CHLOROFORM-d) δ 7.86 (s, 1H), 6.48-6.69 (m, 1H), 6.31-6.48 (m, 1H), 5.80 (d, J=9.3 Hz, 1H), 4.91 (d, J=13.1 Hz, 1H), 4.71 (d, J=8.8 Hz, 1H), 4.44-4.63 (m, 1.5H), 4.05-4.34 (m, 4H), 3.92 (d, J=12.5 Hz, 0.5H), 3.74 (d, J=9.8 Hz, 1.5H), 3.35-3.52 (m, 1.5H), 3.04-3.29 (m, 3H), 2.62 (t, J=11.3 Hz, 0.5H), 2.10 (br. s., 1H), 1.75 (br. s., 1H), 1.40 (br. s., 1.5H), 1.27 (br. s., 1.5H), 1.13 (br. s., 2H), 1.03 (br. s., 4H), 0.81 (d, J=7.0 Hz, 2H). LC-MS: m/z 450.2 (M+H)+
Step 1:
A mixture of 8-4 (50 mg, 0.11 mmol), 5-chloropyridazin-3-ol (21 mg, 0.16 mmol), CsF (33 mg, 0.22 mmol) and Pd(dppf)Cl2 (5 mg) in dioxane and water was heated at 100° C. for 1 hr. The reaction mixture was concentrated and the residue was purified by pre-TLC to afford 35 mg of title compound. 1H NMR (CHLOROFORM-d) δ 12.68 (br. s., 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.02 (br. s., 1H), 4.51-4.64 (m, 2.5H), 4.21 (br. s., 1H), 3.56-3.84 (m, 1H), 3.17-3.32 (m, 2.5H), 1.99 (br. s., 1H), 1.71 (br. s., 1H), 1.24 (br. s., 3H), 1.01-1.08 (m, 4H), 0.72-0.92 (m, 2H), 0.32-0.64 (m, 4H). LC-MS: m/z 431.1 (M+H)+
Step 2:
A solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-hydroxypyridazin-4-yl)nicotinonitrile, Tf2O and TEA in DCM was stirred for 1 hr. The reaction mixture was washed with water, dried and concentrated. The residue was purified by pre-TLC to afford 150 mg of title compound. 1H NMR (CHLOROFORM-d, 400 MHz) δ 9.42 (br. s., 1H), 7.72 (s, 1H), 7.52 (s, 1H), 4.58-4.75 (m, 2.5H), 4.32 (br. s., 0.5H), 4.00 (br. s., 0.5H), 3.73 (br. s., 1H), 3.25-3.39 (m, 2.5H), 1.89-1.94 (m, 1H), 1.72 (br. s., 1H), 1.31 (br. s., 3H), 1.00-1.18 (m, 4H), 0.84 (d, J=6.3 Hz, 2H), 0.45-0.66 (m, 4H).
Step 3:
A mixture of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile (50 mg, 0.09 mmol), potassium vinyltrifluoroborate (24 mg, 0.18 mmol), TEA (27 mg, 0.27 mmol) and Pd(dppf)Cl2 (5 mg) in i-PrOH and water was heated at 100° C. for 1 hr. The reaction mixture was concentrated and the residue was purified by pre-TLC to afford 11 mg of title compound. 1H NMR (CHLOROFORM-d) δ □9.20 (br. s., 1H), 7.68 (br. s., 1H), 7.61 (br. s., 1H), 7.04-7.22 (m, 1H), 6.36 (d, J=17.6 Hz, 1H), 5.78 (d, J=10.8 Hz, 1H), 4.53-4.58 (m, 2.5H), 4.17 (br. s., 1H), 3.72 (br. s., 1H), 3.19-3.34 (m, 1H), 1.94 (br. s., 1H), 1.80 (br. s., 1H), 1.26 (br. s., 3H), 1.07 (br. s., 4H), 0.82 (br. s., 2H), 0.46-0.65 (m, 4H). LC-MS: m/z 441.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.41 (s, 1H), 7.71 (s, 1H), 7.50 (d, J=1.3 Hz, 1H), 4.93 (br. s., 0.5H), 4.56 (d, J=7.8 Hz, 0.5H), 4.47 (d, J=7.3 Hz, 1.5H), 4.25-4.40 (m, 1H), 3.86 (d, J=12.5 Hz, 0.5H), 3.76 (br. s., 2H), 3.57 (br. s., 0.5H), 3.36-3.48 (m, 4H), 3.30 (br. s., 0.5H), 3.11-3.24 (m, 1H), 2.71 (br. s., 1H), 2.61 (br. s., 1H), 1.89-1.93 (m, 1H), 1.37 (d, J=5.5 Hz, 1.5H), 1.22-1.32 (m, 3.5H), 1.08-1.22 (m, 2H). LC-MS: m/z 555.1 (M+H)+
The procedure is similar to Compound 613. 1H NMR (CHLOROFORM-d) δ 9.20 (br. s., 1H), 7.67 (s, 1H), 7.58-7.65 (m, 1H), 7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.37 (d, J=17.8 Hz, 1H), 5.79 (d, J=11.0 Hz, 1H), 4.92 (br. s., 0.5H), 4.48-4.62 (m, 0.5H), 4.35-4.48 (m, 1.5H), 4.31 (d, J=14.1 Hz, 1H), 3.83 (d, J=13.3 Hz, 0.5H), 3.67-3.80 (m, 2H), 3.51-3.63 (m, 0.5H), 3.30-3.45 (m, 4H), 3.13-3.28 (m, 1.5H), 2.65-2.82 (m, 1H), 2.51-2.65 (m, 1H), 1.92-1.96 (m, 1H), 1.38 (d, J=5.5 Hz, 1.5H), 1.24-1.27 (m, 3.5H), 1.07 (d, J=4.8 Hz, 2H). LC-MS: m/z 433.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 12.68 (br. s., 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.02 (br. s., 1H), 4.51-4.64 (m, 2.5H), 4.21 (br. s., 1H), 3.56-3.84 (m, 1H), 3.17-3.32 (m, 2.5H), 1.99 (br. s., 1H), 1.71 (br. s., 1H), 1.24 (br. s., 3H), 1.01-1.08 (m, 4H), 0.72-0.92 (m, 2H), 0.32-0.64 (m, 4H). LC-MS: m/z 431.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.85 (br. s., 1H), 7.60 (br. s., 1H), 6.95 (br. s., 1H), 4.50-4.63 (m, 2.5H), 4.21 (br. s., 1H), 3.84 (br. s., 3H), 3.69 (br. s., 1H), 3.17-3.30 (m, 2.5H), 1.99 (br. s., 1H), 1.76 (br. s., 1H), 1.22 (br. s., 3H), 1.07 (br. s., 4H), 0.81 (br. s., 2H), 0.51 (br. s., 4H). LC-MS: m/z 445.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.51 (d, J=2.3 Hz, 1H), 7.93 (d, J=2.3 Hz, 1H), 7.70 (s, 1H), 4.59-4.72 (m, 2.5H), 4.09-4.26 (m, 1H), 3.75 (br. s., 1H), 3.23-3.39 (m, 2.5H), 1.82-1.95 (m, 1H), 1.65 (br. s., 1H), 1.26-1.34 (m, 3H), 0.96-1.20 (m, 4H), 0.76-0.91 (m, 2H), 0.38-0.75 (m, 4H). LC-MS: m/z 440.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.64-7.74 (m, 3H), 7.43 (t, J=5.9 Hz, 1H), 4.91 (br. s., 0.5H), 4.57-4.53 (d, 0.5H), 4.18-4.39 (m, 2.5H), 3.6-3.77 (m, 1H), 3.34 (br. s., 1H), 3.05-3.25 (m, 1.5H), 1.91 (br. s., 3H), 1.33-1.54 (m, 4H), 1.14-1.17 (m, 2H), 0.82-0.85 (m, 2H). LC-MS: m/z 412.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.59-7.76 (m, 3H), 7.44 (t, J=6.8 Hz, 1H), 4.87-5.02 (m, 0.5H), 4.61-4.64 (m, 0.5H), 4.12-4.43 (m, 2.5), 3.05-3.70 (m, 5.5H), 2.0 (s, 1H), 1.76-1.86 (m, 1H), 1.40-1.62 (m, 3H), 1.27-1.35 (m, 2H), 1.16-1.21 (m, 4H), 0.92-0.99 (m, 1H), 0.81-0.84 (m, 2H). LC-MS: m/z 482.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.37 (s, 1H), 8.54 (dd, J=6.0, 2.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.73 (t, 1H), 7.64-7.69 (m, 2H), 7.46 (q, 1H), 4.73 (m, 0.5H), 4.43-4.62 (m, 2.5H), 4.13-4.26 (m, 2H), 3.68-3.87 (m, 1.5H), 3.50-3.60 (m, 3.5H), 3.19-3.30 (s, 2H), 1.97-2.19 (m, 2H), 1.50-1.54 (m, 1H), 1.16-1.23 (m, 6H), 0.82-0.91 (m, 5H), 0.64-0.68 (m, 2H), 0.43-0.51 (m, 2H). LC-MS: m/z 508.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.91 (s, 1H), 9.38 (s, 1H), 8.55 (br. s., 1H), 8.09 (d, J=8.0 Hz, 1H), 7.74 (t, 1H), 7.66-7.70 (m, 2H), 7.47 (q, 1H), 4.55-4.58 (d, 1H), 4.44-4.47 (d, 1H), 4.09 (br. s., 1H), 3.90 (br. s., 1H), 3.07-3.40 (m, 2.5H), 2.69-2.91 (m, 3.5H), 2.05 (m, 2H), 14.53 (m, 1H), 0.83-0.92 (m, 6H), 0.44-0.71 (br. s., 4H). LC-MS: m/z 480.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (br. s., 1H), 8.53 (br. s., 1H), 8.07 (d, J=8.0 Hz, 1H), 7.68-7.74 (t, 1H), 7.64-7.67 (m, 2H), 7.45 (dd, J=5.8 Hz, 1H), 4.58 (d, J=12.8 Hz, 1H), 4.49 (d, J=11.3 Hz, 1H), 4.13-4.27 (m, 1.5H), 3.80 (br. s., 0.5H), 3.52-3.59 (m, 3H), 3.22 (br. s., 2H), 1.82 (d, J=7.5 Hz, 1H), 1.47-1.57 (m, 2H), 1.17-1.20 (m, 6H), 0.82-0.99 (m, 5H), 0.45-0.65 (m, 4H). LC-MS: m/z 508.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.39 (br. s., 1H), 8.56 (br. s., 1H), 8.08 (d, J=8.0 Hz, 1H), 7.71-7.76 (m, 1H), 7.66-7.70 (m, 1H), 7.64 (s, 1H), 7.47 (br. s., 1H), 4.18-4.89 (m, 4H), 3.25-3.80 (m, 5H), 2.01-2.08 (m, 1H), 1.46-1.57 (m, 2H), 1.24-1.39 (m, 4H), 1.10-1.20 (m, 2H), 0.79-0.91 (m, 3H). LC-MS: m/z 468.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.88 (d, J=1.8 Hz, 1H), 8.91 (d, J=1.5 Hz, 1H), 8.21 (dd, J=8.4, 1.4 Hz, 1H), 7.88 (t, J=8.4, 7.2 Hz, 1H), 7.79 (dd, J=7.2, 1.4 Hz, 1H), 7.73 (s, 1H), 4.53 (d, 1H), 4.56 (d, 1H), 4.53-4.27 (m, 2.5H), 3.05-3.45 (m, 2.5H), 1.74 (br. s., 1H), 1.56-1.65 (m, 1H), 0.97-1.26 (m, 6H), 0.42-0.87 (m, 8H). LC-MS: m/z 465.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.89-8.92 (m, 2H), 8.22 (dd, J=8.4, 1.4 Hz, 1H), 7.89 (t, J=8.3, 7.3 Hz, 1H), 7.79-7.81 (dd, J=8.3, 7.3 Hz, 1H), 7.75 (s, 1H), 4.53 (d, J=13.1 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 4.14 (br. s., 0.5H), 3.75-3.89 (m, 1.5H), 3.07-3.37 (m, 5H), 1.62 (m, 1H), 1.19 (br. s., 2H), 0.48-0.84 (m, 6H). LC-MS: m/z 507.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (dd, J=8.5, 1.3 Hz, 1H), 7.84 (dd, J=8.3, 7.3 Hz, 1H), 7.67-7.74 (m, 1H), 7.01-7.12 (m, 1H), 6.50 (d, J=11.3 Hz, 1H), 5.84 (d, J=11.3 Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (br. s., 0.5H), 4.19-4.40 (m, 2.5H), 3.68-3.78 (m, 2.5H), 3.58 (br. s., 0.5H), 3.39 (s, 3H), 3.02-3.31 (m, 2.5H), 2.58-2.75 (m, 2H), 1.86 (br. s., 1H), 1.62 (m, 1H), 1.43 (d, J=6.3 Hz, 1.5H), 1.33 (d, J=6.3 Hz, 1.5H), 1.16 (br. s., 2H), 0.81 (br. s., 2H). LC-MS: m/z 485.2 (M+H)+
It was obtained as the by-product of Compound 579. 1H NMR (CHLOROFORM-d) δ 9.23 (s, 1H), 9.09 (s, 1H), 8.17-8.20 (m, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.70-7.87 (m, 5H), 7.04-7.11 (q, 1H), 6.53 (d, J=11.3 Hz, 1H), 5.85 (d, J=11.3 Hz, 1H), 4.94 (br. s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.26-4.37 (m, 2.5H), 3.75-3.84 (m, 2.5H), 3.59 (t, 0.5H), 3.40 (s, 3H), 3.06-3.32 (m, 2.5H), 2.59-2.81 (m, 2H), 1.61-1.73 (m, 1H), 1.45 (d, J=6.3 Hz, 1.5H), 1.32 (d, J=6.3 Hz, 1.5H), 1.25-1.29 (m, 2H), 0.83-0.86 (m, 2H). LC-MS: m/z 637.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.62-7.77 (m, 2H), 6.97-7.13 (q, 1H), 6.50 (d, J=11.0 Hz, 1H), 5.84 (d, J=11.0 Hz, 1H), 4.58-4.73 (m, 1.5H), 4.39-4.48 (m, 1.5H), 3.87 (d, J=13.3 Hz, 0.5H), 3.74 (m, 2H), 3.42-3.60 (m, 1H), 3.39 (d, J=3.3 Hz, 3H), 2.93-3.17 (m, 2.5H), 2.53-2.83 (m, 2H), 2.16-2.33 (m, 1H), 1.62 (br. s., 1H), 1.07-1.10 (m, 4H), 0.82-0.93 (m, 6H). LC-MS: m/z 511.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (dd, J=8.5, 1.3 Hz, 1H), 7.84 (dd, J=8.3, 7.3 Hz, 1H), 7.67-7.74 (m, 2H), 7.02-7.07 (m, 1H), 6.50 (d, J=11.3 Hz, 1H), 5.82 (d, J=11.3 Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (br. s., 0.5H), 4.19-4.33 (m, 3H), 3.93 (s, 2.5H), 3.58 (br. s., 0.5H), 3.01-3.48 (m, 4H), 2.48-2.75 (m, 3H), 1.63 (m, 1H), 1.43 (d, J=6.3 Hz, 1.5H), 1.35 (d, J=6.3 Hz, 1.5H), 1.16 (br. s., 2H), 0.82 (br. s., 2H). LC-MS: m/z 469.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.00 (s, 1H), 8.13 (dd, J=8.5, 1.3 Hz, 1H), 7.70-7.72 (m, 2H), 7.01-7.12 (q, 1H), 6.50 (d, J=11.3 Hz, 1H), 5.84 (d, J=11.3 Hz, 1H), 4.71 (br. s., 0.5H), 4.52 (d, 1H), 4.41 (d, 1H), 4.12 (br. s., 0.5H), 3.89 (br. s., 0.5H), 3.74 (m, 2H), 3.39 (s, 3H), 3.01-3.31 (m, 3H), 2.59-2.83 (m, 2H), 1.58-1.68 (m, 1H), 0.97-1.32 (m, 4H), 0.46-0.89 (m, 7H).
LC-MS: m/z 509.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.46 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.57-7.61 (m, 1H), 7.34 (dd, J=5.0, 1.5 Hz, 1H), 4.61 (d, J=12.8 Hz, 1H), 4.49 (d, J=13.6 Hz, 1H), 4.18-4.38 (m, 1H), 3.76 (br. s., 2H), 3.31 (br. s., 1H), 3.15 (br. s., 1H), 1.93-2.08 (m, 1H), 1.72 (br. s., 1H), 1.33 (br. s., 1H), 1.17-1.26 (m, 2H), 0.95-1.12 (m, 4H), 0.76-0.91 (m, 2H), 0.66 (br. s., 1H), 0.35-0.60 (m, 3H). LC-MS: m/z 493.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.29 (d, J=5.0 Hz, 1H), 7.59-7.75 (s, 1H), 7.11-7.41 (d, J=5.0 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.50 (d, J=12.5 Hz, 1H), 4.06 (br. s., 1H), 3.75 (br. s., 1H), 3.65 (br. s., 1H), 3.31 (br. s., 1H), 3.16 (br. s., 1H), 1.70-1.81 (m, 1H), 1.30-1.42 (m, 1H), 1.13-1.25 (m, 2H), 0.94-1.13 (m, 4H), 0.75-0.87 (m, 2H), 0.66 (br. s., 1H), 0.35-0.60 (m, 3H).
LC-MS: m/z 466.9 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (dd, J=5.8, 1.8 Hz, 1H), 8.45 (d, J=8.3 Hz, 1H), 7.87-7.97 (m, 1H), 7.80 (ddd, J=7.2, 2.1, 1.0 Hz, 1H), 7.70 (ddd, J=11.1, 5.8, 0.9 Hz, 1H), 7.64 (d, J=0.8 Hz, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.49 (d, J=12.8 Hz, 1H), 3.42-4.43 (m, 2H), 3.10-3.40 (m, 3H), 1.75 (br. s., 1H), 1.38-1.47 (m, 2H), 0.95-1.12 (m, 2H), 0.75-0.93 (m, 6H), 0.70 (br. s., 1H), 0.38-0.61 (m, 3H). LC-MS: m/z 489.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 10.95 (s, 1H), 8.53 (dd, J=6.4, 3.1 Hz, 1H), 7.57-7.72 (m, 3H), 7.17 (br. s., 1H), 6.31 (dd, J=12.9, 7.4 Hz, 1H), 4.38-4.61 (m, 2H), 4.15 (br. s., 0.5H), 3.69-3.95 (m, 1.5H), 3.03-3.41 (m, 5H), 1.53-1.77 (m, 3H), 1.16 (dd, J=8.3, 4.5 Hz, 2H), 0.81-0.98 (m, 2H), 0.47-0.64 (m, 3H). LC-MS: m/z 522.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.17 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.66-7.73 (m, 2H), 7.64 (d, J=1.0 Hz, 1H), 7.49 (d, J=14.8 Hz, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.49 (d, J=12.8 Hz, 1H), 3.42-4.43 (m, 2H), 3.10-3.40 (m, 3H), 1.69 (br. s., 1H), 1.39-1.57 (m, 2H), 1.15-1.23 (m, 2H), 1.08 (br. s., 2H), 0.79-0.93 (m, 4H), 0.70 (br. s., 1H), 0.38-0.63 (m, 3H). LC-MS: m/z 498.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 11.20 (br. s., 1H), 8.52 (dd, J=7.0, 2.3 Hz, 1H), 7.51-7.76 (m, 3H), 7.12-7.24 (m, 1H), 6.33 (dd, J=12.7, 7.4 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.44 (d, J=12.3 Hz, 1H), 3.52-4.35 (m, 2H), 3.05-3.45 (m, 3H), 1.63 (td, J=7.8, 4.0 Hz, 1H), 1.27-1.45 (m, 2H), 0.96-1.23 (m, 4H), 0.77-0.96 (m, 4H), 0.70 (br. s., 1H), 0.36-0.62 (m, 3H). LC-MS: m/z 480.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.29 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.55-7.77 (m, 3H), 7.31 (d, J=12.5 Hz, 1H), 6.88 (ddd, J=17.3, 10.6, 6.8 Hz, 1H), 6.38 (ddd, J=17.2, 5.6, 1.3 Hz, 1H), 5.44-5.59 (m, 1H), 4.59 (d, J=11.8 Hz, 1H), 4.47 (d, J=12.5 Hz, 1H), 3.55-4.35 (m, 2H), 3.05-3.45 (m, 3H), 1.68-1.80 (m, 1H), 1.42-1.61 (m, 2H), 1.22-1.34 (m, 2H), 1.00-1.14 (m, 2H), 0.76-0.92 (m, 4H), 0.71 (br. s., 1H), 0.39-0.63 (m, 3H). LC-MS: m/z 490.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.23 (s, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.53-7.67 (m, 3H), 7.21 (d, J=6.5 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.15-4.43 (m, 2.5H), 3.86-4.02 (m, 2H), 3.68-3.83 (m, 0.5H), 3.51-3.68 (m, 0.5H), 3.26-3.42 (m, 1H), 2.97-3.24 (m, 1.5H), 2.49-2.78 (m, 5H), 1.49-1.58 (m, 1H), 1.41-1.49 (m, 1.5H), 1.30-1.40 (m, 1.5H), 1.06-1.20 (m, 2H), 0.72-0.91 (m, 2H). LC-MS: m/z 456.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.69-8.87 (m, 1H), 7.70-7.91 (m, 1H), 6.91 (dd, J=17.3, 10.5 Hz, 1H), 6.59-6.78 (m, 1H), 5.71-5.98 (m, 1H), 4.66 (d, J=12.8 Hz, 1H), 4.53 (d, J=12.5 Hz, 1H), 3.09-4.42 (m, 5H), 1.76-1.85 (m, 1H), 1.39-1.46 (m, 1H), 1.21-1.25 (m, 2H), 0.99-1.10 (m, 4H), 0.90 (t, J=6.9 Hz, 1H), 0.78-0.85 (m, 2H), 0.66 (br. s., 1H), 0.41-0.60 (m, 3H). LC-MS: m/z 475.2 (M+H)+
To a solution of 4,6-dichloropyrimidine (50 mg, 0.32 mmol) in a mixture of dimethoxyethane (3 mL) and a 2M aqueous sodium carbonate solution (0.6 mL) were added 8-4 (100 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.1 eq) under nitrogen atmosphere, and the mixture was heated for 2 hours at 100° C. After cooling to ambient temperature, the separated organic layer was evaporated under reduced pressure. The residue was taken up into ethyl acetate, washed in turn with a 10% aqueous potassium carbonate solution and brine, and dried over sodium sulfate. After evaporation, the residue was purified on silica gel eluding with 5%-20% ethyl acetate in petroleum ether to give 4-chloro-6-phenylpyrimidine (75 mg), 69% yield. 1H NMR (CHLOROFORM-d) δ 8.67-8.84 (m, 1H), 8.07 (s, 1H), 7.43 (d, J=5.0 Hz, 1H), 4.68 (d, J=13.1 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H), 4.07 (br. s., 1H), 3.88 (s, 1H), 3.68 (br. s., 1H), 3.33 (br. s., 1H), 3.17 (br. s., 1H), 2.34-2.47 (m, 1H), 1.96-2.08 (m, 2H), 1.30-1.42 (m, 2H), 1.00-1.11 (m, 3H), 0.85-0.93 (m, 1H), 0.82 (dd, J=8.0, 2.5 Hz, 2H), 0.65 (br. s., 1H), 0.39-0.59 (m, 3H). LC-MS: m/z 449.2 (M+H)+
A mixture of above (R)-5-(6-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile (60 mg, 0.06 mmol) (60 mg, 0.13 mmol), vinyl potassium-trifluoroborate (25 mg, 0.2 mmol), Pd(PPh3)4 (3 mg, 0.1 eq), and CsF (40 mg, 0.26 mmol) were suspended in 5 mL of dioxane and 1 mL of water, the resulting mixture was refluxed for 1 h. After the reaction was complete, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to afford 35 mg of title compound as yellow solid. 75% yield. 1H NMR (CHLOROFORM-d) δ 9.16-9.30 (m, 1H), 7.93-8.07 (m, 1H), 7.49-7.56 (m, 1H), 6.82 (dd, J=17.3, 10.5 Hz, 1H), 6.57 (dd, J=17.3, 1.0 Hz, 1H), 5.72-5.83 (m, 1H), 4.68 (d, J=13.1 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.39-3.11 (br. s., 5H), 2.34-2.43 (m, 1H), 1.70 (br. s., 1H), 1.31-1.40 (m, 2H), 0.99-1.11 (m, 4H), 0.89-0.94 (m, 1H), 0.82 (dd, J=7.9, 2.4 Hz, 2H), 0.64 (br. s., 1H), 0.41-0.58 (m, 3H). LC-MS: m/z 441.2 (M+H)+
1H NMR (CHLOROFORM-d) δ9.24 (d, J=1.3 Hz, 1H), 7.94-8.05 (m, 1H), 7.46-7.58 (m, 1H), 6.82 (dd, J=17.3, 10.8 Hz, 1H), 6.57 (dd, J=17.3, 1.0 Hz, 1H), 5.73-5.84 (m, 1H), 4.68 (d, J=12.5 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.08 (br. s., 1H), 3.76 (s, 1H), 3.66 (t, J=6.7 Hz, 1H), 3.40-3.58 (m, 1H), 3.33 (br. s., 1H), 3.17 (br. s., 1H), 2.34-2.45 (m, 1H), 1.29-1.35 (m, 2H), 1.00-1.11 (m, 4H), 0.89-0.92 (m, 1H), 0.82 (dd, J=7.9, 2.4 Hz, 2H), 0.64 (br. s., 1H), 0.43-0.58 (m, 3H). LC-MS: m/z 441.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.24 (d, J=1.3 Hz, 1H), 7.82-8.04 (m, 1H), 7.47-7.61 (m, 1H), 6.68-6.93 (m, 1H), 6.42-6.62 (m, 1H), 5.64-5.88 (m, 1H), 4.88 (br. s., 1H), 4.29-4.57 (m, 3H), 4.17 (br. s., 1H), 3.93 (br. s., 2H), 3.74 (d, J=13.3 Hz, 1H), 3.47-3.63 (m, 1H), 3.29-3.41 (m, 1H), 3.05-3.25 (m, 2H), 2.51-2.72 (m, 2H), 2.33-2.42 (m, 1H), 1.32-1.44 (m, 2H), 1.22-1.28 (m, 3H), 1.02-1.11 (m, 2H). LC-MS: m/z 419.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.24 (s, 1H), 7.95-8.11 (m, 1H), 7.50-7.56 (m, 1H), 6.74-6.87 (m, 1H), 6.48-6.65 (m, 1H), 5.74-5.89 (m, 1H), 4.67 (d, J=12.8 Hz, 1H), 4.53 (d, J=11.0 Hz, 1H), 4.10 (br. s., 0.5H), 3.83-3.93 (m, 0.5H), 3.61-3.81 (m, 3H), 3.39 (s, 3H), 3.21-3.35 (m, 2H), 3.08-3.21 (m, 1H), 2.72 (br. s., 1H), 2.65 (br. s., 1H), 2.33-2.43 (m, 1H), 1.21-1.36 (m, 3H), 1.03-1.13 (m, 2H), 0.60 (br. s., 2H), 0.45 (br. s., 2H). LC-MS: m/z 459.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.09-9.32 (m, 1H), 7.99 (s, 1H), 7.51 (s, 1H), 6.81 (dd, J=17.3, 10.5 Hz, 1H), 6.56 (d, J=17.3 Hz, 1H), 5.78 (d, J=11.3 Hz, 1H), 4.67-4.76 (m, 1H), 4.50 (d, J=14.6 Hz, 1H), 3.88 (d, J=13.6 Hz, 1H), 3.68-3.79 (m, 2H), 3.60 (d, J=10.5 Hz, 1H), 3.39-3.55 (m, 1H), 3.02-3.24 (m, 2H), 2.85-3.02 (m, 1H), 2.52-2.82 (m, 2H), 2.33-2.43 (m, 1H), 1.92-2.05 (m, 1H), 1.23-1.31 (m, 2H), 1.00-1.10 (m, 5H), 0.83-0.92 (m, 3H). LC-MS: m/z 461.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.98 (s, 1H), 7.50 (s, 1H), 6.80 (dd, J=17.3, 10.8 Hz, 1H), 6.44-6.69 (m, 1H), 5.64-5.92 (m, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=9.5 Hz, 0.5H), 4.28-4.46 (m, 2H), 3.65-3.95 (m, 3H), 3.44-3.65 (m, 1H), 3.27-3.44 (m, 4H), 3.00-3.27 (m, 2H), 2.51-2.81 (m, 2H), 2.25-2.47 (m, 1H), 1.14-1.44 (m, 5H), 0.93-1.14 (m, 2H). LC-MS: m/z 433.2 (M+H)+
To a solution of (R)-5-(6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (80 mg 0.21 mmol), CuI (10 mg, 10%), and Pd(PPh3)2Cl2 (15 mg) in 5 ml of DMF was added (1-fluorovinyl)(methyl) diphenylsilane (7.6 mg, 0.41 mmol). The mixture was stirred at room temperature for 2 h under nitrogen atmosphere. After removal of the solvent under reduced pressure, the residue was purified by prep-TLC (20% ethyl acetate in petroleum ether) to afford 20 mg of pure product, 30% yield. 1H NMR (CHLOROFORM-d) δ □9.25 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 6.11 (d, J=3.0 Hz, 1H), 5.99 (d, J=3.0 Hz, 1H), 5.27 (dd, J=15.8, 3.0 Hz, 1H), 4.91 (br. s., 1H), 4.54 (d, J=10.3 Hz, 1H), 4.31-4.49 (m, 1H), 3.71-3.78 (m, 1H), 3.49-3.63 (m, 1H), 3.31-3.44 (m, 4H), 3.16-3.28 (m, 1H), 3.13 (br. s., 1H), 2.51-2.81 (m, 2H), 2.30-2.44 (m, 1H), 1.35 (d, J=6.5 Hz, 2H), 1.25 (dd, J=4.3, 2.8 Hz, 3H), 1.04-1.13 (m, 2H). LC-MS: m/z 451.2 (M+H)+
Synthesized according to the procedure described for Compound 602 except using trimethyl(prop-1-en-2-yl) silane instead of (1-fluorovinyl)(methyl) diphenylsilane. 1H NMR (CHLOROFORM-d) δ8.67 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.16-7.27 (m, 1H), 5.92 (s, 1H), 5.38 (s, 1H), 4.57 (d, J=12.3 Hz, 1H), 4.45 (d, J=12.3 Hz, 1H), 4.07 (br. s., 1H), 3.78 (br. s., 1H), 3.56-3.74 (m, 1H), 3.50 (s, 1H), 3.29 (br. s., 1H), 3.14 (br. s., 1H), 2.26 (s, 3H), 1.98-2.10 (m, 1H), 1.72 (br. s., 1H), 1.17-1.27 (m, 2H), 0.97-1.09 (m, 4H), 0.86-0.95 (m, 1H), 0.76-0.84 (m, 2H), 0.66 (br. s., 1H), 0.40-0.59 (m, 3H). LC-MS: m/z 453.2 (M+H)+
To a solution NH3/MeOH (10 mL, 7 M) was added (R)-5-(2-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile (40 mg, 0.09 mmol), the mixture was stirred at 50 C overnight. After removal of the solvent under reduced pressure, the residue was purified by prep-TLC (30% ethyl acetate in petroleum ether) to afford 21 mg of pure product, 51% yield. 1H NMR (CHLOROFORM-d) δ 8.36 (d, J=5.3 Hz, 1H), 7.97 (s, 1H), 6.90 (d, J=5.0 Hz, 1H), 5.25 (br. s., 2H), 4.64 (d, J=12.5 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 3.69 (br. s., 1H), 3.32 (br. s., 1H), 3.26 (br. s., 1H), 3.15 (br. s., 2H), 2.32-2.45 (m, 1H), 2.03-2.08 (m, 1H), 1.02-1.10 (m, 4H), 0.77-0.89 (m, 4H), 0.63 (br. s., 2H), 0.43-0.58 (m, 3H). LC-MS: m/z 430.2 (M+H)+
Synthesized according to the procedure described for Compound 507 except using dimethylamine instead of NH3.EtOH. 1H NMR (CHLOROFORM-d) δ 8.38 (d, J=5.0 Hz, 1H), 7.90-8.06 (m, 1H), 6.72 (d, J=5.0 Hz, 1H), 4.61 (d, J=12.8 Hz, 1H), 4.49 (d, J=12.5 Hz, 1H), 4.09-4.26 (m, 1H), 3.30-3.58 (m, 2H), 3.26 (s, 6H), 3.16-3.24 (m, 1H), 3.11 (d, J=18.3 Hz, 1H), 2.48-2.56 (m, 1H), 1.19-1.24 (m, 3H), 0.98-1.08 (m, 4H), 0.86-0.92 (m, 1H), 0.76-0.84 (m, 2H), 0.64 (br. s., 1H), 0.40-0.58 (m, 3H). LC-MS: m/z 458.3 (M+H)+
1H NMR (CHLOROFORM-d) δ8.37 (d, J=5.3 Hz, 1H), 7.97 (s, 1H), 6.89 (d, J=5.0 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.51 (d, J=12.8 Hz, 1H), 4.00-4.17 (m, 1H), 3.68-3.87 (m, 1H), 3.17-3.38 (m, 3H), 3.12 (d, J=11.8 Hz, 1H), 2.82 (s, 2H), 2.33-2.45 (m, 1H), 1.35 (br. s., 1H), 1.18-1.25 (m, 2H), 0.98-1.10 (m, 2H), 0.64 (br. s., 1H), 0.57 (br. s., 1H), 0.38-0.54 (m, 2H). LC-MS: m/z 472.2 (M+H)+
Synthesized according to the procedure described in Compound 507 except using 2-(methylamino)ethanol instead of NH3.EtOH. 1H NMR (CHLOROFORM-d) δ 8.32 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 6.83 (d, J=5.3 Hz, 1H), 5.91 (br. s., 1H), 4.63 (d, J=12.8 Hz, 1H), 4.50 (d, J=12.5 Hz, 1H), 3.96-4.33 (m, 1H), 3.82-3.92 (m, 2H), 3.63-3.72 (m, 2H), 3.29 (br. s., 1H), 3.14 (br. s., 1H), 2.68-2.78 (m, 1H), 2.66 (br. s., 1H), 2.34-2.44 (m, 1H), 1.20-1.35 (m, 4H), 1.04 (dd, J=7.7, 3.4 Hz, 4H), 0.77-0.90 (m, 3H), 0.64 (br. s., 1H), 0.49-0.55 (m, 1H), 0.44 (dt, J=9.3, 4.4 Hz, 1H).
LC-MS: m/z 474.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.42 (d, J=5.3 Hz, 1H), 8.00 (s, 1H), 6.75 (d, J=5.3 Hz, 1H), 4.62 (d, J=13.1 Hz, 1H), 4.50 (d, J=12.8 Hz, 1H), 3.96-4.20 (m, 1H), 3.68-3.96 (m, 1H), 3.28-3.42 (m, 2H), 3.09-3.15 (m, 1H), 2.42-2.54 (m, 1H), 1.39-1.56 (m, 1H), 1.14-1.25 (m, 2H), 0.98-1.08 (m, 2H), 0.65 (br. s., 1H), 0.56 (br. s., 1H), 0.43-0.53 (m, 2H). LC-MS: m/z 500.2 (M+H)+
Step 1:
To a flask was added with (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (70 mg, 0.151 mmol), 2, 6-dichloropyrazine (30 mg, 0.197 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), K2CO3 (63 mg, 0.453 mmol), and 1.5 mL DMF. The mixture was stirred at 120° C. for 2 h. After washing with Satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Prep-TLC purification (20% EtOAc/petroleum ether) afforded 25 mg of (R)-5-(6-chloropyrazin-2-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile.
Step 2:
To a flask was added with (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(6-vinylpyrazin-2-yl)nicotinonitrile (18 mg 0.04 mmol), tributyl(vinyl) stannane (17 mg, 0.052 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), K2CO3 (14 mg, 0.052 mmol), and 1.5 mL DMF. The mixture was stirred at 120° C. for 2 h. After washing with Satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Prep-TLC purification (20% EtOAc/petroleum ether) afforded 10 mg of title compound. 1H NMR (CHLOROFORM-d) δ 8.72 (s, 1H), 8.56 (s, 1H), 8.00 (s, 1H), 6.90 (dd, J=17.3, 10.8 Hz, 1H), 6.47 (dd, J=17.6, 1.0 Hz, 1H), 5.70 (dd, J=10.8, 1.0 Hz, 1H), 4.65 (d, J=13.1 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.99-4.29 (m, 1H), 3.52-3.91 (m, 1H), 3.32 (br. s., 1H), 3.16 (br. s., 1H), 2.22-2.35 (m, 1H), 1.23-1.38 (m, 5H), 0.97-1.14 (m, 4H), 0.81 (dd, J=7.8, 2.3 Hz, 2H), 0.65 (br. s., 1H), 0.48-0.55 (m, 1H), 0.45 (dt, J=9.6, 4.6 Hz, 1H).
LC-MS: m/z 441.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.61 (d, J=5.0 Hz, 1H), 7.55-7.68 (m, 1H), 7.36 (s, 1H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.84 (dd, J=17.6, 10.8 Hz, 1H), 6.17-6.35 (m, 1H), 5.53 (dd, J=10.8, 0.8 Hz, 1H), 4.53 (d, J=12.5 Hz, 1H), 4.32-4.47 (m, 1H), 4.01-4.16 (m, 0.5H), 3.86 (d, J=12.5 Hz, 0.5H), 3.70 (t, J=5.5 Hz, 3H), 3.35 (s, 3H), 3.18 (d, J=11.3 Hz, 2H), 2.94-3.14 (m, 1H), 2.56-2.73 (m, 2H), 1.90-2.10 (m, 1H), 1.22-1.34 (m, 1H), 1.14-1.32 (m, 2H), 0.83-1.06 (m, 2H), 0.58 (br. s., 1H), 0.52 (br. s., 1H), 0.28-0.48 (m, 2H). LC-MS: m/z 458.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.5 Hz, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.0 Hz, 1H), 6.88 (dd, J=17.3, 10.8 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.65 (br. s., 0.5H), 4.55 (d, J=12.5 Hz, 1H), 4.43 (d, J=12.0 Hz, 1H), 4.08 (br. s., 0.5H), 3.77 (br. s., 1H), 3.21 (br. s., 2H), 3.11 (br. s., 1H), 2.17 (br. s., 2H), 2.11 (br. s., 1H), 2.03 (br. s., 1H), 1.28 (d, J=12.0 Hz, 2H), 1.24-1.50 (br. s., 3H), 0.60 (br. s., 2H), 0.45 (br. s., 2H). LC-MS: m/z 414.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.66 (s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.0 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 5.16 (br. s., 1H), 4.56 (d, J=13.1 Hz, 1H), 4.43 (d, J=12.5 Hz, 1H), 4.14 (d, J=8.8 Hz, 0.5H), 3.65-3.78 (m, 1H), 3.17-3.91 (m, 1.5H), 3.04-3.14 (m, 1H), 2.43-2.57 (m, 2H), 2.02-2.07 (m, 1H), 1.33 (s, 6H), 1.25-1.30 (m, 2H), 1.21 (br. s., 2H), 1.02 (dd, J=7.5, 3.3 Hz, 2H), 0.65 (d, J=6.5 Hz, 1H), 0.42-0.53 (m, 2H). LC-MS: m/z 472.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.65 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.36-7.41 (m, 1H), 7.23 (dd, J=5.0, 1.8 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H), 6.21-6.35 (m, 1H), 5.57 (dd, J=10.9, 0.9 Hz, 1H), 4.84 (br. s., 0.5H), 4.35 (br. s., 2H), 4.27 (br. s., 1H), 4.20 (br. s., 2H), 3.89 (br. s., 0.5H), 3.53-3.65 (m, 2.5H), 3.24-3.35 (m, 1H), 3.17 (br. s., 1.5H), 1.98-2.08 (m, 1H), 1.29-1.41 (m, 3H), 1.23-1.28 (m, 3H), 1.15-1.23 (m, 2H), 0.95-1.07 (m, 2H). LC-MS: m/z 432.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.63 (d, J=5.0 Hz, 1H), 7.53-7.75 (m, 2H), 7.37 (s, 1H), 7.22 (dd, J=4.8, 1.5 Hz, 1H), 6.86 (dd, J=17.6, 10.8 Hz, 1H), 6.19-6.37 (m, 1H), 5.54 (d, J=11.5 Hz, 1H), 4.55 (d, J=13.1 Hz, 1H), 4.42 (d, J=12.8 Hz, 1H), 4.11-4.17 (m, 2H), 3.44 (s, 4H), 3.19-3.25 (m, 1H), 3.04-3.11 (m, 1H), 2.80 (s, 1H), 1.89-2.07 (m, 2H), 1.17-1.27 (m, 4H), 0.95-1.02 (m, 2H), 0.41-0.54 (m, 3H). LC-MS: m/z 444.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.61-7.69 (m, 1H), 7.36-7.44 (m, 1H), 7.24 (dd, J=5.0, 1.8 Hz, 1H), 6.89 (dd, J=17.3, 10.8 Hz, 1H), 6.29 (dd, J=17.6, 1.0 Hz, 1H), 5.58 (dd, J=10.8, 0.8 Hz, 1H), 4.90 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.26-4.40 (m, 2H), 4.12-4.23 (m, 1H), 3.93 (br. s., 2H), 3.74 (d, J=13.1 Hz, 1H), 3.29-3.34 (m, 1H), 3.06-3.18 (m, 1H), 2.50-2.63 (m, 1H), 2.17-2.25 (m, 1H), 2.02-2.07 (m, 1H), 1.41 (d, J=6.8 Hz, 1H), 1.29-1.33 (m, 2H), 1.28 (d, J=2.8 Hz, 1H), 1.19-1.22 (m, 1.5H), 1.02 (dd, J=7.9, 3.1 Hz, 1.5H). LC-MS: m/z 418.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.5 Hz, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.46 (s, 1H), 7.36-7.44 (m, 1H), 7.25 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.56 (s, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.60 (d, J=13.1 Hz, 1H), 4.44 (d, J=12.8 Hz, 1H), 4.27 (br. s., 1H), 3.93 (br. s., 1H), 3.66 (br. s., 1H), 3.19-3.38 (m, 1H), 3.09 (t, J=11.3 Hz, 1H), 2.03 (dd, J=7.4, 3.1 Hz, 1H), 1.35-1.50 (m, 1H), 1.13-1.35 (m, 2H), 0.90-1.08 (m, 2H), 0.59-0.76 (m, 1H), 0.52 (t, J=8.0 Hz, 1H), 0.42 (br. s., 2H). LC-MS: m/z 466.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.43 (d, J=12.5 Hz, 1H), 4.17-4.33 (m, 2H), 3.96-4.17 (m, 1H), 3.79 (br. s., 1H), 3.71 (d, J=11.8 Hz, 1H), 3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48 (m, 1H), 2.04 (m, 1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br. s., 1H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H). LC-MS: m/z 458.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 1H NMR (CHLOROFORM-d) v 8.61 (d, J=5.0 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.20 (dd, J=5.0, 1.5 Hz, 1H), 6.84 (dd, J=17.3, 10.8 Hz, 1H), 6.25 (d, J=17.6 Hz, 1H), 5.52 (d, J=11.0 Hz, 1H), 4.50-4.79 (m, 2H), 4.28-4.50 (m, 2H), 3.85 (d, J=13.6 Hz, 1H), 3.63-3.79 (m, 2H), 3.57 (d, J=10.0 Hz, 1H), 3.30-3.49 (m, 3H), 2.99-3.27 (m, 2H), 2.83-2.98 (m, 1H), 2.49-2.79 (m, 1H), 2.17 (dt, J=10.5, 6.7 Hz, 1H), 1.08-1.30 (m, 3H), 0.78-1.08 (m, 7H). LC-MS: m/z 460.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.64 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.31-7.50 (m, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.87 (dd, J=17.4, 10.9 Hz, 1H), 6.27 (dd, J=17.4, 0.9 Hz, 1H), 5.42-5.72 (m, 1H), 4.84 (br. s., 1H), 4.20-4.40 (m, 3H), 4.00-4.20 (m, 1H), 3.36-3.65 (m, 2H), 3.20-3.36 (m, 2H), 2.97-3.20 (m, 1H), 2.70-2.96 (m, 4H), 1.86-2.06 (m, 1H), 1.40 (d, J=6.3 Hz, 1H), 1.09-1.36 (m, 4H), 0.79-1.09 (m, 2H). LC-MS: m/z 404.0 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.43 (d, J=12.5 Hz, 1H), 4.17-4.33 (m, 2H), 3.96-4.17 (m, 1H), 3.79 (br. s., 1H), 3.71 (d, J=11.8 Hz, 1H), 3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48 (m, 1H), 2.04 (m, 1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br. s., 1H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H). LC-MS: m/z 458.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 10.76 (br. s., 1H), 8.37 (br. s., 1H), 8.00 (s, 1H), 7.65-7.77 (m, 1H), 7.48 (d, J=3.3 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 4.71 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 1H), 4.41 (d, J=12.5 Hz, 1H), 4.14 (d, J=7.3 Hz, 0.5H), 3.66-3.95 (m, 1.5H), 3.15-3.44 (m, 4.5H), 2.40 (br. s., 1H), 2.05-2.15 (m, 1H), 1.39-1.48 (m, 1H), 1.17-1.25 (m, 2H), 0.94-1.04 (m, 2H), 0.44-0.81 (m, 4H). LC-MS: m/z 495.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.58-7.63 (m, 1H), 7.33-7.43 (m, 2H), 7.09-7.21 (m, 2H), 4.39-4.50 (m, 2.5H), 4.05-4.13 (m, 1H), 3.82 (br. s., 0.5H), 3.50-3.72 (m, 4H), 2.97-3.29 (m, 3H), 1.99-2.06 (m, 1H), 1.84-1.96 (m, 1H), 1.14-1.27 (m, 7H), 0.93-1.00 (m, 2H), 0.38-0.72 (m, 4H). LC-MS: m/z 475.3 (M+H)+
1H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (d, J=8.5 Hz, 1H), 7.91 (dd, J=11.4, 8.9 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.64 (s, 1H), 7.46-7.57 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.78 (dq, J=13.5, 6.8 Hz, 0.5H), 4.57 (d, J=11.8 Hz, 1.5H), 4.45 (d, J=11.0 Hz, 1H), 3.92-4.07 (m, 0.5H), 3.57-3.76 (m, 0.5H), 3.40 (q, J=7.0 Hz, 1H), 3.18-3.35 (m, 2H), 1.65-1.82 (m, 1H), 1.20-1.31 (m, 4H), 1.07-1.20 (m, 2H), 0.64-0.91 (m, 4H), 0.38-0.60 (m, 4H). LC-MS: m/z 498.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.33-7.43 (m, 2H), 7.09-7.20 (m, 2H), 4.55 (br. s., 1H), 4.47 (br. s., 1H), 4.25 (d, J=13.1 Hz, 3H), 3.40 (br. s., 1H), 3.31 (br. s., 1H), 3.15 (br. s., 1H), 1.95-2.10 (m, 1H), 1.77 (br. s., 2H), 1.64 (br. s., 2H), 1.39-1.53 (m, 2H), 1.34 (br. s., 2H), 0.90-1.12 (m, 5H), 0.69-0.90 (m, 2H).
LC-MS: m/z 405.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.60 (s, 1H), 7.33-7.41 (m, 2H), 7.15 (t, J=8.7 Hz, 2H), 4.69-4.72 (m, 0.5H), 4.31-4.58 (m, 2H), 4.20 (d, J=13.8 Hz, 1H), 3.16-3.82 (m, 7.5H), 1.98-2.09 (m, 1H), 1.77-1.90 (m, 1H), 1.08-1.32 (m, 7H), 0.86-1.08 (m, 2H), 0.31-0.62 (m, 4H). LC-MS: m/z 475.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.36 (br. s., 1H), 8.52 (br. s., 1H), 8.07 (d, J=8.0 Hz, 1H), 7.70-7.75 (m, 1H), 7.65-7.69 (m, 1H), 7.63 (s, 1H), 7.47 (t, J=5.6 Hz, 1H), 4.89-5.55 (m, 3H), 4.15-4.58 (m, 4H), 1.56-1.68 (m, 1H), 1.42-1.56 (m, 1H), 1.12-1.21 (m, 2H), 0.97-1.09 (m, 4H), 0.75-0.96 (m, 6H). LC-MS: m/z 438.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.49 (s, 1H), 6.47-6.77 (m, 1H), 6.22-6.44 (m, 1H), 5.88 (br. s., 1H), 5.76 (d, J=10.0 Hz, 1H), 3.01-4.86 (m, 11H), 2.40 (br. s., 2H), 1.95-2.16 (m, 1H), 1.76 (br. s., 1H), 1.29-1.38 (m, 3H), 1.08-1.19 (m, 2H), 0.92-1.08 (m, 4H), 0.71-0.86 (m, 2H). LC-MS: m/z 448.0 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.51-7.57 (m, 1H), 6.53-6.73 (m, 1H), 6.25-6.41 (m, 1H), 5.65-5.80 (m, 1H), 4.02-5.02 (m, 6H), 2.94-4.00 (m, 5H), 2.37-2.49 (m, 1H), 2.28-2.37 (m, 1H), 1.92-2.13 (m, 1H), 1.57-1.80 (m, 6H), 0.96-1.22 (m, 6H), 0.69-0.88 (m, 2H). LC-MS: m/z 448.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.80 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.0, 2.3 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 4.09-4.85 (m, 4H), 3.22-3.64 (m, 3H), 1.82-1.93 (m, 1H), 1.75 (br. s., 1H), 1.19-1.27 (m, 2H), 0.96-1.12 (m, 4H), 0.73-0.92 (m, 2H). LC-MS: m/z 413.2 (M+H)+
1H NMR (CHLOROFORM-d) □ 8.79 (d, J=1.5 Hz, 1H), 7.90 (dd, J=8.0, 2.3 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=9.8 Hz, 0.5H), 4.19-4.44 (m, 2.5H), 3.65-3.78 (m, 2.5H), 3.54 (t, J=11.0 Hz, 0.5H), 3.28-3.43 (m, 4H), 3.03-3.27 (m, 1.5H), 2.50-2.80 (m, 2H), 1.82-1.92 (m, 1H), 1.36 (d, J=6.5 Hz, 1.5H), 1.23-1.28 (m, 1.5H), 1.17-1.23 (m, 2H), 0.94-1.06 (m, 2H); LC-MS: m/z 431.2 (M+H)
1H NMR (CHLOROFORM-d) δ 8.67 (d, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.46-7.59 (m, 1H), 7.35 (dd, J=5.1, 1.6 Hz, 1H), 4.15-4.90 (m, 4H), 3.13-3.75 (m, 4H), 1.94-2.04 (m, 1H), 1.76 (br. s., 1H), 1.28-1.39 (m, 3H), 1.21 (dt, J=7.0, 3.5 Hz, 2H), 0.95-1.09 (m, 4H), 0.76-0.88 (m, 2H). LC-MS: m/z 413.9 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.48 (d, J=5.5 Hz, 1H), 5.90 (d, J=11.3 Hz, 1H), 4.01-4.85 (m, 7), 3.96 (t, J=5.9 Hz, 1H), 3.82 (t, J=5.9 Hz, 1H), 3.03-3.80 (m, 4H), 2.82 (s, 1H), 2.44 (d, J=3.5 Hz, 1H), 2.38 (d, J=3.5 Hz, 1H), 2.06-2.12 (m, 1H), 1.31-1.37 (m, 3H), 0.97-1.17 (m, 6H), 0.81 (d, J=7.8 Hz, 2H). LC-MS: m/z 444.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.46 (d, J=4.8 Hz, 1H), 7.64 (s, 1H), 7.19 (t, J=5.1 Hz, 1H), 7.08 (ddd, J=17.4, 11.0, 1.3 Hz, 1H), 6.51 (dd, J=17.3, 1.8 Hz, 1H), 5.66 (dd, J=10.9, 1.6 Hz, 1H), 4.59 (d, J=12.8 Hz, 1H), 4.47 (d, J=12.5 Hz, 1H), 4.22 (br. s., 0.5H), 4.05 (br. s., 0.5H), 3.76 (dt, J=8.2, 4.0 Hz, 1H), 3.47-3.70 (m, 1H), 3.29 (br. s., 1H), 3.14 (br. s., 1H), 1.77-1.85 (m, 1H), 1.57-1.70 (m, 1H), 1.32-1.41 (m, 1H), 1.14-1.24 (m, 2H), 0.88-1.11 (m, 4H), 0.73-0.86 (m, 2H), 0.59-0.73 (m, 1H), 0.36-0.59 (m, 3H). LC-MS: m/z 458.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.35 (s, 1H), 8.54 (dd, J=5.9, 1.9 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.69-7.75 (m, 1H), 7.64-7.68 (m, 2H), 7.44 (dd, J=12.5, 6.0 Hz, 1H), 4.46-4.59 (m, 2.5H), 4.08-4.18 (m, 1H), 3.86 (br. s., 0.5H), 3.53-3.74 (m, 3H), 3.21-3.32 (m, 2H), 1.87-2.06 (m, 2H), 1.49-1.58 (m, 1H), 1.33 (d, J=5.8 Hz, 1H), 1.14-1.28 (m, 7H), 0.81-0.90 (m, 2H), 0.65 (br. s., 1H), 0.36-0.59 (m, 3H). LC-MS: m/z 508.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.81 (d, J=5.0 Hz, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 7.59 (dd, J=5.1, 1.6 Hz, 1H), 4.86 (br. s., 1H), 4.48 (br. s., 1H), 4.35 (d, J=13.6 Hz, 2H), 3.63 (br. s., 0.5H), 3.53 (br. s., 1H), 3.25 (br. s., 1.5H), 1.85-1.99 (m, 1H), 1.76 (br. s., 1H), 1.60 (br. s., 3H), 1.17-1.34 (m, 4H), 1.07 (dd, J=7.8, 3.0 Hz, 4H). LC-MS: m/z 413.5 (M+H)+
1H NMR (CHLOROFORM-d) □□8.56 (d, J=5.0 Hz, 1H), 7.62 (s, 1H), 7.21 (s, 1H), 7.17 (d, J=5.3 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.44 (d, J=12.3 Hz, 1H), 4.04 (br. s., 1H), 3.75 (br. s., 1.5H), 3.28 (br. s., 1.5H), 3.12 (br. s., 1H), 2.58-2.68 (m, 3H), 1.97-2.07 (m, 1H), 1.72 (br. s., 1H), 1.37 (br. s., 1H), 1.14-1.23 (m, 2H), 0.93-1.10 (m, 4H), 0.74-0.85 (m, 2H), 0.65 (br. s., 1H), 0.36-0.58 (m, 3H). LC-MS: m/z 428.5 (M+H)+
1H NMR (CHLOROFORM-d) δ8.90 (d, 2H), 8.04 (s, 1H), 7.64 (s, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.13 (br. s., 1H), 3.78 (br. s., 1H), 3.51 (s, 1H), 3.33 (d, J=9.0 Hz, 2H), 3.24 (d, J=12.5 Hz, 1H), 3.15 (d, J=12.3 Hz, 1H), 2.03 (dt, J=15.3, 7.4 Hz, 1H), 1.01-1.12 (m, 3H), 0.82-0.95 (m, 4H), 0.66 (br. s., 1H), 0.45-0.53 (m, 1H)
LC-MS: m/z 481.4 (M+H)+
1H NMR (METHANOL-d) δ9.05 (br. s., 1H), 8.81 (br. s., 1H), 8.26 (t, J=2.1 Hz, 1H), 7.60-7.77 (m, 1H), 6.81 (br. s., 1H), 6.25 (br. s., 1H), 4.57 (d, J=13.1 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 4.01-4.25 (m, 1H), 3.65-3.88 (m, 2H), 3.12-3.38 (m, 4H), 2.03-2.24 (m, 1H), 1.86-1.96 (m, 1H), 1.15-1.28 (m, 4H), 0.97-1.06 (m, 2H), 0.28-0.58 (m, 4H)
LC-MS: m/z 499.5 (M+H)+
1H NMR (CHLOROFORM-d) δ9.47 (br. s., 1H), 8.86 (s, 1H), 8.62 (s, 1H), 7.73 (s, 1H), 4.59-4.47 (m., 7H), 1.19-1.30 (m, 1H), 1.14-1.05 (m, 3H), 0.84-0.98 (m, 10H), 0.42-0.57 (m, 4H) LC-MS: m/z 482.5 (M+H)+
1H NMR (CHLOROFORM-d) δ8.62 (d, J=1.8 Hz, 1H), 8.35-8.44 (m, 1H), 7.03 (dd, J=17.3, 10.8 Hz, 1H), 6.70-6.82 (m, 1H), 5.81-5.92 (m, 1H), 4.90 (br. s., 0.5H), 4.52 (m, 3.5H), 4.28-4.47 (m, 3H), 3.68-3.86 (m, 3H), 3.54 (br. s., 1H), 3.01-3.21 (m, 3H), 2.63-2.79 (m, 1H), 2.51-2.63 (m, 1H), 1.23-1.26 (m, 4H), 1.18-1.23 (m, 2H), 1.04 (m, 2H)
LC-MS: m/z 451.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.82 (d, J=9.5 Hz, 1H), 7.70-7.84 (m, 1H), 7.55-7.70 (m, 2H), 7.11-7.23 (m, 1H), 5.52 (br. s., 2H), 4.39-4.67 (m, 2.5H), 4.16-4.32 (m, 1H), 3.60-3.85 (m, 1H), 3.10-3.41 (m, 2.5H), 1.73 (s, 1H), 1.53-1.65 (m, 1H), 1.27-1.33 (m, 1H), 1.18-1.24 (m, 1H), 1.11-1.18 (m, 1H), 0.98-1.10 (m, 2H), 0.79-0.90 (m, 4H), 0.61-0.74 (m, 1H), 0.40-0.61 (m, 3H)
LC-MS: m/z 480.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.83 (d, J=1.8 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.77-7.87 (m, 1H), 7.65 (s, 1H), 4.40-4.72 (m, 2.5H), 3.97-4.20 (m, 1H), 3.51-3.78 (m, 1H), 3.08-3.62 (m, 2.5H), 1.86-1.98 (m, 1H), 1.72 (s, 1H), 1.34-1.45 (m, 1H), 1.20-1.28 (m, 2H), 0.97-1.10 (m, 4H), 0.76-0.87 (m, 2H), 0.40-0.67 (m, 3H)
LC-MS: m/z 482.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.61 (s, 1H), 7.34 (s, 2H), 4.91 (s, 0.5H), 4.50-4.56 (m, 0.5H), 4.22-4.50 (m, 2.5H), 3.68-3.89 (m, 2.5H), 3.49-3.62 (m, 0.5H), 3.28-3.43 (m, 4H), 3.06-3.27 (m, 1.5H), 2.64-2.83 (m, 1H), 2.55-2.64 (m, 1H), 1.92-2.01 (m, 1H), 1.37 (d, J=6.5 Hz, 2H), 1.21-1.31 (m, 3H), 1.01-1.12 (m, 2H) LC-MS: m/z 474.1 (M+H)+
The mixture of (R)-2′-chloro-2-cyclopropyl-6′-methoxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile (40 mg, 0.085 mmol), Potassium vinyltrifluoroborate (18 mg, 0.128 mmol), Pd(dppf)Cl2 (4 mg, 0.0043 mmol), CsF (39 mg, 0.255 mmol) in dioxane/H2O was stirred at 100° C. for 16 hours, the mixture was partitioned between EtOAc and water, the organic was washed with water, brine and concentrated to give the crude which was purified by column to give 15 mg of the product.
1H NMR (CHLOROFORM-d) □□7.60 (s, 1H), 6.86 (d, J=1.0 Hz, 1H), 6.75 (dd, J=17.1, 10.5 Hz, 1H), 6.66 (d, J=1.0 Hz, 1H), 6.36 (dd, J=17.2, 1.6 Hz, 1H), 5.49 (dd, J=10.5, 1.8 Hz, 1H), 4.90 (s, 0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.22-4.38 (m, 2.5H), 4.02 (s, 3H), 3.78-3.84 (m, 0.5H), 3.75 (t, J=6.1 Hz, 2H), 3.51-3.58 (m, 0.5H), 3.38 (s, 3H), 3.28 (t, J=9.9 Hz, 1H), 3.00-3.19 (m, 1.5H), 2.65-2.79 (m, 1H), 2.54-2.64 (m, 1H) 2.03-2.10 (m, 1H), 1.38 (d, J=6.3 Hz, 1H), 1.28 (d, J=6.8 Hz, 2H), 1.13-1.21 (m, 2H), 0.94-1.03 (m, 2H)
LC-MS: m/z 461.2 (M+H)+
To a solution of (R)-2′,6′-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile (300 mg, 0.623 mmol) MeOH was added NaOMe (69 mg, 1.26 mmol), the mixture was refluxed for 16 hours. After cooling, the mixture was partitioned between EtOAc and water, the organic layer was washed with water, brine and dried over Na2SO4. The organic layer was concentrated to give the crude which was purified by prep-HPLC to obtained 150 mg of the product.
1H NMR (CHLOROFORM-d) □□7.54-7.63 (m, 1H), 6.97 (d, J=1.3 Hz, 1H), 6.70 (d, J=1.0 Hz, 1H), 4.91 (s, 0.5H), 4.54 (d, J=12.8 Hz, 0.5H), 4.23-4.39 (m, 2.5H), 3.96 (s, 3H), 3.79-3.85 (m, 0.5H), 3.68-3.78 (m, 2H), 3.49-3.60 (m, 0.5H), 3.39 (s, 3H), 3.26-3.36 (m, 1H), 3.04-3.20 (m, 1.5H), 2.64-2.82 (m, 1H), 2.50-2.63 (m, 1H), 2.00-2.04 (m, 1), 1.38 (d, J=6.5 Hz, 1H), 1.28 (d, J=5.5 Hz, 2H), 1.13-1.21 (m, 2H), 0.97-1.06 (m, 2H)
LC-MS: m/z 470.2 (M+H)+
The mixture of (R)-2′,6′-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile (50 mg, 0.105 mmol), Potassium vinyltrifluoroborate (50 mg, 0.316 mmol), Pd(dppf)Cl2 (4 mg, 0.0043 mmol), CsF (50 mg, 0.316 mmol) in dioxane/H2O was stirred at 100° C. for 16 hours, the mixture was partitioned between EtOAc and water, the organic was washed with water, brine and concentrated to give the crude which was purified by column to give 25 mg of the product.
1H NMR (CHLOROFORM-d) □□7.63 (s, 1H), 7.24 (s, 1H), 7.28 (s, 1H), 6.77-6.98 (m, 2H), 6.30 (s, 1H), 6.34 (s, 1H), 5.55 (d, J=10.8 Hz, 2H), 4.09 (s, 0.5H), 4.53 (d, J=12.3 Hz, 0.5H), 4.21-4.36 (m, 2.5H), 3.68-3.85 (m, 3H), 3.50-3.61 (m, 0.5H), 3.38 (s, 4H), 3.03-3.15 (m, 1H), 2.70 (dd, J=15.7, 6.4 Hz, 1H), 2.51-2.59 (m, 1H), 1.90-2.12 (m, 1H), 1.36-1.42 (m, 1H), 1.22-1.30 (m, 2H), 1.18 (s, 2H), 0.94-1.05 (m, 2H)
LC-MS: m/z 458.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.15 (d, J=11.3 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.50 (dd, J=10.3, 7.3 Hz, 1H), 7.04 (dd, J=17.2, 10.7 Hz, 1H), 6.78 (d, J=17.1 Hz, 1H), 5.85 (d, J=10.5 Hz, 1H), 4.64-4.76 (m, 1H), 4.42-4.49 (m, 1H), 3.88 (d, J=13.6 Hz, 0.5H), 3.73 (d, J=5.8 Hz, 2H), 3.61 (d, J=9.8 Hz, 0.5H), 3.39-3.50 (m, 0.5H), 3.37 (s, 3H), 3.05-3.25 (m, 2H), 2.85-3.10 (m, 0.5H), 2.50-2.85 (m, 2H), 2.18-2.33 (m, 1H), 1.99-2.15 (m, 1H), 0.99-1.22 (m, 6H), 0.82-0.94 (m, 5H)
LC-MS: m/z 511.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.15 (d, J=7.8 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.43-7.56 (m, 1H), 7.04 (dd, J=17.3, 10.5 Hz, 1H), 6.78 (d, J=17.1 Hz, 1H), 5.85 (d, J=10.5 Hz, 1H), 4.33-4.80 (m, 2.5H), 4.07-4.22 (m, 0.5H), 3.85-4.02 (m, 1H), 3.60-3.81 (m, 3H), 3.37 (s, 3H), 2.98-3.26 (m, 2H), 2.37-2.76 (m, 2H), 1.98-2.28 (m, 1H), 1.51-1.61 (m, 1H), 1.11-1.26 (m, 2H), 0.86 (d, J=7.8 Hz, 2H), 0.40-0.55 (m, 4H)
LC-MS: m/z 509.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.16 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.62-7.72 (m, 1H), 7.44-7.56 (m, 1H), 7.05 (dd, J=17.3, 10.5 Hz, 1H), 6.78 (d, J=17.1 Hz, 1H), 5.75-5.95 (m, 1H), 4.49-4.66 (m, 2.5H), 4.05-4.25 (m, 1H), 3.75-3.88 (m, 1H), 3.06-3.32 (m, 2.5H), 2.29 (s, 1H), 1.50-1.57 (m, 1H), 1.34-1.47 (m, 1H), 1.14-1.22 (m, 2H), 0.98-1.09 (m, 2H), 0.77-0.91 (m, 4H), 0.39-0.67 (m, 4H)
LC-MS: m/z 491.2 (M+H)+
(Core synthesis method 1 using 4-chloro-2-vinyl-1,8-naphthyridine as starting material)
In a sealed tube was added 120 mg of 4-chloro-2-vinyl-1,8-naphthyridine, 242 mg of 8-3 (0.5 mmol), 230 mg of CsF (1.5 mmol), 41 mg of Pd(dppf)2Cl2 (0.05 mmol) and 10 mL of Dioxane, then the mixture was heated in a microwave reactor (100° C., 30 minutes), when LC-MS indicated the product formation. Then the resulting mixture was filtered, the filtrated was concentrated, purified by Prep-TLC (Petroleum ether: Ethyl acetate=2:1) to give 45 mg of title compound.
1H NMR (CHLOROFORM-d) δ 9.17 (dd, J=4.3, 1.8 Hz, 1H), 8.03 (td, J=8.7, 1.8 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.61 (d, J=3.5 Hz, 1H), 7.48 (dd, J=8.3, 4.3 Hz, 1H), 7.15 (dd, J=17.7, 10.9 Hz, 1H), 6.57 (dd, J=17.6, 1.8 Hz, 1H), 5.83 (d, J=11.0 Hz, 1H), 4.60 (d, J=12.3 Hz, 2H), 4.49 (d, J=12.8 Hz, 1H), 4.15 (br. s., 0.5H), 3.91 (br. s., 0.5H), 3.65-3.85 (m, 3H), 3.40 (s, 4H), 3.27 (d, J=12.0 Hz, 2H), 2.67 (br. s., 2H), 1.20 (d, J=4.5 Hz, 2H), 0.82-0.98 (m, 2H), 0.66 (br. s., 1H), 0.59 (br. s., 1H), 0.49 (d, J=5.0 Hz, 2H)
LC-MS: m/z 509.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.99-9.21 (m, 1H), 7.99 (dd, J=12.4, 8.4 Hz, 1H), 7.50-7.72 (m, 2H), 7.45 (dt, J=7.8, 3.7 Hz, 1H), 7.11 (dd, J=17.4, 10.9 Hz, 1H), 6.53 (d, J=17.6 Hz, 1H), 5.79 (d, J=10.8 Hz, 1H), 4.56-4.78 (m, 1.5H), 4.35-4.56 (m, 2H), 3.74-3.99 (m, 2.5H), 3.37-3.60 (m, 1H), 3.06-3.28 (m, 2H), 2.92-3.06 (m, 1H), 2.53-2.83 (m, 3H), 2.12 (dt, J=10.0, 6.5 Hz, 1H), 1.43-1.55 (m, 1H), 0.98-1.15 (m, 4H), 0.72-0.97 (m, 5H)
LC-MS: m/z 497.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.05-9.19 (m, 1H), 7.98 (ddd, J=6.1, 4.3, 2.1 Hz, 1H), 7.63-7.68 (m, 1H), 7.55-7.61 (m, 1H), 7.41-7.47 (m, 1H), 7.03-7.17 (m, 1H), 6.52 (d, J=17.6 Hz, 1H), 5.72-5.84 (m, 1H), 4.89 (br. s., 0.5H), 4.54 (d, J=12.5 Hz, 1H), 4.39 (d, J=13.8 Hz, 1H), 4.29 (d, J=19.8 Hz, 2H), 4.20 (br. s., 1H), 3.82-4.00 (m, 2.5H), 3.01-3.24 (m, 2H), 2.46-2.76 (m, 3H), 1.06-1.19 (m, 2H), 0.75-0.94 (m, 3H)
LC-MS: m/z 469.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.12 (S, 1h), 7.99 (br. s., 1H), 7.52-7.69 (m, 2H), 7.36-7.50 (m, 1H), 7.00-7.19 (m, 1H), 6.53 (d, J=17.6 Hz, 1H), 5.78 (d, J=10.8 Hz, 1H), 4.71 (br. s., 1.5H), 4.35-4.52 (m, 2H), 3.58-3.81 (m, 3.5H), 3.37 (d, J=3.0 Hz, 4H), 3.18 (dd, J=13.6, 3.5 Hz, 2H), 2.52-2.82 (m, 2H), 1.08 (dt, J=12.0, 5.7 Hz, 4H), 0.87 (d, J=6.8 Hz, 6H)
LC-MS: m/z 511.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.14 (dd, J=4.1, 1.9 Hz, 1H), 7.98 (br. s., 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.45 (dd, J=8.3, 4.3 Hz, 1H), 7.11 (d, J=10.8 Hz, 1H), 6.44-6.62 (m, 1H), 5.80 (d, J=10.8 Hz, 1H), 4.94 (br. S., 0.5H), 4.55 (br. s., 0.5H), 4.42 (br. s., 3H), 3.75 (d, J=6.3 Hz, 3H), 3.39 (s, 4H), 3.15 (br. s., 2H), 2.63 (br. s., 2H), 1.10-1.22 (m, 3H), 0.72-0.97 (m, 4H)
LC-MS: m/z 483.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.67 (d, J=5.3 Hz, 1H), 7.89 (s, 1H), 7.50 (s, 3H), 6.63-6.82 (m, 1H), 6.04 (d, J=17.6 Hz, 1H), 5.57 (d, J=11.0 Hz, 1H), 4.91 (br. s., 0.5H), 4.51 (br. s., 1H), 4.34 (br. s., 3H), 3.65-3.83 (m, 2.5H), 3.33-3.44 (m, 4H), 3.29 (br. s., 1H), 2.71 (br. s., 1H), 2.62 (br. s., 2H), 1.33-1.43 (m, 3H), 1.15-1.25 (m, 4H)
LC-MS: m/z 431.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.48-7.56 (m, 1H), 6.31-6.57 (m, 2H), 5.97 (d, J=2.0 Hz, 1H), 5.65-5.88 (m, 1H), 4.01-4.90 (m, 8H), 3.02-3.81 (m, 3H), 2.09-2.34 (m, 1H), 1.75 (br. s., 2H), 1.25-1.37 (m, 3H), 1.09-1.22 (m, 2H), 0.95-1.09 (m, 4H), 0.67-0.94 (m, 2H)
LC-MS: m/z 432.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.63 (d, J=2.0 Hz, 1H), 7.66-7.74 (m, 1H), 7.58-7.65 (m, 1H), 7.40-7.50 (m, 1H), 6.87 (dd, J=17.6, 10.8 Hz, 1H), 6.27 (dd, J=17.6, 1.0 Hz, 1H), 5.54 (dd, J=10.8, 1.0 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.17-4.41 (m, 2.5H), 3.66-3.88 (m, 2.5H), 3.54 (t, J=11.2 Hz, 0.5H), 3.37 (s, 3H), 3.28 (t, J=9.8 Hz, 1H), 2.99-3.20 (m, 1.5H), 2.52-2.81 (m, 2H), 1.94-2.06 (m, 1H), 1.33-1.41 (m, 1.5H), 1.24-1.29 (m, 1.5H), 1.14-1.23 (m, 2H), 0.91-1.04 (m, 2H)
LC-MS: m/z 432.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.54-8.72 (m, 1H), 7.45-7.58 (m, 2H), 7.18-7.34 (m, 1H), 6.53-6.69 (m, 1H), 6.38-6.47 (m, 1H), 5.43 (d, J=10.8 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.14-4.39 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.54 (d, J=4.8 Hz, 0.5H), 3.37 (s, 3H), 3.23-3.33 (m, 1H), 2.99-3.21 (m, 1.5H), 2.51-2.80 (m, 2H), 1.55-1.69 (m, 1H), 1.39 (br. s., 1.5H), 1.29 (br. s., 1.5H), 1.04-1.19 (m, 2H), 0.79-1.00 (m, 2H)
LC-MS: m/z 432.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.45 (s, 1H), 6.64 (td, J=16.1, 10.7 Hz, 1H), 6.29-6.42 (m, 1H), 5.67-5.86 (m, 2H), 4.00-5.00 (m, 6H), 3.85-3.93 (m, 1H), 3.79 (t, J=5.3 Hz, 1H), 3.00-3.63 (m, 3H), 2.39-2.52 (m, 2H), 1.96-2.12 (m, 1H), 1.75 (br. s., 1H), 1.28-1.51 (m, 3H), 1.08-1.17 (m, 2H), 0.94-1.08 (m, 4H), 0.76-0.86 (m, 2H)
LC-MS: m/z 446.0 (M+H)+
1H NMR (CHLOROFORM-d) δ 0.39-0.53 (m, 1H) 0.56 (d, J=4.52 Hz, 3H) 0.79-0.94 (m, 4H) 0.94-1.14 (m, 3H) 1.22 (br. s., 2H) 1.27 (br. s., 2H) 1.33 (br. s., 2H) 3.01 (s, 3H) 4.53 (d, J=12.55 Hz, 2.5H) 7.46 (s, 1H) 7.58 (br. s., 1H) 7.67 (s, 1H) 8.14 (br. s., 1H) 9.22 (br. s., 1H)
LC-MS: m/z 479.3 (M+H)+
70 mg of (R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(1H-indazol-5-yl)nicotinonitrile (NB247-78) (0.18 mmol), 83 mg of HATU (0.22 mmol), 37 mg of TEA in 10 mL of DCM was added 23 mg of 3,3,3-trifluoropropanoic acid (0.18 mmol), then the mixture was stirred at room temperature for 2 hours, concentrated, purified by Prep-TLC (Petroleum ether: Ethyl acetate=1:1) to give 31.5 mg of title compound. 1H NMR (CHLOROFORM-d) □□7.98 (br. s., 1H), 7.77 (s, 1H), 7.42-7.62 (m, 2H), 7.15 (d, J=7.0 Hz, 1H), 4.56 (d, J=13.1 Hz, 2H), 4.13 (br. s., 0.5H), 3.84 (br. s., 1.5H), 3.35 (d, J=10.0 Hz, 2H), 3.23 (br. s., 2H), 3.12 (br. s., 1H), 1.94 (s, 1H), 1.15-1.32 (m, 5H), 0.94 (dd, J=7.8, 3.3 Hz, 2H), 0.52 (d, J=5.3 Hz, 2H)
LC-MS: m/z 495.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.07 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.99 (d, J=1.5 Hz, 1H), 7.71 (s, 1H), 7.57 (dd, J=8.4, 1.6 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H), 4.42 (d, J=12.8 Hz, 1H), 3.98-4.21 (m, 0.5H), 3.67-3.95 (m, 1.5H), 3.26-3.38 (m, 2H), 3.15-3.26 (m, 2H), 3.09 (t, J=11.3 Hz, 1H), 2.04-2.12 (m, 1H), 1.42 (d, J=14.3 Hz, 1H), 1.17-1.24 (m, 2H), 0.95-1.03 (m, 2H), 0.67 (br. s., 1H), 0.57 (br. s., 1H), 0.45-0.53 (m, 2H)
LC-MS: m/z 512.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.45-8.58 (m, 1H), 7.59-7.69 (m, 2H), 7.47-7.59 (m, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 4.53 (d, J=13.1 Hz, 1H), 4.43 (d, J=12.0 Hz, 1H), 4.12 (br. s., 0.5H), 3.78 (br. s., 1H), 3.67 (s, 3H), 3.33 (q, J=9.8 Hz, 2H), 3.16-3.26 (m, 1H), 3.03-3.16 (m, 0.5H), 1.92 (br. s., 1H), 1.69-1.80 (m, 1H), 1.20-1.28 (m, 2H), 1.07-1.19 (m, 2H), 0.81-0.95 (m, 2H), 0.67 (br. s., 1H), 0.57 (br. s., 1H), 0.43-0.54 (m, 2H)
LC-MS: m/z 536.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.56 (s, 1H), 8.59 (d, J=5.8 Hz, 1H), 7.74 (s, 1H), 7.64-7.70 (m, 1H), 7.44-7.52 (m, 1H), 7.11 (dd, J=17.7, 10.9 Hz, 1H), 6.44 (dd, J=17.7, 1.6 Hz, 1H), 5.83 (d, J=11.0 Hz, 1H), 4.95 (br. s., 0.5H), 4.58 (d, J=11.3 Hz, 0.5H), 4.42 (d, J=11.3 Hz, 1.5H), 4.31 (br. s., 1H), 3.86 (d, J=13.1 Hz, 0.5H), 3.72-3.81 (m, 2H), 3.55-3.68 (m, 0.5H), 3.4 (s, 3H) 3.34-3.39 (m, 0.5H), 3.04-3.30 (m, 2H), 2.53-2.83 (m, 2H), 1.47-1.55 (m, 1H), 1.37-1.46 (m, 1.5H), 1.29-1.37 (m, 1.5H), 1.20 (t, J=4.9 Hz, 2H), 0.84-0.96 (m, 2H)
LC-MS: m/z 483.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.50-9.65 (m, 1H), 8.60 (d, J=6.0 Hz, 1H), 7.74-7.82 (m, 1H), 7.62-7.72 (m, 1H), 7.48-7.57 (m, 1H), 7.11 (dd, J=17.7, 10.9 Hz, 1H), 6.45 (dd, J=17.6, 1.8 Hz, 1H), 5.85 (d, J=11.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.50-4.64 (m, 0.5H), 4.40-4.49 (m, 1H), 4.31-4.40 (m, 1H), 4.22 (br. s., 0.5H), 3.91-4.01 (m, 2H), 3.78 (d, J=11.3 Hz, 0.5H), 3.61 (d, J=11.8 Hz, 0.5H), 3.39 (d, J=13.6 Hz, 1H), 3.10-3.31 (m, 1.5H), 2.65-2.80 (m, 1H), 2.52-2.65 (m, 1H), 1.43-1.54 (m, 3H), 1.35 (t, J=5.6 Hz, 2H), 1.21 (dd, J=6.9, 3.6 Hz, 2H), 0.87-0.98 (m, 2H)
LC-MS: m/z 469.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.57 (s, 1H), 8.60 (dd, J=5.6, 3.1 Hz, 1H), 7.75 (d, J=12.0 Hz, 1H), 7.66 (dd, J=4.8, 3.3 Hz, 1H), 7.45-7.55 (m, 1H), 7.04-7.17 (m, 1H), 6.44 (d, J=17.6 Hz, 1H), 5.84 (d, J=10.8 Hz, 1H), 4.61-4.81 (m, 1.5H), 4.42-4.56 (m, 1.5H), 3.92 (d, J=13.6 Hz, 0.5H), 3.70-3.83 (m, 2H), 3.44-3.56 (m, 0.5H), 3.37-3.43 (m, 3H), 3.08-3.31 (m, 2H), 2.90-3.05 (m, 0.5H), 2.55-2.85 (m, 2H), 1.49 (dd, J=7.4, 4.4 Hz, 1H), 1.14-1.32 (m, 2H), 1.11 (ddd, J=15.2, 6.5, 4.1 Hz, 4H), 0.83-0.98 (m, 5H)
LC-MS: m/z 511.3 (M+H)+
Step 1:
To 10 mg PdCl2(dppf).CH2Cl2 in a reaction tube under nitrogen were added 5 mL dioxane, 3 mL water, 150 mg (0.98 mmol) CsF, 75 mg (0.43 mmol) quinolin-4-ylboronic acid and 150 mg (0.36 mmol) (R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile. The reaction solution was heated to 100° C. for half hour under microwave irradiation. The reaction was extracted with ethyl acetate, washed several times with water and purified by TLC preparation (petroleum ether:ethyl acetate=1:1) to give desired compound 50 mg (32%, yield). LC-MS: m/z 438.22 (M+H)+
Step 2:
To a stirred solution of (R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-(quinolin-4-yl)nicotinonitrile (50 mg, 0.108 mmol) in 10 mL of anhydrous CH2Cl2 was added 3-chlorobenzoperoxoic acid (37 mg, 0.216 mmol) portionwise over 1 min. The resulting mixture was stirred at room temperature for 3 hours. Then saturated aqueous Na2SO3 (10 mL) was added to the reaction. The reaction was extracted with ethyl acetate to give desired compound (R)-4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)quinoline 1-oxide 48 mg (93%). LC-MS: m/z 453.22 (M+H)+
Step 3:
To a solution of (R)-4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropylpyridin-3-yl)quinoline 1-oxide (35 mg, 0.07 mmol) in 20 mL of CHCl3 was added POCl3 (32 mg, 0.209) dropwise at room temperature. The reaction mixture was then heated at reflux for 3 hours. After LC-MS showed completion of reaction, the mixture was cooled to room temperature and poured into water and extracted with methylene chloride. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo to give the title compound as a brown solid 30 mg (83.3%). LC-MS: m/z 472.18 (M+H)+
Step 4 is Similar to Compound 390 Step 2: Compound 542
1H NMR (CHLOROFORM-d) δ: 8.21 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.5 Hz, 1H), 7.68 (d, J=1.0 Hz, 1H), 7.48-7.66 (m, 3H), 7.13 (dd, J=17.4, 10.9 Hz, 1H), 6.35 (d, J=17.6 Hz, 1H), 5.76 (d, J=11.0 Hz, 1H), 4.61 (d, J=12.5 Hz, 1.5H), 4.49 (d, J=12.3 Hz, 1.5H), 4.12 (br. s., 1H), 3.67-3.82 (m, 1H), 3.34 (br. s., 1.5H), 3.19 (br. s., 1.5H), 1.58 (ddd, J=12.0, 7.8, 4.5 Hz, 1H), 1.14-1.35 (m, 4H), 1.00-1.13 (m, 2H), 0.76-0.93 (m, 4H), 0.71 (br. s., 1H), 0.38-0.63 (m, 3H)
LC-MS: m/z 490.6 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (CHLOROFORM-d) δ: 8.12 (d, J=8.3 Hz, 1H), 7.76-7.84 (m, 1H), 7.61-7.68 (m, 2H), 7.53-7.61 (m, 1H), 7.38 (d, J=1.8 Hz, 1H), 4.63 (d, J=12.5 Hz, 1H), 4.51 (d, J=12.5 Hz, 1H), 3.97-4.20 (m, 1H), 3.82 (br. s., 1H), 3.59-3.78 (m, 1H), 3.34 (br. s., 1H), 3.20 (br. s., 1H), 1.74 (br. s., 2H), 1.50-1.59 (m, 1H), 1.14-1.26 (m, 2H), 0.97-1.14 (m, 2H), 0.79-0.97 (m, 4H), 0.70 (br. s., 1H), 0.42-0.63 (m, 3H)
LC-MS: m/z 499.0 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (CHLOROFORM-d) δ: 8.18 (d, J=8.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.46-7.64 (m, 3H), 7.11 (dd, J=17.7, 10.9 Hz, 1H), 6.28-6.39 (m, 1H), 5.75 (d, J=11.0 Hz, 1H), 4.59 (d, J=13.1 Hz, 1H), 4.47 (d, J=13.1 Hz, 1H), 4.13 (d, J=8.3 Hz, 0.5H), 3.94 (br. s., 2H), 3.82 (br. s., 1H), 3.76 (br. s., 1H), 3.43 (br. s., 1H), 3.21-3.37 (m, 1.5H), 3.15 (d, J=11.5 Hz, 1H), 2.55-2.70 (m, 2H), 1.67 (br. s., 1H), 1.59 (tt, J=8.1, 4.3 Hz, 1H), 1.10-1.24 (m, 2H), 0.80-0.94 (m, 2H), 0.69 (br. s., 1H), 0.58 (br. s., 1H), 0.51 (br. s., 2H)
LC-MS: m/z 494.2 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (CHLOROFORM-d) δ 8.15 (d, J=8.5 Hz, 1H), 7.71-7.78 (m, 1H), 7.67 (d, J=1.0 Hz, 1H), 7.56-7.64 (m, 1H), 7.54 (d, J=4.5 Hz, 1H), 7.46-7.53 (m, 1H), 7.02-7.14 (m, 1H), 6.32 (dd, J=17.6, 1.3 Hz, 1H), 5.73 (d, J=11.3 Hz, 1H), 4.71-4.74 (m, 0.5H), 4.53-4.66 (m, 1H), 4.45 (d, J=13.1 Hz, 1H), 4.06-4.24 (m, 0.5H), 3.91 (d, J=11.5 Hz, 0.5H), 3.68-3.84 (m, 3H), 3.39 (s, 3H), 3.26 (br. s., 1.5H), 3.07-3.21 (m, 1H), 2.61-2.85 (m, 2H), 1.53-1.64 (m, 1H), 1.32-1.44 (m, 1H), 1.11-1.24 (m, 2H), 0.80-0.94 (m, 2H), 0.48-0.78 (m, 1H)
LC-MS: m/z 508.1 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (CHLOROFORM-d) δ 8.18 (d, J=8.3 Hz, 1H), 7.76 (ddd, J=8.3, 6.8, 1.4 Hz, 1H), 7.68 (s, 1H), 7.57-7.63 (m, 1H), 7.48-7.57 (m, 2H), 7.10 (dd, J=17.7, 10.9 Hz, 1H), 6.34 (dd, J=17.6, 1.8 Hz, 1H), 5.74 (d, J=11.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.48-4.68 (m, 0.5H), 4.26-4.45 (m, 2H), 3.87-3.98 (m, 2H), 3.74-3.87 (m, 0.5H), 3.61 (t, J=12.3 Hz, 0.5H), 3.31-3.48 (m, 2H), 3.05-3.29 (m, 1H), 2.49-2.79 (m, 2H), 1.53-1.63 (m, 1H), 1.46 (dd, J=6.5, 2.5 Hz, 1.5H), 1.32-1.40 (m, 1.5H), 1.15-1.23 (m, 2H), 0.80-0.93 (m, 2H)
LC-MS: m/z 468.2 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (CHLOROFORM-d) δ 8.19 (d, J=8.3 Hz, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.65-7.68 (m, 1H), 7.58-7.64 (m, 1H), 7.48-7.57 (m, 2H), 7.11 (dd, J=17.7, 10.9 Hz, 1H), 6.34 (d, J=17.8 Hz, 1H), 5.75 (d, J=10.8 Hz, 1H), 4.95 (br. s., 0.5H), 4.50-4.70 (m, 0.5H), 4.24-4.47 (m, 2.5H), 3.71-3.89 (m, 2.5H), 3.59 (d, J=9.8 Hz, 0.5H), 3.31-3.45 (m, 4H), 3.07-3.28 (m, 1.5H), 2.67-2.85 (m, 1H), 2.54-2.67 (m, 1H), 1.52-1.62 (m, 1H), 1.33-1.49 (m, 3H), 1.11-1.21 (m, 2H), 0.78-0.93 (m, 2H)
LC-MS: m/z 482.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.53 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 7.65 (s, 1H), 7.42-7.50 (m, 2H), 4.63 (d, J=9.3 Hz, 1H), 4.51 (d, J=11.0 Hz, 2.5H), 3.08-3.48 (m, 4.5H), 2.87 (s, 3H), 1.59-1.68 (m, 1H), 1.46-1.53 (m, 1H), 1.22 (d, J=3.0 Hz, 1H), 1.05-1.11 (m, 2H), 0.92-0.98 (m, 2H), 0.87-0.92 (m, 2H), 0.84 (dd, J=7.9, 2.6 Hz, 2H), 0.70 (br. s., 1H), 0.42-0.63 (m, 3H)
LC-MS: m/z 479.6 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d, J=8.2 Hz, 1H), 7.91 (dd, J=12.5, 8.8 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.64-7.71 (m, 1H), 7.57-7.64 (m, 1H), 7.46 (dd, J=6.9, 2.3 Hz, 1H), 6.97-7.17 (m, 1H), 6.34 (d, J=17.8 Hz, 1H), 5.75 (d, J=10.7 Hz, 1H), 4.56 (dd, J=13.0, 1.7 Hz, 1H), 4.45 (d, J=11.8 Hz, 1H), 4.15 (m, 0.5H), 3.87 (m, 1.5H), 3.26-3.44 (m, 2.5H), 3.01-3.20 (m, 2.5H), 1.42-1.52 (m, 1H), 1.07-1.21 (m, 2H), 0.79-0.92 (m, 3H), 0.66-0.76 (m, 2H), 0.46-0.56 (m, 2H)
LC-MS: m/z 532.2 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.11-8.17 (m, 1H), 7.85-7.95 (m, 1H), 7.78 (t, J=7.3 Hz, 1H), 7.64-7.68 (m, 1H), 7.60 (dd, J=8.8, 1.5 Hz, 1H), 7.42-7.47 (m, 1H), 7.00-7.13 (m, 1H), 6.32 (d, J=17.6 Hz, 1H), 5.72 (d, J=11.0 Hz, 1H), 4.72 (m, 0.5H), 4.54 (d, J=12.5 Hz, 1H), 4.43 (d, J=12.8 Hz, 1H), 4.14 (d, J=7.8 Hz, 0.5H), 3.91 (d, J=11.8 Hz, 0.5H), 3.75 (t, J=5.6 Hz, 2.5H), 3.40 (s, 3H), 3.23 (d, J=8.0 Hz, 1H), 3.01-3.17 (m, 1H), 2.70-2.81 (m, 1H), 2.67 (m, 1H), 2.03 (d, J=5.5 Hz, 1H), 1.56 (td, J=7.8, 4.0 Hz, 1H), 1.11-1.20 (m, 3H), 0.78-0.86 (m, 2H), 0.58-0.66 (m, 2H), 0.42-0.52 (m, 2H)
LC-MS: m/z 508.2 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ8.10-8.19 (m, 1H), 7.90 (dd, J=12.3, 8.8 Hz, 1H), 7.74-7.82 (m, 1H), 7.67 (s, 1H), 7.58-7.63 (m, 1H), 7.45 (ddd, J=7.0, 3.0, 1.0 Hz, 1H), 7.07 (dd, J=17.6, 10.9 Hz, 1H), 6.33 (d, J=17.5 Hz, 1H), 5.73 (d, J=11.0 Hz, 1H), 4.72 (d, J=9.5 Hz, 0.5H), 4.55 (d, J=13.0 Hz, 1H), 4.43 (d, J=12.5 Hz, 1H), 4.12 (d, J=7.2 Hz, 0.5H), 3.87-3.99 (m, 2H), 3.73-3.84 (m, 1H), 3.46 (m, 1H), 3.26 (m, 1.5H), 3.13 (d, J=10.5 Hz, 1H), 2.59-2.68 (m, 1.5H), 2.03 (d, J=6.0 Hz, 1H), 1.54-1.59 (m, 1H), 1.11-1.19 (m, 3H), 0.86-0.94 (m, 2H), 0.80-0.86 (m, 2H), 0.51-0.57 (m, 2H)
LC-MS: m/z 493.3 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ8.16-8.24 (m, 1H), 7.90-7.97 (m, 1H), 7.76-7.83 (m, 1H), 7.59-7.66 (m, 2H), 7.46 (d, J=7.0 Hz, 1H), 7.12 (dd, J=17.6, 10.9 Hz, 1H), 6.35 (d, J=17.5 Hz, 1H), 5.76 (d, J=11.0 Hz, 1H), 4.95 (m, 0.5H), 4.58 (d, J=12.5 Hz, 0.5H), 4.19-4.44 (m, 2.5H), 3.67-3.91 (m, 1.5H), 3.40 (s, 3H), 3.15-3.26 (m, 1.5H), 2.67-2.82 (m, 1.5H), 2.03 (d, J=5.7 Hz, 1H), 1.55 (td, J=8.0, 4.1 Hz, 1H), 1.31-1.37 (m, 3H), 1.11-1.18 (m, 2H) 0.77-0.86 (m, 2H)
LC-MS: m/z 482.2 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J=8.2 Hz, 1H), 7.87-7.99 (m, 1H), 7.75-7.85 (m, 1H), 7.58-7.69 (m, 2H), 7.41-7.50 (m, 1H), 7.12 (dd, J=17.0, 11.0 Hz, 1H), 6.35 (d, J=17.5 Hz, 1H), 5.76 (d, J=11.0 Hz, 1H), 4.93 (m, 0.5H), 4.51-4.61 (m, 0.5H), 4.37 (d, J=12.8 Hz, 1H), 4.21-4.29 (m, 1H), 3.88-3.99 (m, 2H), 3.77 (d, J=12.0 Hz, 0.5H), 3.60 (t, J=12.3 Hz, 0.5H), 3.27-3.44 (m, 2H), 3.02-3.26 (m, 1H), 2.49-2.79 (m, 2H), 1.96-2.07 (m, 1H), 1.51-1.60 (m, 1H), 1.27 (s, 3H), 1.08-1.17 (m, 2H), 0.77-0.87 (m, 2H)
LC-MS: m/z 468.2 (M+H)+
The synthesis was similar to Compound 542.
1H NMR (CHLOROFORM-d) δ 8.07 (d, J=8.3 Hz, 1H), 7.85-7.96 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.57 (td, J=7.7, 1.0 Hz, 1H), 7.08 (dd, J=17.3, 10.5 Hz, 1H), 6.81 (dd, J=17.3, 1.8 Hz, 1H), 5.79-5.94 (m, 1H), 4.82-4.98 (m, 0.5H), 4.54 (d, J=12 Hz, 0.5H), 4.29-4.48 (m, 2H), 3.93 (br. s., 2H), 3.69-3.82 (m, 0.5H), 3.52-3.66 (m, 0.5H), 3.43-3.52 (m, 1H), 3.31-3.43 (m, 1H), 3.01-3.30 (m, 1.5H), 2.47-2.77 (m, 2H), 1.64-1.79 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.11-1.24 (m, 2H), 0.90 (d, J=5.8 Hz, 2H)
LC-MS: m/z 469.2 (M+H)+
1H NMR (METHANOL-d) δ 7.59 (s, 1H), 7.33-7.36 (d, J=4.4 Hz, 2H), 7.24-7.27 (m, 1H), 7.12-7.13 (d, J=7.6 Hz, 1H), 4.40-4.46 (m, 1H), 4.14-4.23 (m, 2H), 3.92-3.96 (d, J=14.4 Hz, 0.5H), 3.34 (s, 3H), 3.14-3.19 (m, 2H), 3.34 (s, 4H), 2.99-3.14 (m, 0.5H), 2.60-2.81 (m, 2H), 2.46-2.50 (m, 2H), 1.64-1.69 (m, 1H), 1.37-1.41 (q, J=7.2 Hz, 1.3H), 1.26-1.30 (t, J=6.4 Hz, 1.7H), 1.02-1.11 (m, 5H), 0.82-0.91 (m, 2H); LC-MS: m/z 433.6 (M+H)
1HNMR (METHANOL-d) δ 7.48 (s, 1H), 7.11-7.18 (m, 3H), 4.79 (s, 1H), 4.39-4.45 (m, 1H), 4.21-4.24 (d, J=12.8 Hz, 1.5H), 4.13-4.17 (d, J=13.2 Hz, 0.5H), 3.91-3.95 (d, J=13.6 Hz, 0.5H), 3.66-3.69 (t, J=5.2 Hz, 2H), 3.55-3.61 (t, J=7.2 Hz, 0.5H), 3.34 (s, 4H), 3.10-3.21 (m, 1H), 2.96-3.01 (m, 0.5H), 2.69-2.80 (m, 1H), 2.60-2.65 (m, 1H), 2.01-2.02 (d, J=2.8 Hz, 6H), 1.51-1.57 (m, 1H), 1.38-1.39 (d, J=6.4 Hz, 1.3H), 1.26-1.28 (d, J=6.8 Hz, 1.7H), 1.08-1.11 (m, 1H), 0.75-0.91 (m, 2H) LC-MS: m/z 433.2 (M+H)
1HNMR (METHANOL-d) δ 7.63 (s, 1H), 7.58-7.60 (d, J=7.6 Hz, 1H), 7.40-7.44 (t, J=7.6 Hz, 1H), 7.33-7.36 (t, J=7.6 Hz, 1H), 7.16-7.18 (d, J=7.6 Hz, 1H), 4.78 (s, 1H), 4.36-4.49 (m, 3H), 4.13-4.24 (m, 2H), 3.91-3.95 (d, J=13.2 Hz, 0.5H), 3.66-6.69 (m, 2H), 3.54-3.61 (m, 0.5H), 3.33-3.34 (m, 4H), 3.25-3.28 (m, 0.5H), 3.13-3.15 (m, 1H), 2.96-3.02 (m, 0.5H), 2.69-2.81 (m, 1H), 2.60-2.65 (m, 1H), 1.62-1.68 (m, 1H), 1.37-1.39 (m, 1.5H), 1.25-1.28 (m, 1.5H), 1.11-1.12 (m, 2H), 0.83-0.92 (m, 2H); LC-MS: m/z 435.2 (M+H)
1HNMR (METHANOL-d) δ 8.17-8.18 (dd, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.61-7.63 (dd, J=7.2 Hz, 1H), 7.04-7.07 (dd, J=7.2 Hz, 1H), 4.76-4.78 (m, 0.5H), 4.38-4.44 (m, 1H), 4.13-4.25 (m, 2H), 3.90 (s, 3H), 3.66-3.69 (t, J=5.6 Hz, 2H), 3.54-6.60 (m, 0.5H), 3.33 (s, 3H), 3.15-3.19 (m, 0.5H), 3.12-3.13 (m, 1H), 2.97-3.03 (m, 0.5H), 2.69-2.80 (m, 1H), 2.59-2.65 (m, 1H), 1.67-1.73 (m, 1H), 1.37-1.38 (d, J=6.4 Hz, 1H), 1.25-1.27 (d, J=6.8 Hz, 2H), 1.10-1.11 (m, 2H), 0.85-0.92 (m, 2H) LC-MS: m/z 436.2 (M+H)
1HNMR (METHANOL-d) δ 7.63 (s, 1H), 7.51-7.53 (d, J=6.4 Hz, 1H), 7.39-7.42 (m, 2H), 7.22-7.23 (dd, J=6.8 Hz, 1H), 4.15-4.45 (m, 4H), 3.93-3.96 (m, 0.5H), 3.66-3.69 (m, 2H), 3.34 (s, 4H), 3.16-3.17 (d, J=4.0 Hz, 3H), 3.13-3.14 (m, 0.5H), 3.00-3.04 (m, 0.5H), 2.70-2.81 (m, 1H), 2.61-2.64 (m, 1H), 1.63-1.67 (m, 1H), 1.38-1.40 (m, 1H), 1.26-1.29 (m, 2H), 1.12-1.25 (m, 2H), 0.83-0.94 (m, 2H) LC-MS: m/z 449.2 (M+H)
1H NMR (METHANOL-d) δ 8.38 (S, 1H), 8.00-8.02 (m, 2H), 7.85 (t, J=7.2 Hz, 2H), 7.81 (S, 1H), 7.68 (t, J=8.0 Hz, 1H), 4.8 (m, 1H), 4.4-4.5 (m, 1H), 4.2-4.4 (m, 1H), 3.95 (d, J=14.0 Hz, 0.5H), 3.67 (t, J=18.0 Hz, 2h), 3.54-3.60 (m, 0.5H), 3.32-3.45 (m, 4.5H), 3.22-3.25 (m, 1H), 3.09-3.22 (m, 0.5H), 2.71-2.79 (m, 1H), 2.60-2.65 (m, 1H), 1.63-1.69 (m, 1H), 1.39-1.41 (m, 1H), 1.30 (t, J=6.8 Hz, 2H), 1.18-1.24 (m, 1H), 1.12-1.17 (m, 1H), 0.95-1.15 (m, 1H), 0.85-0.95 (m, 1H).
LC-MS: m/z 490.1 (M+H)+.
1H NMR (METHANOL-d) δ 7.77 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 4.78 (m, 0.5H), 4.21-4.44 (m, 3H), 3.94 (d, J=12.6 Hz, 0.5H), 3.66-3.69 (m, 4.5H), 3.54-3.62 (m, 0.5H), 3.33 (m, 3.5H), 2.70-2.82 (m, 1H), 2.59-2.65 (m, 1H), 1.68-1.74 (m, 1H), 1.36 (d, J=6.8 Hz, 1H), 1.27 (d, J=11.2 Hz, 2H), 1.14-1.24 (m, 2H), 0.97-1.02 (m, 2H). LC-MS: m/z 409.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.70 (s, 1H), 4.77-4.80 (m, 0.5H), 4.42 (d, J=13.2 Hz, 1H), 4.17-4.28 (m, 2H), 3.94 (d, J=13.2 Hz, 0.5H), 3.68 (t, J=5.2 Hz, 2H), 3.51-3.62 (m, 1H), 3.31-3.33 (m, 3H), 3.14-3.24 (m, 1H), 3.01-3.08 (m, 0.5H), 2.71-2.80 (m, 1H), 2.59-2.70 (m, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 1.75-1.82 (m, 1H), 1.38 (d, J=6.8 Hz, 1H), 1.25 (d, J=11.2 Hz, 2H), 1.15-1.20 (m, 2H), 0.98-1.02 (m, 2H). LC-MS: m/z 424.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 8.27 (s, 1H), 7.79 (s, 1H0, 7.64 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.65 (t, J=1.2 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J=13.2 Hz, 0.5H), 4.23-4.35 (m, 2.5H), 3.72-3.77 (m, 2.5H), 3.54-3.60 (m, 0.5H), 3.37 (s, 3H), 3.26-3.32 (m, 1H), 3.04-3.17 (m, 1H), 2.55-2.72 (m, 2H), 2.36-2.43 (m, 1H), 1.37 (d, J=5.6 Hz, 1H), 1.26 (d, J=6.8 Hz, 2H), 1.18-1.20 (m, 2H), 1.03-1.04 (m, 2H). LC-MS: m/z 444.2 (M+H)+.
1H NMR (METHANOL-d) 8.226 (s, 1H), 7.764 (s, 1H), 7.697-7.614 (m, 2H), 7.333-7.313 (d, J=8 Hz, 2H), 4.775-4.856 (m, 0.5H), 4.459-4.389 (m, 1H), 4.268-4.147 (m, 2H), 3.968-3.929 (m, 0.5H), 3.688-3.567 (m, 3H), 3.342 (s, 3H), 3.193-3.022 (m, 2H), 2.814-2.626 (m, 2H), 2.125-2.076 (m, 1H), 1.402-1.274 (m, 3H), 1.175 (s, 2H), 1.54-0.928 (m, 2H). LC-MS: m/z 445.1 (M+H)+.
1H NMR (METHANOL-d) 9.301 (s, 1H), 8.163-8.142 (d, J=8.4 Hz, 1H), 8.102-8.099 (d, J=1.2, 1H), 7.807 (s, 1H), 7.559-7.535 (dd, J1=9.6 Hz, J2=1.6 Hz, 1H), 4.792 (m, 0.5H), 4.453-4.418 (m, 1H), 4.282-4.170 (m, 2H), 3.959-3.926 (m, 0.5H), 3.682-3.667 (m, 2H), 3.616-3.561 (m, 0.5H), 3.338 (s, 3H), 3.212-3.004 (m, 2H), 2.806-2.594 (m, 2H), 2.085-2.022 (m, 1H), 1.392-1.262 (m, 3H), 1.211-1.176 (m, 2H), 1.000-0.900 (m, 2H). LC-MS: m/z 462.1 (M+H)+.
1H NMR (METHANOL-d) 9.292 (s, 1H), 8.131 (s, 2H), 7.806 (s, 1H), 7.624-7.606 (d, J=7.2 Hz, 1H), 4.775-4.856 (m, 0.5H), 4.412-4.172 (m, 3H), 3.960-3.931 (m, 0.5H), 3.555-3.688 (m, 3H), 3.345 (s, 3H), 3.188-3.038 (m, 2H), 2.762-2.640 (m, 2H), 2.047-2.035 (m, 1H), 1.379-1.266 (m, 3H), 1.192 (s, 2H), 0.965 (s, 2H). LC-MS: m/z 462.0 (M+H)+.
1H NMR (CHLOROFORM-d) 7.844 (s, 1H), 7.719-7.715 (d, J=1.6 Hz, 1H), 7.547 (s, 2H), 7.402-7.381 (d, J=8.4 Hz, 1H), 7.266-7.242 (d, J=9.6, 1H), 4.631-4.664 (m, 0.5H), 4.297-4.017 (m, 3H), 3.869-3.838 (m, 0.5H), 3.564-3.453 (m, 3H), 3.349-3.228 (m, 3H), 3.109-2.929 (m, 2H), 2.669-2.500 (m, 2H), 2.081-2.058 (m, 1H), 1.236 (s, 1H), 1.135-1.079 (m, 4H), 0.964-0.936 (m, 2H). LC-MS: m/z 477.1 (M+H)+.
1H NMR (METHANOL-d) 9.213-9.215 (d, J=0.8 Hz, 1H), 8.131-8.154 (d, J=9.2 Hz, 1H), 7.917-7.947 (m, 2H), 4.784 (s, 0.5H), 4.220-4.782 (m, 3H), 3.973-3.939 (d, J=13.6 Hz, 0.5H), 3.680 (s, 0.5H), 3.051-3.40 (m, 6H), 2.595-2.821 (m, 2H), 1.973-2.033 (m, 1H), 1.231-1.369 (m, 5H), 0.90-1.120 (s, 2H). LC-MS: m/z 447.1 (M+H)+.
1H NMR (METHANOL-d) 9.342-9.356 (d, J=5.6 Hz, 1H), 8.626-8.642 (d, J=6.4 Hz, 1H), 8.530-8.546 (d, J=6.4 Hz 1H), 8.347-8.368 (d, J=8.4 Hz 1H), 8.263-8.284 (d, J=8.4 Hz 1H), 7.976-7.994 (d, J=7.2 Hz, 1H), 7.912 (s, 1H), 4.814 (s, 0.5H), 4.265-4.808 (m, 3H), 3.968-4.002 (m, 2.5H), 3.151-3.441 (m, 5H), 2.622-2.804 (m, 2H), 1.182-1.496 (m, 5H), 0.801-0.981 (m, 2H). LC-MS: m/z 456.1 (M+H)+.
1H NMR (METHANOL-d) 7.759 (s, 1H), 7.579-7.599 (d, J=8 Hz, 1H), 7.218 (s, 1H), 7.080-7.099 (d, J=7.6 Hz 1H), 7.000-7.018 (d, J=7.2 Hz 1H), 6.506-6.513 (d, J=7.2 Hz, 1H), 4.417-4.466 (dd, J=8 Hz, 1H), 4.191-4.261 (m, 3H), 3.940-3.976 (d, J=1.44 Hz, 0.5H), 3.603-3.642 (m, 3H), 2.617-3.346 (m, 7H), 1.717-1.828 (m, 1H), 1.155-1.421 (m, 5H), 0.832-0.851 (dd, J=4.4 HZ, 2H). LC-MS: m/z 444.2 (M+H)+.
1H NMR (METHANOL-d) 9.170-9.183 (d, J=5.2 Hz, 1H), 9.076-9.097 (d, J=8.4 Hz, 1H), 8.304-8.333 (t, 2H), 8.194-8.216 (d, J=8.8 Hz 1H), 8017-8.050 (m, 1H), 7.918 (s, 1H), 4.787 (s, 0.5H), 4.214-4.447 (m, 3H), 3.974-4.214 (d, J=96 Hz, 0.5H), 3.336-3.397 (m, 3H), 3.076-3.3.250 (m, 5H), 2.599-2.811 (m, 2H), 2.023-2.043 (m, 1H), 1.363-1.379 (d, J=6.4 Hz 1H), 1.244-1.263 (d, J=7.6 Hz 4H), 0.99-1.026 (m, 2H). LC-MS: m/z 456.1 (M+H)+.
1H NMR (METHANOL-d) 8.313 (s, 1H), 8.280 (s, 1H), 7.831 (s, 1H), 7.563-7.572 (d, J=3.6 Hz 1H), 6.682-6.690 (d, J=3.2 Hz 1H), 4.795 (s, 0.5H), 4.183-4.455 (m, 3H), 3.929-3.969 (m, 0.5H), 3.568-3.687 (m, 3H), 3.179-3.342 (m, 4H), 3.046-3.078 (m, 1H), 2.609-2.810 (m, 2H), 2.020 (s, 1H), 1.194-1.392 (m, 5H), 0.964-0.991 (m, 2H). LC-MS: m/z 445.2 (M+H)+.
1H NMR (CHLOROFORM-d) 8.282 (s, 1H), 7.884-7.889 (d, J=2 Hz, 1H), 6.947-6.951 (d, J=1.6 Hz, 1H), 4.888 (s, 0.5H), 4.493-4.524 (d, J=12.4 Hz, 0.5H), 4.205-4.371 (m, J=44.8 Hz, 2.5H), 3.719-3.790 (m, J=28.4 Hz, 2.5H), 3.499-3.550 (m, J=20.4, 0.5H), 3.367-3.372 (d, J=2 Hz, 3H), 3.218-3.246 (t, J=11.2 Hz, 1H), 3.006-3.118 (m, J=44.8 Hz, 1.5H), 2.544-2.745 (m, J=80.4 Hz, 2H), 2.404-2.465 (m, J=24.4 Hz, 1H), 1.532 (s, 9H), 1.243-1.355 (q, J=44.8 Hz, 3H), 1.153-1.158 (d, J=2 Hz, 2H), 0.969-0.985 (t, J=6.4 Hz, 2H). LC-MS: m/z 527.2 (M+H)+.
1H NMR (CHLOROFORM-d) 8.506-8.526 (d, J=8.0 Hz, 1H), 7.617-7.658 (t, J=16.4 Hz, 1H), 7.596 (s, 1H), 7.529-7.569 (t, J=16 Hz, 1H), 7.209-7.240 (t, J=12.4 Hz, 1H), 7.036 (s, 1H), 4.916 (s, 0.5H), 4.534-4.642 (m, J=43.2 Hz, 3H), 4.208-4.351 (m, J=57.2 Hz, 3H), 3.836-3.869 (m, J=13.2 Jz, 0.5H), 3.681-3.739 (t, J=23.2 Hz, 2H), 3.589 (s, 3H), 3.287-3.371 (m, J=33.6 Hz, 1H), 3.155-3.192 (m, 1.5H), 2.594-2.773 (m, 2H), 1.678-1.740 (m, J=24.8 Hz, 1H), 1.301-1.423 (d, J=48.8 Hz, 3H), 1.089-1.143 (m, 2H), 0.809-0.909 (m, 2H). LC-MS: m/z 486.2 (M+H)+.
1H NMR (CHLOROFORM-d) 7.665 (s, 1H), 7.348-7.327 (d, J=8.4 Hz, 2H), 7.129-7.107 (d, J=8.8 Hz, 2H), 4.824-4.780 (m, 1H), 4.440-4.408 (m, 1H), 4.220-4.109 (m, 2H), 3.884-3.860 (m, 4H), 3.693-3.520 (m, 3H), 3.361-3.4 (s, 3H), 3.230-3.298 (m, 4.5H), 3.183-2.988 (m, 1.5H), 2.798-2.600 (m, 2H), 2.115-2.076 (m, 1H), 1.382-1.253 (m, 3H), 1.162-1.128 (m, 2H), 0.986-0.957 (m, 2H). LC-MS: m/z 490.2 (M+H)+.
1H NMR (CHLOROFORM-d) 8.201-8.207 (d, J=2.4 Hz, 1H), 7.531 (s, 2H), 6.718-6.739 (d, J=8.4 Hz, 1H), 4.867 (m, 1H), 4.477-4.507 (m, 4H), 4.149-4.302 (m, 3H), 4.17-4.39 (m, 3H), 3.601-3.807 (m, 6H), 3.494-3.549 (m, 1H), 3.349 (s, 3H), 2.992-3.213 (m, 6H), 2.531-2.734 (m, 2H), 1.974-2.030 (m, 1H), 1.352-1.367 (d, J=6 Hz, 1H), 1.235-1.265 (t, 2H), 0.967-0.992 (m, 2H). LC-MS: m/z 490.2 (M+H)+.
1H NMR (CHLOROFORM-d) 8.030 (s, 2H), 7.735 (s, 1H), 7.589-7.613 (m, 2H), 7.423-7.462 (m, 1H), 7.242-7.269 (m, 1H), 4.781 (m, 0.5H), 4.376-4.441 (m, 1H), 4.131-4.243 (m, 2H), 3.908-3.940 (d, J=12.8 Hz, 1H), 3.660-3.675 (m, 2H), 3.540-3.602 (m, 0.5H), 3.334 (s, 3H), 3.253-3.262 (d, J=3.6 Hz, 0.5H), 3.122-3.183 (t, 1H), 2.966-3.022 (t, 0.5H), 2.631-2.810 (m, 1H), 2.586-2.615 (m, 1H), 2.061-2.124 (m, 1H), 1.362-1.379 (d, J=6.8 Hz, 1H), 1.249-1.266 (d, J=6.8 Hz, 2H), 1.165-1.182 (m, 2H), 0.900-0.970 (m, 2H) 137. LC-MS: m/z 471.2 (M+H)+.
1H NMR (CHLOROFORM-d) 7.820-7.824 (d, J=1.6 Hz, 1H), 7.767-7.795 (t, 2H), 7.686-7.692 (d, J=2.4 Hz, 1H), 7.490-7.528 (t, 1H), 7.374-7.393 (d, J=7.6 Hz, 1H), 6.720-6.725 (d, J=2 Hz, 1H), 4.790 (m, 0.5H), 4.396-4.452 (m, 1H), 4.153-4.264 (m, 2H), 3.920-3.953 (d, J=13.2 Hz, 0.5H), 3.608-3.680 (m, 2H), 3.554-3.582 (t, 0.5H), 3.337 (s, 3H), 3.220 (m, 0.5H), 3.140-3.197 (t, 1H), 2.986-3.043 (t, 0.5H), 2.751-2.803 (m, 1H), 2.591-2.729 (m, 1H), 2.069-2.120 (m, 1H), 1.372-1.388 (d, J=6.4 Hz, 1H), 1.259-1.276 (d, J=6.8 Hz, 2H), 1.156-1.191 (m, 2H), 0.982 (m, 2H). LC-MS: m/z 471.4 (M+H)+.
1H NMR (CHLOROFORM-d) 8.126 (s, 1H), 7.952 (bs, 1H), 7.681-7.684 (d, J=1.2 Hz, 1H), 7.621 (s, 1H), 7.547 (s, 1H), 7.257-7.280 (d, J=13.6 Hz, 1H), 4.823 (br, 0.5H), 4.436-4.467 (d, J=12.4 Hz, 0.5H), 4.149-4.278 (m, 3H)), 3.649-3.717 (m, 2.5H), 3.446-3.501 (m, 0.5H), 3.299 (s, 3H), 3.219-3.254 (m, 1H), 3.019-3.121 (m, 2H), 2.628-2.646 (m, 1H), 2.501-2.531 (m, 1H), 1.842-1.897 (m, 1H), 1.293-1.308 (d, J=6 Hz, 1.5H), 1.183-1.204 (d, J=8.4 Hz, 1.5H), 1.097-1.115 (m, 2H), 0.902-0.933 (m, 2H). LC-MS: m/z 445.1 (M+H)+.
1H NMR (CHLOROFORM-d) 7.785-7.808 (d, J=9.2 Hz, 1H), 7.646 (s, 1H), 7.433-7.473 (d, J=16 Hz, 1H), 7.335-7.353 (dd, J=7.2 Hz, 1H), 4.835 (m, 0.5H), 4.441 (m, 0.5H), 4.201-4.320 (m, 3H)), 3.669-3.725 (m, 2.5H), 3.478-3.487 (m, 0.5H), 3.312 (s, 3H), 3.103-3.106 (m, 1H), 3.402-3.705 (m, 2H), 2.596-2.654 (m, 1H), 2.484-2.537 (m, 1H), 1.769-1.800 (m, 1H), 1.308 (m, 1.5H), 1.204-1.219 (d, J=6 Hz, 1.5H), 1.127-1.145 (m, 2H), 0.870-0.889 (m, 2H). LC-MS: m/z 447.1 (M+H)+.
1H NMR (CHLOROFORM-d) 7.887 (bs, 1H), 7.646 (s, 1H), 7.462-7.483 (d, J=8.4 Hz, 1H), 7.391-7.429 (t, J=15.2 Hz, 1H), 7.055-7.071 (d, J=6.4 Hz, 1H), 4.859 (m, 0.5H), 4.465-4.500 (d, J=14 Hz, 0.5H), 4.166-4.281 (m, 3H)), 3.671-3.733 (m, 2.5H), 3.486-3.510 (m, 0.5H), 3.312 (s, 3H), 3.200-3.252 (m, 1H), 2.992-3.103 (m, 2H), 2.614-2.670 (m, 1H), 2.527-2.557 (m, 1H), 1.819-1.840 (m, 1H), 1.340-1.355 (d, J=6 Hz, 1.5H), 1.238-1.253 (d, J=6 Hz, 1.5H), 1.101-1.117 (m, 2H), 0.819-0.846 (m, 2H). LC-MS: m/z 445.1 (M+H)+.
1H NMR (CHLOROFORM-d) 8.492 (s, 1H), 7.568-7.569 (d, J=0.4 Hz, 1H), 7.277 (s, 1H), 7.121-7.125 (t, 1H), 7.064-7.068 (d, J=1.6 Hz, 1H), 6.720-6.725 (d, J=2 Hz, 1H), 4.897 (m, 0.5H), 4.510-4.549 (m, 0.5H), 4.175 (m, 2.5H), 3.780 (m, 2.5H), 3.543 (t, 0.5H), 3.369 (s, 3H), 3.246-3.273 (m, 1H), 3.113-3.119 (m, 1H), 3.019-3.048 (t, 0.5H), 2.649-2.759 (m, 1H), 2.556-2.609 (m, 1H), 1.998-2.006 (m, 1H), 1.268-1.387 (m, 3H), 1.129-1.155 (m, 2H), 0.928-0.955 (m, 2H). LC-MS: m/z 462.1 (M+H)+.
1H NMR (CHLOROFORM-d) 8.350-8.325 (d, J=10 Hz, 1H), 7.913 (s, 1H), 7.660-7.415 (m, 4H), 4.915 (s, 0.5H), 4.562-4.530 (m, 0.5H), 4.278-4.228 (m, 2.5H), 4.261 (s, 3H), 3.797-3.553 (m, 3H), 3.797 (s, 3H), 3.577-3.044 (m, 2.5H), 2.750-2.568 (m, 2H), 1.633-1.625 (m, 1H), 1.429-1.322 (m, 3H), 1.137-1.093 (m, 2H), 0.842-0.765 (m, 2H). LC-MS: m/z 486.1 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.10-7.16 (m, 4H), 4.62-4.65 (m, 0.5H), 4.23 (d, J=12.8 Hz, 1H), 4.15 (d, J=12.5 Hz, 1H), 4.04 (d, J=8.3 Hz, 0.5H), 3.61-3.88 (m, 3.5H), 3.31-3.38 (m, 3H), 3.25 (br. s., 0.5H), 3.02-3.17 (m, 1H), 2.89-3.02 (m, 1H), 2.51-2.73 (m, 2H), 2.09-2.18 (m, 3H), 1.53-1.59 (m, 1H), 1.33-1.44 (m, 1H), 0.99-1.08 (m, 2H), 0.75-0.86 (m, 2H), 0.29-0.63 (m, 4H)
LC-MS: m/z 463.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.19 (d, J=7.3 Hz, 4H), 4.70 (br. s., 0.5H), 4.30 (d, J=13.1 Hz, 1H), 4.18-4.27 (m, 1H), 4.12 (d, J=8.3 Hz, 0.5H), 3.81-3.94 (m, 1H), 3.66-3.78 (m, 1H), 3.32 (q, J=9.8 Hz, 2H), 3.08-3.21 (m, 1H), 2.97-3.08 (m, 1H), 2.14-2.25 (m, 3H), 1.58-1.67 (m, 1H), 1.50 (br. s., 1H), 1.04-1.14 (m, 2H), 0.81-0.89 (m, 2H), 0.65 (br. s., 1H), 0.56 (br. s., 1H), 0.37-0.52 (m, 2H)
LC-MS: m/z 487.2 (M+H)30
1H NMR (CHLOROFORM-d) δ 9.30 (d, J=1.1 Hz, 1H), 9.30 (d, J=1.1 Hz, 1H), 7.32 (t, J=4.5 Hz, 1H), 6.82 (dd, J=17.4, 10.7 Hz, 1H), 6.64-6.49 (m, 1H), 5.81 (dd, J=14.9, 4.1 Hz, 1H), 4.93 (d, J=17.7 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H), 4.20 (dd, J=33.1, 13.9 Hz, 2H), 3.77 (dd, J=18.0, 11.5 Hz, 2H), 3.57 (dd, J=12.8, 9.6 Hz, 1H), 3.39 (s, 3H), 3.34-2.95 (m, 3H), 2.82-2.49 (m, 2H), 2.26 (s, 3H), 2.88-1.49 (m, 8H), 1.57 (ddd, J=12.5, 8.0, 4.5 Hz, 1H), 1.45-1.37 (m, 2H), 1.33-1.28 (m, 2H), 1.14 (dt, J=7.4, 3.5 Hz, 2H), 0.96-0.81 (m, 3H).
LC-MS: m/z 447.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.70 (d, J=4.9 Hz, 1H), 7.23 (s, 1H), 7.08 (d, J=4.1 Hz, 1H), 6.88 (dd, J=17.4, 10.8 Hz, 1H), 6.30 (d, J=17.4 Hz, 1H), 5.58 (d, J=10.9 Hz, 1H), 4.92 (s, 1H), 4.53 (t, J=14.2 Hz, 1H), 4.29-4.08 (m, 3H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (dd, J=23.8, 17.1 Hz, 1H), 3.40 (s, 3H), 3.31-2.95 (m, 3H), 2.68 (ddd, J=33.7, 17.4, 11.1 Hz, 2H), 2.20 (d, J=8.0 Hz, 3H), 1.57 (ddd, J=12.5, 8.1, 4.6 Hz, 1H), 1.41 (d, J=6.3 Hz, 2H), 1.36-1.25 (m, 4H), 1.10 (s, 2H), 0.94-0.74 (m, 3H).
LC-MS: m/z 446.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 6.97-7.10 (m, 2H), 6.87-6.97 (m, J=8.0 Hz, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.23 (br. s., 0.5H), 3.95-4.18 (m, 2H), 3.71-3.83 (m, 2.5H), 3.58 (m, 0.5H) 3.40 (s, 3H), 3.11-3.27 (m, 1.5H), 2.88-3.10 (m, 1H), 2.53-2.82 (m, 2H), 2.16-2.28 (m, 3H), 1.68-1.78 (m, 1H), 1.38-1.47 (m, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H), 0.98-1.13 (m, 2H), 0.75-0.93 (m, 2H)
LC-MS: m/z 433.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.83 (d, J=8.3 Hz, 1H), 7.71-7.78 (m, 1H), 7.60 (s, 1H), 7.25-7.32 (m, 1H), 7.17-7.24 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.05-4.21 (m, 2.5H), 3.91-4.00 (m, 3H), 3.69-3.87 (m, 2.5H), 3.52-3.69 (m, 0.5H), 3.33-3.46 (m, 3H), 3.13-3.29 (m, 1.5H), 2.97-3.11 (m, 1H), 2.65-2.83 (m, 1H), 2.60 (dd, J=13.1, 6.5 Hz, 1H), 2.17-2.28 (m, 3H), 1.61-1.74 (m, 1H), 1.39-1.49 (m, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H), 0.99-1.17 (m, 2H), 0.69-0.84 (m, 2H)
LC-MS: m/z 499.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.61 (d, J=8.0 Hz, 2H), 7.44-7.57 (m, 3H), 7.37-7.44 (m, 1H), 7.00-7.10 (m, 2H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.04-4.32 (m, 2.5H), 3.69-3.89 (m, 2.5H), 3.58 (t, J=10.8 Hz, 0.5H), 3.34-3.42 (m, 3H), 3.12-3.30 (m, 1.5H), 2.93-3.12 (m, 1H), 2.64-2.82 (m, 1H), 2.59 (dd, J=13.3, 6.5 Hz, 1H), 2.25 (s, 3H), 1.66-1.76 (m, 1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.04-1.15 (m, 2H), 0.87 (dt, J=7.5, 3.7 Hz, 2H)
LC-MS: m/z 513.1 (M+H)+
1H NMR (METHANOL-d) δ 8.79 (s, 1H), 8.70 (s, 1H), 8.40 (d, J=0.4 Hz, 1H), 4.77-4.79 (m, 0.5H), 4.42 (d, J=14.4 Hz, 1H), 4.22-4.24 (m, 1.5H), 4.14 (d, J=13.2 Hz, 0.5H), 3.94 (d, J=13.2 Hz, 0.5H), 3.68 (t, J=6.0 Hz, 2H), 3.55-3.62 (m, 0.5H), 3.31-3.33 (m, 3H), 3.13-3.22 (m, 1H), 3.00-3.06 (m, 0.5H), 2.68-2.82 (m, 1H), 2.58-2.63 (m, 4H), 2.22 (s, 3H), 1.47-1.54 (m, 1H), 1.37 (d, J=6.8 Hz, 1H), 1.26 (d, J=11.2 Hz, 2H), 1.13-1.17 (m, 2H), 0.91-0.94 (m, 2H)
LC-MS: m/z 434.2 (M+H)+.
1H NMR (METHANOL-d) d 8.07 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.43 (s, 3H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H)
LC-MS: m/z 497.2 (M+H)+
1H NMR (METHANOL-d) δ 8.22 (dd, J1=2.0 Hz, J2=4.8 Hz, 1H), 7.54 (dd, J1=2.0 Hz, J2=7.2 Hz, 1H), 7.07-7.10 (m, 1H), 4.78 (s, 0.5H), 4.38-4.45 (m, 1H), 4.01-4.13 (m, 2H), 3.88-3.94 (m, 3.5H), 3.66-3.69 (m, 2H), 3.55-3.61 (m, 0.5H), 3.33 (s, 3H), 3.09-3.25 (m, 2H), 2.91-2.97 (m, 0.5H), 2.69-2.78 (m, 1H), 2.60-2.64 (m, 1H), 2.12 (s, 3H), 1.49-1.52 (m, 1H), 1.40 (d, J=6.4 Hz, 1.3H), 1.28 (dd, J1=2.4 Hz, J2=6.4 Hz, 1.7H), 0.99-1.10 (m, 2H), 0.80-0.83 (m, 2H)
LC-MS: m/z 450.2 (M+H)+
1H NMR (METHANOL-d) δ 7.71 (dd, J1=2.0 Hz, J2=6.4 Hz, 1H), 7.60-7.64 (m, 1H), 7.50 (t, J=9.2 Hz, 1H), 4.77-4.79 (m, 0.5H), 4.38-4.44 (m, 1H), 4.05-4.16 (m, 2H), 3.93 (d, J=13.6 Hz, 0.5H), 3.67-369 (m, 2H), 3.57-3.58 (m, 0.5H), 3.33 (s, 3H), 3.21-3.28 (m, 1H), 3.11-3.15 (m, 1H), 2.96-2.97 (m, 0.5H), 2.69-2.77 (m, 1H), 2.59-2.65 (m, 1H), 2.17 (s, 3H), 1.50-1.54 (m, 1H), 1.38 (d, J=6.4 Hz, 1.3H), 1.26 (d, J=6.8 Hz, 1.7H), 1.09-1.10 (m, 2H), 0.84-0.89 (m, 2H)
LC-MS: m/z 462.1 (M+H)+
1H NMR (METHANOL-d) δ 7.47 (t, J=7.6 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 4.79 (s, 0.5H), 4.50 (s, 2H), 4.37-4.45 (m, 1H), 4.01-4.12 (m, 2H), 3.93 (d, J=13.6 Hz, 0.5H), 3.66-3.69 (m, 2H), 3.55-3.62 (m, 0.6H), 3.39 (s, 3H), 3.33 (s, 3H), 3.04-3.29 (m, 2H), 2.90-2.97 (m, 0.5H), 2.59-2.81 (m, 2H), 2.15 (s, 3H), 1.62-1.66 (m, 1H), 1.42 (d, J=6.4 Hz, 1.4H), 1.31 (d, J=6.4 Hz, 1.6H), 1.02-1.09 (m, 2H), 0.77-0.84 (m, 2H)
LC-MS: m/z 463.2 (M+H)+
1H NMR (METHANOL-d) δ 7.19 (t, J=8.4 Hz, 1H), 6.95-6.99 (m, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H)
LC-MS: m/z 467.2 (M+H)+
1H NMR (METHANOL-d) δ 7.25-7.34 (m, 2H), 6.75-6.79 (m, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H)
LC-MS: m/z 467.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.45 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.21 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 472.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.66 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 476.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.87 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.56-7.62 (m, 1H), 7.41 (d, J=8.0 Hz, 1H) 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 3.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 476.2 (M+H)+.
1H NMR (METHANOL-d) δ 8.02 (d, J=7.6 Hz, 1H), 7.85 (s, 1H), 7.75-7.79 (m, 1H), 7.61 (d, J=7.6 Hz, 1H) 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 5H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 497.1 (M+H)+.
1H NMR (METHANOL-d) δ 7.51 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 3.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 526.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.95 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.43 (s, 3H), 3.16-3.25 (m, 1.5H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 4H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 512.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.57-7.59 (m, 2H), 7.40 (s, 1H), 7.34-7.37 (m, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.45-3.62 (m, 4.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.88-1.99 (m, 4H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 516.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.65 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 4.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.88-1.99 (m, 4H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 516.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.42-7.50 (m, 2H), 7.26 (s, 1H), 7.22 (d, J=7.2 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.31 (s, 2H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.87 (s, 3H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 526.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.11 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.88-4.12 (m, 5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.21-1.41 (m, 4H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H), 0.61-0.69 (m, 2H), 0.35-0.41 (m, 2H).
LC-MS: m/z 489.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.10 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.98-4.12 (m, 4H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.78-1.89 (m, 2H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 5H), 0.78-0.85 (m, 2H).
LC-MS: m/z 477.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.41 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 2.01 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 490.1 (M+H)+.
1H NMR (METHANOL-d) δ 8.10-8.09 (d, J=2.4 Hz, 1H), 7.89-7.85 (m, 1H), 7.23-7.20 (m, 1H), 4.79-4.78 (d, J=1.2 Hz, 0.5H), 4.44-4.41 (d, J=14 Hz, 1H), 4.18-4.01 (m, 2H), 3.95-3.92 (d, J=13.6 Hz, 0.5H), 3.68-3.67 (d, J=5.6 Hz, 2H), 3.62-3.56 (t, J=11.6 Hz, 0.5H), 3.33 (s, 3H), 3.26-3.24 (m, 1H), 3.20-3.11 (m, 1H), 3.01-2.98 (m, 0.5H), 2.80-2.69 (m, 1H), 2.64-2.59 (m, 1H), 2.19 (s, 3H), 1.56-1.54 (m, 1H), 1.39-1.37 (d, J=6.4 Hz, 1H), 1.27-1.26 (d, J=6.8 Hz, 1H), 1.11-1.09 (t, J=3.6 Hz, 2H), 0.89-0.87 (m, 2H). LC-MS: m/z 438.1 (M+H)+.
1H NMR (METHANOL-d) δ 7.87-7.85 (d, J=8.4 Hz, 2H), 7.47-7.45 (d, J=8 Hz, 2H), 4.79 (s, 1H), 4.45-4.39 (m, 1H), 4.16-4.05 (m, 2H), 3.95-3.92 (d, J=13.2 Hz, 0.5H), 3.69-3.66 (t, J=11.6 Hz, 2H), 3.62-3.55 (m, 0.5H), 3.33 (s, 3H), 3.27-3.08 (m, 2H), 2.99-2.94 (m, 0.5H), 2.81-2.69 (m, 1H), 2.64-2.59 (m, 1H), 2.16 (s, 3H), 1.55-1.49 (m, 1H), 1.39-1.28 (m, 3H), 1.12-1.09 (m, 1H), 0.89-0.86 (m, 2H). LC-MS: m/z 444.1 (M+H)+.
1H NMR (METHANOL-d) δ 7.53-7.55 (m, 1H), 7.40-7.45 (m, 2H), 7.11-7.14 (m, 1H), 4.79 (s, 0.5H), 4.42 (t, J=14.4 Hz, 1H), 4.04-4.15 (m, 4H), 3.93 (d, J=12.8 Hz, 0.5H), 3.59-3.69 (m, 2.5H), 3.33 (s, 3H), 3.20 (d, J=4.8 Hz, 4H), 2.95-3.18 (m, 1H), 2.71-2.76 (m, 1H), 2.60-2.65 (m, 1H), 2.08 (s, 3H), 1.40-1.5 (m, 2.3H), 1.27-1.38 (m, 1.7H), 1.02-1.09 (m, 2H), 0.75-0.82 (m, 2H).
LC-MS: m/z 463.2 (M+H)+.
1H NMR (METHANOL-d) d 7.60 (s, 1H), 6.33 (s, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.21-4.38 (m, 2H), 3.88-3.95 (m, 0.5H), 3.65-3.72 (m, 2H), 3.63 (s, 3H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 1H), 2.97-3.08 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.19 (m, 2H), 0.78-0.95 (m, 2H). LC-MS: m/z 423.2 (M+H)+.
1H NMR (METHANOL-d) d 7.45-7.48 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=7.6 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.98 (s, 3H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 512.1 (M+H)+.
1H NMR (METHANOL-d) d 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.12 (m, 2H), 0.85-0.95 (m, 2H).
LC-MS: m/z 438.2 (M+H)+.
1H NMR (METHANOL-d) 7.742 (s, 1H), 7.499 (s, 1H), 4.365-7.255 (m, 5H), 5.410 (s, 2H), 4.773 (s, 0.5H), 4.429-4.359 (m, 1H), 4.109-4.004 (m, 2H), 3.924-3.891 (m, 0.5H), 3.683-3.655 (m, 2H), 3.592-3.535 (m, 0.5H), 3.328 (s, 3H), 3.255-3.041 (m, 2H), 2.954-2.898 (m, 0.5H), 2.801-2.588 (m, 2H), 2.260 (s, 3H), 1.909-1.869 (m, 1H), 1.375-1.246 (m, 3H), 1.071 (s, 2H), 0.90-0.80 (m, 2H). LC-MS: m/z 499.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.40-7.37 (m, 2H), 7.35-7.27 (m, 1H), 7.07-7.04 (m, 1H), 4.80-4.79 (d, J=2.4 Hz, 0.5H), 4.46-4.38 (m, 1H), 4.14-4.04 (m, 2H), 3.95-3.92 (d, J=12.8 Hz, 0.5H), 3.68-3.63 (m, 2H), 3.60 (m, 0.5H), 3.34 (s, 3H), 3.26-3.06 (m, 2H), 2.97-2.94 (d, J=12 Hz, 0.5H), 2.80-2.60 (m, 2H), 2.42-2.30 (m, 2H), 2.09 (s, 3H), 1.55-1.50 (m, 1H), 1.43-1.39 (m, 1H), 1.32-1.27 (m, 1H), 1.08-1.03 (m, 5.5H) 0.82-0.80 (m, 2H). LC-MS: m/z 447.2 (M+H)+.
1H NMR (METHANOL-d) δ 7.53 (t, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J=7.2 Hz, 1H), 4.78 (s, 1H), 4.38-4.45 (m, 1H), 4.03-4.14 (m, 2H), 3.91-3.95 (m, 0.5H), 3.65-3.70 (m, 2H), 3.53-3.62 (m, 0.5H), 3.34 (s, 4H), 3.21-3.31 (m, 1.5H), 3.16 (s, 7H), 2.96-2.98 (m, 0.5H), 2.71-2.79 (m, 1H), 2.62-2.65 (m, 1H), 2.19 (s, 3H), 1.61-1.67 (m, 1H), 1.38-1.40 (d, J=6.4 Hz, 1.3H), 1.27-1.28 (d, J=6.4 Hz, 1.7H), 1.07-1.09 (m, 2H), 0.81-0.84 (m, 2H). LC-MS: m/z 462.1 (M+H)+.
1H NMR (METHANOL-d) d 7.64 (s, 1H), 7.44 (s, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.88-4.12 (m, 5.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 423.1 (M+H)+.
1H NMR (METHANOL-d) d 8.06 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.58-7.63 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 477.1 (M+H)+.
1H NMR (METHANOL-d) δ 8.31-8.30 (d, J=4.4 Hz, 1H), 7.90-7.86 (t, J=8.4 Hz, 1H), 7.48-7.45 (m, 1H), 4.82-4.79 (m, 0.5H), 4.45-4.37 (m, 0.5H), 4.20-4.10 (m, 2H), 3.95-3.92 (d, J=12.8 Hz, 0.5H), 3.68-3.67 (m, 2H), 3.62-3.56 (t, J=12 Hz, 0.5H), 3.34-3.33 (m, 3.5H), 3.18-3.16 (d, J=10.8 Hz, 1H), 3.01 (m, 1H), 2.80-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.2 (s, 3H), 1.52-1.49 (m, 1H), 1.39-1.38 (d, J=2.8 Hz, 1H), 1.28-1.27 (d, J=6.4 Hz, 1H), 1.13-0.90 (m, 1H), 0.90-0.88 (m, 1H). LC-MS: m/z 438.2 (M+H)+.
1H NMR (CHLOROFORM-d) δ 7.61-7.59 (d, J=7.6 Hz, 1H), 7.46-7.37 (m, 2H), 7.10-7.08 (d, J=7.2 Hz, 1H), 4.90 (s, 0.5H), 4.53-4.34 (M, 2.5H), 4.22-4.05 (m, 2.5H), 3.79-3.71 (m, 2.5H), 3.60-3.54 (M, 0.5H), 3.48 (S, 1H), 3.37 (S, 3H), 3.19-3.14 (M, 1.5H), 3.03-2.98 (m, 1H), 2.75-2.66 (M, 1H), 2.60-2.55 (m, 1H), 2.11 (s, 3H), 1.48-1.44 (m, 2H), 1.31-1.30 (d, J=4.8 Hz, 1.5H), 1.10-1.07 (m, 2H). LC-MS: m/z 449.1 (M+H)+.
1H NMR (METHANOL-d) d 7.36 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.43 (s, 3H), 3.16-3.25 (m, 1.5H), 3.03 (s, 3H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 512.2 (M+H)+.
1H NMR (METHANOL-d) d 8.02 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 498.1 (M+H)+.
1H NMR (METHANOL-d) δ 7.26-7.39 (m, 2H), 7.07 (t, J=6.8 Hz, 1H), 4.72 (s, 0.5H), 4.41-4.45 (m, 1H), 4.07-4.19 (m, 2H), 3.93 (d, J=13.6 Hz, 0.5H), 3.66-3.69 (m, 2H), 3.56-3.62 (m, 0.5H), 3.33 (s, 3H), 3.20-3.28 (m, 1H), 3.14-3.17 (m, 1H), 2.96-3.02 (m, 0.5H), 2.60-2.81 (m, 2H), 2.18 (s, 3H), 1.55-1.61 (m, 1H), 1.38 (d, J=6.4 Hz, 1.3H), 1.27 (d, J=6.8 Hz, 1.7H), 1.06-1.1 (m, 2H), 0.82-0.89 (m, 2H). LC-MS: m/z 455.1 (M+H)+.
It was obtained by the same procedure of Compound 527.
1H NMR (CHLOROFORM-d) δ 8.70 (d, J=5.0 Hz, 1H), 7.26 (s, 1H), 7.10 (d, J=3.8 Hz, 1H), 6.90 (dd, J=17.4, 10.9 Hz, 1H), 6.32 (d, J=17.3 Hz, 1H), 5.61 (d, J=11.3 Hz, 1H), 4.60-4.76 (m, 0.5H), 4.34 (d, J=12.8 Hz, 1H), 4.26 (d, J=12.8 Hz, 1H), 4.08 (d, J=9.0 Hz, 0.5H), 3.92 (br. s., 2H), 3.78 (br. s., 1H), 3.39-3.56 (m, 1H), 3.23 (br. s., 1H), 3.15 (d, J=11.8 Hz, 1H), 3.05 (br. s., 1H), 2.61 (br. s., 2H), 2.17-2.29 (m, 3H), 1.55-1.60 (m, 1H), 1.38-1.47 (m, 1H), 1.27-1.33 (br. s., 1H), 1.12 (br. s., 2H), 0.64 (br. s., 2H), 0.33-0.54 (m, 2H)
LC-MS: m/z 458.3 (M+H)+
A mixture of (R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (200 mg, 0.42 mmol), 5-chloropyridazin-3-ol (109 mg, 0.625 mmol), CsF (127 mg, 0.84 mmol) and Pd(dppf)Cl2 (17 mg) in dioxane and water was heated at 100° C. for 2 hrs. The reaction mixture was concentrated and the residue was purified by pre-TLC to afford 120 mg of title compound.
LC-MS: m/z 449.2 (M+H)+
A solution of (R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(6-hydroxypyridazin-4-yl)nicotinonitrile (120 mg, 0.27 mmol), Tf2O (100 mg, 0.48 mmol) and TEA (0.1 mL) in DCM was stirred for 1 hr. The reaction mixture was washed with water, dried and concentrated. The residue was purified by pre-TLC to afford 60 mg of title compound.
1H NMR (CHLOROFORM-d) δ: 9.41 (d, J=1.5 Hz, 1H), 7.71 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 4.71 (d, J=12.8 Hz, 1.5H), 4.58 (d, J=11.5 Hz, 1H), 4.14 (brs, 0.5H), 3.93 (br. s., 0.5H), 3.75 (br. s., 2.5H), 3.39 (s, 3H), 3.21-3.36 (m, 3H), 2.54-2.83 (m, 2H), 1.86-1.96 (m, 1H), 1.08-1.28 (m, 5H), 0.48-0.63 (m, 4H).
LC-MS: m/z 580.7 (M+H)+
A mixture of (R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)pyridin-3-yl)pyridazin-3-yl trifluoromethanesulfonate (25 mg, 0.043 mmol), Potassium vinyltrifluoroborate (12 mg, 0.083 mmol), TEA (20 mg, 0.215 mmol) and Pd(dppf)Cl2 (3.5 mg) in i-PrOH and water was heated at 100° C. for 2 hrs. The reaction mixture was concentrated and the residue was purified by pre-TLC to afford 11 mg of title compound.
1H NMR (CHLOROFORM-d) δ9.21 (br. s., 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.13 (dd, J=17.6, 11.0 Hz, 1H), 6.37 (d, J=17.6 Hz, 1H), 5.79 (d, J=11.0 Hz, 1H), 4.63 (d, J=12.8 Hz, 1.5H), 4.50 (d, J=12.3 Hz, 1H), 4.05-4.18 (m, 0.5H), 3.90 (d, J=11.0 Hz, 0.5H), 3.63-3.83 (m, 2.5H), 3.38 (s, 3H), 3.18-3.33 (m, 2H), 3.15 (br. s., 1H), 2.71-2.64 (m, 2H), 1.89-1.99 (m, 1H), 1.29-1.40 (m, 3H), 1.07 (dd, J=7.4, 2.9 Hz, 2H), 0.61-0.44 (m, 4H).
LC-MS: m/z 459.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.41 (d, J=1.5 Hz, 1H), 7.71 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 4.71 (d, J=12.8 Hz, 1.5H), 4.58 (d, J=11.5 Hz, 1H), 4.14 (brs, 0.5H), 3.93 (br. s., 0.5H), 3.75 (br. s., 2.5H), 3.39 (s, 3H), 3.21-3.36 (m, 3H), 2.54-2.83 (m, 2H), 1.86-1.96 (m, 1H), 1.08-1.28 (m, 5H), 0.48-0.63 (m, 4H).
LC-MS: m/z 580.7 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.42 (br. s., 1H), 7.72 (s, 1H), 7.52 (s, 1H), 4.73 (d, J=12.8 Hz, 1.5H), 4.60 (d, J=12.0 Hz, 1H), 4.33 (brs, 0.5H), 4.05 (brs, 0.5H), 3.76 (br. s., 1H), 3.24-3.40 (m, 2.5H), 1.89-1.97 (m, 1H), 1.72 (br. s., 1H), 1.29-1.34 (m, 3H), 0.99-1.20 (m, 4H), 0.78-0.90 (m, 2H), 0.41-0.66 (m, 4H).
LC-MS: m/z 563.0 (M+H)+
A stirred solution of (R)-tert-butyl 4-(3-cyano-6-cyclopropyl-5-(5-vinylpyridazin-3-yl) pyridin-2-yl)-2-cyclopropylPiperazine-1-carboxylate (100 mg, 0.2 mmol) in TFA (2 mL) was stirred at room temperature overnight. When LC-MS showed completion of the reaction, the mixture was evaporated under reduced pressure and the residue was dissolved in DCM, washed with Sat. NaHCO3, and brine. The organic layer was evaporated under reduced pressure to give crude product which was used without further purification (70 mg)
To a stirred 2-(oxetan-2-yl)acetic acid (20 mg) in CH2Cl2 was added HATU (72 mg, 0.19 mmol) followed by DIPEA, the mixture was stirred at room temperature for 1 hr, then (R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(5-vinylpyridazin-3-yl)nicotinonitrile (70 mg) was added. The mixture was stirred at room temperature overnight. It was quenched with water, extracted with CH2Cl2. The organic layer was washed with Sat. NaHCO3, brine and dried over Na2SO4, evaporated and purified by prepTLC to give product.
1H NMR (CHLOROFORM-d) δ: 9.23 (br. s., 1H), 7.97 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.76 (d, J=10.9 Hz, 1H), 5.11-5.36 (m, 1H), 4.48-4.77 (m, 4H), 4.08 (d, J=8.5 Hz, 0.5H), 3.95 (d, J=13.2 Hz, 0.5H), 3.75 (d, J=11.2 Hz, 0.5H), 3.32 (br. s., 1H), 3.05-3.27 (m, 2H), 2.98 (dd, J=14.8, 6.0 Hz, 1.5H), 2.79-2.90 (m, 2H), 2.54 (d, J=7.9 Hz, 1H), 2.12-2.26 (m, 1H), 1.25 (dd, J=6.6, 3.7 Hz, 3H), 0.94-1.12 (m, 2H), 0.51-0.72 (m, 2H), 0.35-0.49 (m, 2H)
LC-MS: m/z 471.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.27 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 6.87 (dt, J=14.8, 7.3 Hz, 1H), 6.73 (dd, J=17.8, 11.0 Hz, 1H), 6.26-6.48 (m, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 4.42 (d, J=12.9 Hz, 1H), 4.33 (d, J=12.6 Hz, 1H), 3.89-4.21 (m, 1H), 3.79 (t, J=6.0 Hz, 2H), 3.38 (br. s., 1H), 3.23 (d, J=10.0 Hz, 1H), 3.08 (td, J=12.5, 2.9 Hz, 1H), 2.50 (q, J=6.2 Hz, 2H), 2.18-2.29 (m, 3H), 1.36-1.50 (m, 2H), 1.15 (br. s., 2H), 0.88 (dd, J=7.6, 3.2 Hz, 2H), 0.65 (br. s., 1H), 0.51 (br. s., 1H), 0.44 (br. s., 2H)
LC-MS: m/z 485.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.28 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 6.74 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.9 Hz, 1H), 5.71-5.86 (m, 1H), 5.27 (quin, J=6.7 Hz, 1H), 4.64-4.76 (m, 1H), 4.49-4.63 (m, 1H), 4.41 (d, J=12.6 Hz, 1H), 4.23-4.37 (m, 1H), 4.07 (d, J=8.2 Hz, 1H), 3.92 (d, J=12.6 Hz, 1H), 3.69-3.86 (m, 1H), 3.20-3.36 (m, 1H), 2.93-3.20 (m, 3H), 2.74-2.93 (m, 2H), 2.46-2.66 (m, 1H), 2.18-2.30 (m, 3H), 1.78 (br. s., 1H), 1.41-1.51 (m, 2H), 1.33-1.41 (m, 1H), 1.10-1.20 (m, 2H), 0.89 (dd, J=7.8, 3.1 Hz, 2H), 0.58-0.72 (m, 1H), 0.53 (br. s., 1H), 0.45 (d, J=5.6 Hz, 2H)
LC-MS: m/z 485.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.28 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.28 (s, 1H), 6.74 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.78 (d, J=10.9 Hz, 1H), 4.37-4.47 (m, 1H), 4.26-4.36 (m, 1H), 4.01-4.13 (m, 1H), 3.83-3.98 (m, 2H), 3.65-3.83 (m, 1H), 3.13-3.29 (m, 2H), 2.98-3.13 (m, 1H), 2.46-2.68 (m, 2H), 2.19-2.29 (m, 3H), 1.84-2.10 (m, 1H), 1.42-1.55 (m, 1H), 1.15 (br. s., 1H), 0.81-0.95 (m, 3H), 0.63 (br. s., 1H), 0.53 (br. s., 1H), 0.32-0.48 (m, 2H)
LC-MS: m/z 459.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.21 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.15 (dd, J=17.8, 11.0 Hz, 1H), 6.39 (d, J=17.9 Hz, 1H), 5.81 (d, J=10.9 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.52 (d, J=12.9 Hz, 1H), 4.10 (d, J=9.7 Hz, 1H), 3.85-3.99 (m, 2H), 3.71-3.83 (m, 1H), 3.07-3.36 (m, 3H), 2.42-2.71 (m, 2H), 1.88-2.02 (m, 1H), 1.20-1.40 (m, 3H), 1.01-1.12 (m, 2H), 0.45-0.78 (m, 4H)
LC-MS: m/z 473.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.22 (s, 1H), 7.93-8.03 (m, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.76 (d, J=10.9 Hz, 1H), 4.65 (d, J=13.2 Hz, 1H), 4.52 (d, J=12.6 Hz, 1H), 4.16 (m, 1H), 3.80-4.02 (m, 2H), 3.58-3.74 (m, 1H), 3.45 (s, 3H), 3.26 (d, J=10.3 Hz, 2H), 3.12 (t, J=10.6 Hz, 1H), 2.11-2.32 (m, 1H), 1.23-1.30 (m, 3H), 0.98-1.08 (m, 2H), 0.41-0.72 (m, 4H)
LC-MS: m/z 445.2 (M+H)+
The mixture of ((R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (67 mg, 0.157 mmol), tert-butyl (6-chloropyridazin-4-yl)carbamate (30 mg, 0.131 mmol), Pd(dppf)Cl2 (5 mg, 0.007 mmol) and CsF (40 mg, 0.216 mmol) in dioxane/H2O was stirred at 100° C. for 16 hours. The mixture was diluted with EtOAc (30 mL) and filtered. The filtrated was partitioned between EtOAc (30 mL) and water (10 mL), the organic layer was washed with water (10 mL), brine and dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 20 mg of the product.
1H NMR (CHLOROFORM-d) δ: 9.08 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.60 (br. s., 1H), 4.64 (d, J=12.9 Hz, 1H), 4.52 (d, J=12.3 Hz, 1H), 4.08 (d, J=8.5 Hz, 1H), 3.93 (s, 2H), 3.66-3.84 (m, 1H), 3.25 (m, 3H), 2.50-2.61 (m, 2H), 1.56 (s, 9H), 1.21-1.28 (m, 3H), 1.07 (s, 2H), 0.41-0.80 (m, 4H)
LC-MS: m/z 534.3 (M+H)+
1H NMR (CHLOROFORM-d) δ9.23 (s, 1H), 7.98 (s, 1H), 7.61 (d, J=2.1 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.71-5.84 (m, 1H), 4.64 (d, J=12.9 Hz, 1H), 4.51 (d, J=12.6 Hz, 1H), 4.01-4.16 (m, 1H), 3.92 (s, 2H), 3.65-3.83 (m, 1H), 3.05-3.25 (d, J=11.2 Hz, 2H), 2.50-2.68 (m, 2H), 2.12-2.30 (m, 1H), 1.19-1.27 (m, 3H), 1.00-1.11 (m, 2H), 0.39-0.62 (m, 1H)
LC-MS: m/z 445.2 (M+H)+
1H NMR (CHLOROFORM-d) δ9.20 (s, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.11 (dd, J=17.8, 11.0 Hz, 1H), 6.36 (d, J=17.9 Hz, 1H), 5.77 (d, J=11.2 Hz, 1H), 4.64 (d, J=12.9 Hz, 1H), 4.50 (d, J=12.6 Hz, 1H), 4.15 (s, 2H), 3.80-4.12 (m, 1H), 3.60-3.66 (m, 1H), 3.44 (s, 3H), 3.26 (dd, J=13.2, 3.5 Hz, 1H), 3.07-3.18 (m, 1H), 1.87-2.04 (m, 1H), 1.19-1.29 (m, 3H), 1.06 (dd, J=7.9, 2.9 Hz, 2H), 0.47-0.65 (m, 4H)
LC-MS: m/z 445.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.23 (d, J=2.1 Hz, 1H), 7.98 (s, 1H), 7.63 (d, J=2.1 Hz, 1H), 6.75 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.78 (d, J=10.9 Hz, 1H), 4.66 (d, J=12.9 Hz, 2.5H), 3.98-4.54 (m, 1H), 3.51-3.88 (m, 1H), 3.00-3.45 (m, 1H), 2.16-2.28 (m, 1H), 1.72 (s, 1H), 1.17-1.30 (m, 3H), 0.95-1.11 (m, 4H), 0.77-0.87 (m, 2H), 0.39-0.64 (m, 1H)
LC-MS: m/z 441.2 (M+H)+
The mixture of (R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (100 mg, 0.235 mmol), 5-chloro-3-vinylpyridazine (30 mg, 0.213 mmol), Pd(dppf)Cl2 (8 mg, 0.011 mmol) and CsF (98 mg, 0.640 mmol) in dioxane/H2O was stirred at 100° C. for 16 hours. The mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was partitioned between EtOAc (30 mL) and water (10 mL), the organic layer was washed with water (10 mL), brine, dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 25 mg of the product.
1H NMR (CHLOROFORM-d) δ: 9.21 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.15 (dd, J=17.8, 11.0 Hz, 1H), 6.39 (d, J=17.9 Hz, 1H), 5.81 (d, J=10.9 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.52 (d, J=12.9 Hz, 1H), 4.10 (d, J=9.7 Hz, 1H), 3.87-4.01 (m, 2H), 3.71-3.87 (m, 1H), 3.07-3.36 (m, 3H), 2.46-2.70 (m, 2H), 1.81-2.03 (m, 1H), 1.20-1.34 (m, 3H), 1.03-1.13 (m, 2H), 0.60-0.69 (m, 1H), 0.46-0.57 (m, 4H)
LC-MS: m/z 445.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 12.36 (br. s., 1H), 7.95 (d, J=2.0 Hz, 1H), 7.65 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.50 (d, J=12.8 Hz, 1H), 4.01-4.19 (m, 1H), 3.89-3.98 (m, 2H), 3.60-3.85 (m, 1H), 3.01-3.29 (m, 3H), 2.60 (dd, J=11.8, 6.0 Hz, 2H), 1.87-2.05 (m, 1H), 1.14-1.26 (m, 3H), 0.31-1.14 (m, 4H).
LC-MS: m/z 435.2 (M+H)+
The mixture of (R)-2′,6′-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile (40 mg, 0.084 mmol), CuCN (15 mg, 0.169 mmol), CuI (1 mg) in NMP (2 mL) was stirred at 230° C. for 2 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (30 mL) and water (10 mL), the organic layer was washed with water (10 mL), brine and dried over Na2SO4, concentrated to give the crude which was purified by prep-TLC to give 20 mg of the product.
1H NMR (CHLOROFORM-d) δ: 7.72 (d, J=1.0 Hz, 1H), 7.59-7.66 (m, 2H), 4.91 (s, 0.5H), 4.54 (d, J=10.3 Hz, 0.5H), 4.24-4.48 (m, 2.5H), 3.69-3.79 (m, 2H), 3.51-3.62 (m, 0.5H), 3.33-3.44 (m, 4H), 3.18-3.29 (m, 1.5H), 3.10-3.25 (m, 1.5H), 2.63-2.82 (m, 1H), 2.52-2.63 (m, 1H), 1.82-1.95 (m, 1H), 1.36 (d, J=6.5 Hz, 1H), 1.23-1.28 (m, 4H), 1.04-1.15 (m, 2H)
LC-MS: m/z 465.2 (M+H)+
The mixture of (R)-6′-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-2′,5-dicarbonitrile (10 mg, 0.0215 mmol), Potassium vinyltrifluoroborate (5 mg, 0.032 mmol), Pd(dppf)Cl2 (1 mg, 0.001 mmol) and CsF (10 mg, 0.064 mmol) in dioxane/H2O was stirred at 100° C. for 16 hours. The mixture was diluted with EtOAc (30 mL) and filtered. The filtrated was partitioned between EtOAc (30 mL) and water (10 mL), the organic layer was washed with water (10 mL), brine and dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 5 mg of the product.
1H NMR (CHLOROFORM-d) δ: 7.63 (s, 2H), 7.52-7.59 (m, 1H), 6.86 (dd, J=17.4, 10.7 Hz, 1H), 6.42 (d, J=17.6 Hz, 1H), 5.71 (d, J=10.8 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=9.5 Hz, 0.5H), 4.25-4.46 (m, 2.5H), 3.71-3.86 (m, 3.5H), 3.35-3.42 (m, 3.5H), 3.03-3.29 (m, 1.5H), 2.63-2.82 (m, 1H), 2.53-2.62 (m, 1H), 1.83-1.96 (m, 1H), 1.34-1.40 (m, 2H), 1.20-1.26 (m, 3H), 1.00-1.11 (m, 2H).
LC-MS: m/z 457.2 (M+H)+
A mixture of (R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (100 mg, 0.22 mmol), 4-bromopyridin-2-ol (38 mg, 0.22 mmol), CsF (66 mg, 0.44 mmol) and Pd(dppf)Cl2 (5 mg) in dioxane and water was heated at 100° C. for 0.5 hr. The reaction mixture was concentrated and the residue was purified by pre-TLC to afford 52 mg of title compound.
LC-MS: m/z 422.1 (M+H)+
A solution of (R)-2-cyclopropyl-2′-hydroxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridine]-5-carbonitrile (100 mg, 0.24 mmol), Tf2O (40 mg) and TEA (1 drop) in DCM (5 ml) was stirred for 1 hr. The reaction mixture was washed with water, dried and concentrated. The residue was purified by pre-TLC to afford 60 mg of title compound.
LC-MS: m/z 554.1 (M+H)+
A mixture of (R)-5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-[3,4′-bipyridin]-2′-yltrifluoromethanesulfonate (150 mg, 0.27 mmol), prop-2-en-1-ol (31 mg, 0.54 mmol), TEA (30 mg, 0.30 mmol), Pd(OAc)2 (15 mg, 0.0675 mmol), and Dppf (72 mg, 0.13 mmol) in DMF (10 mL) was heated at 100° C. for 2 hrs. The reaction mixture was diluted with DCM and washed with water and brine, dried and concentrated and the residue was purified by prep-TLC and prep-HPLC to afford 16 mg of title compound.
1H NMR (CHLOROFORM-d) δ8.62 (d, J=5.3 Hz, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.31 (dd, J=5.0, 1.3 Hz, 1H), 5.87 (s, 1H), 5.60 (s, 1H), 4.92 (brs, 0.5H), 4.65 (s, 2H), 4.54 (d, J=12.5 Hz, 0.5H), 4.20-4.46 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.39 (s, 3H), 3.33 (d, J=13.3 Hz, 1H), 3.01-3.27 (m, 1.5H), 2.64-2.85 (m, 1H), 2.51-2.64 (m, 1H), 1.96-2.08 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.25-1.36 (m, 1.5H), 1.17-1.25 (m, 2H), 0.95-1.09 (m, 2H).
LC-MS: m/z 462.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.00 (s, 1H), 8.09-8.21 (m, 1H), 7.80-7.91 (m, 1H), 7.53-7.66 (m, 1H), 7.00-7.13 (m, 1H), 6.51 (d, J=17.6 Hz, 1H), 5.85 (d, J=11.2 Hz, 1H), 4.71 (d, J=10.0 Hz, 0.5H), 4.47 (d, J=10.3 Hz, 0.5H), 4.40 (d, J=13.5 Hz, 1H), 4.23-4.35 (m, 1H), 3.85 (d, J=13.5 Hz, 0.5H), 3.71-3.81 (m, 2H), 3.59 (d, J=10.3 Hz, 0.5H), 3.46-3.55 (m, 0.5H), 3.40 (d, J=5.0 Hz, 3H), 3.05-3.14 (m, 2H), 3.02 (d, J=9.7 Hz, 1H), 2.55-2.83 (m, 3H), 2.28-2.44 (m, 1H), 2.15-2.28 (m, 1H), 2.04-2.10 (m, 3H), 1.02-1.12 (m, 6H), 0.84-0.95 (m, 2H), 0.72-0.81 (m, 1H), 0.59-0.70 (m, 1H)
LC-MS: m/z 525.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.70 (d, J=4.4 Hz, 1H), 7.25 (s, 1H), 7.09 (d, J=3.5 Hz, 1H), 6.90 (dd, J=17.5, 10.7 Hz, 1H), 6.32 (d, J=17.3 Hz, 1H), 5.60 (d, J=10.9 Hz, 1H), 5.22-5.34 (m, 1H), 4.65-4.77 (m, 1H), 4.52-4.63 (m, 1H), 4.22-4.41 (m, 2H), 4.09 (d, J=8.2 Hz, 1H), 3.91 (br. s., 1H), 3.38 (s, 1H), 3.14 (br. s., 1H), 2.94-3.09 (m, 2H), 2.68-2.94 (m, 3H), 2.49-2.63 (m, 1H), 2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12 (br. s., 2H), 0.88 (dd, J=7.6, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.55 (br. s., 1H), 0.34-0.51 (m, 2H)
LC-MS: m/z 484.7 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.70 (d, J=4.4 Hz, 1H), 7.25 (s, 1H), 7.09 (d, J=3.5 Hz, 1H), 6.90 (dd, J=17.5, 10.7 Hz, 1H), 6.32 (d, J=17.3 Hz, 1H), 5.60 (d, J=10.9 Hz, 1H), 5.22-5.34 (m, 1H), 4.65-4.77 (m, 1H), 4.52-4.63 (m, 1H), 4.22-4.41 (m, 2H), 4.09 (d, J=8.2 Hz, 1H), 3.91 (br. s., 1H), 3.38 (s, 1H), 3.14 (br. s., 1H), 2.94-3.09 (m, 2H), 2.68-2.94 (m, 3H), 2.49-2.63 (m, 1H), 2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12 (br. s., 2H), 0.88 (dd, J=7.6, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.55 (br. s., 1H), 0.34-0.51 (m, 2H)
LC-MS: m/z 484.7 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.64 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.40 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.6, 10.8 Hz, 1H), 6.27 (d, J=17.6 Hz, 1H), 5.57 (d, J=11.3 Hz, 1H), 4.87 (br. s., 1H), 4.50 (d, J=11.8 Hz, 1H), 4.39 (d, J=12.8 Hz, 1H), 4.32 (d, J=11.5 Hz, 1H), 3.32 (dd, J=13.1, 2.8 Hz, 1H), 3.21-3.66 (m, 2H), 1.99-2.07 (m, 1H), 1.30-1.50 (m, 3H), 1.21 (dt, J=7.2, 3.5 Hz, 2H), 1.11-1.17 (m, 1H), 0.91-1.09 (m, 5H).
LC-MS: m/z 430.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.48 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 7.30 (d, J=4.4 Hz, 1H), 4.59 (d, J=12.3 Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 4.06 (br. s., 1H), 3.81-3.94 (m, 1H), 3.72 (s, 3H), 3.06-3.36 (m, 1.5H), 2.84 (br. s., 1.5H), 2.71 (d, J=7.9 Hz, 3H), 2.50-2.66 (m, 1H), 1.91-2.07 (m, 1H), 1.33 (br. s., 1H), 1.27 (br. s., 1H), 1.14-1.25 (m, 2H), 1.05 (dd, J=7.5, 3.4 Hz, 2H), 0.61 (br. s., 1H), 0.54 (br. s., 1H), 0.45 (d, J=4.1 Hz, 2H).
LC-MS: m/z 494.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.55-8.78 (m, 1H), 7.66 (s, 1H), 7.39 (br. s., 1H), 7.17-7.26 (m, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.56 (d, J=12.9 Hz, 1H), 4.43 (d, J=12.9 Hz, 1H), 4.22 (br. s., 1H), 4.18 (br. s., 1H), 4.01 (br. s., 0.5H), 3.68 (br. s., 1.5H), 3.34-3.53 (m, 1H), 3.24 (d, J=10.9 Hz, 1H), 3.09 (t, J=11.3 Hz, 1H), 2.00-2.07 (m, 1H), 1.32 (br. s., 1H), 1.27 (br. s., 1H), 1.21 (br. s., 2H), 1.02 (br. s., 2H), 0.66 (br. s., 1H), 0.57 (br. s., 1H), 0.48 (br. s., 1H).
LC-MS: m/z 430.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.67 (d, J=4.7 Hz, 1H), 7.66 (s, 1H), 7.46 (br. s., 1H), 7.31 (br. s., 1H), 6.95 (dd, J=17.3, 10.9 Hz, 1H), 6.38 (d, J=17.3 Hz, 1H), 5.66 (d, J=10.6 Hz, 1H), 4.58 (d, J=12.9 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 3.70-4.12 (br. s., 2H), 3.46 (br. s., 2H), 3.36 (s, 3H), 3.23 (br. s., 1H), 3.11 (br. s., 1H), 2.49 (br. s., 2H), 1.89-2.14 (m, 4H), 1.27-1.31 (m, 1H), 1.18-1.25 (m, 2H), 1.00-1.08 (m, 2H), 0.59 (d, J=15.6 Hz, 2H), 0.47 (d, J=5.0 Hz, 2H).
LC-MS: m/z 472.5 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.64 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.39 (s, 1H), 7.18-7.27 (m, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.42 (d, J=12.6 Hz, 1H), 4.09 (d, J=7.9 Hz, 0.5H), 3.86 (d, J=13.2 Hz, 0.5H), 3.73 (br. s., 2H), 3.05-3.32 (m, 2H), 2.97 (s, 1H), 2.89 (s, 1H), 2.57 (br. s., 3H), 2.00-2.08 (m, 1H), 1.91-1.98 (m, 2H), 1.28 (d, J=17.3 Hz, 1H), 1.21 (br. s., 2H), 1.01 (dd, J=7.6, 3.2 Hz, 2H), 0.61 (br. s., 1H), 0.54 (br. s., 1H), 0.30-0.50 (m, 2H).
LC-MS: m/z 458.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.64 (d, J=5.0 Hz, 1H), 7.58-7.66 (m, 1H), 7.37 (s, 1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.21-6.33 (m, 1H), 5.50-5.60 (m, 1H), 4.54-4.71 (m, 1H), 4.33-4.49 (m, 1.5H), 4.02-4.22 (m, 2H), 3.87 (d, J=13.8 Hz, 0.5H), 3.33-3.50 (m, 4H), 3.03-3.23 (m, 2.5H), 2.21 (d, J=7.6 Hz, 0.5H), 1.96-2.16 (m, 2H), 1.11-1.24 (m, 2H), 0.94-1.11 (m, 5H), 0.84-0.92 (m, 3H).
LC-MS: m/z 446.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.66 (d, J=5.0 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.40 (s, 1H), 7.25 (dd, J=5.1, 1.6 Hz, 1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.23-6.35 (m, 1H), 5.55-5.63 (m, 1H), 4.58-4.74 (m, 1.5H), 4.38-4.50 (m, 1.5H), 3.87-4.00 (m, 2H), 3.78 (d, J=13.8 Hz, 1H), 3.39-3.55 (m, 1H), 3.05-3.24 (m, 2H), 2.56-2.66 (m, 2H), 2.20-2.30 (m, 1H), 1.98-2.06 (m, 2H), 1.25-1.33 (m, 6H), 0.84-0.95 (m, 4H)
LC-MS: m/z 446.1 (M+H)+
To a solution of 4,6-dichloropyrimidin-2-amine (270 mg, 0.58 mmol) in a mixture of dimethoxyethane (5 mL) and a 2M aqueous sodium carbonate solution (0.8 mL) were added (R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (100 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.1 eq) under nitrogen atmosphere, and the mixture was heated for 2 hours at 100° C. After cooling to ambient temperature, the separated organic layer was evaporated under reduced pressure. The residue was taken up into ethyl acetate, washed in turn with a 10% aqueous potassium carbonate solution and brine, and dried over sodium sulfate. After evaporation, the residue was chromatographed on silica gel eluding with 5%-20% ethyl acetate in petroleum ether to give (R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl) piperazin-1-yl)nicotinonitrile (140 mg crude).
LC-MS: m/z 468.2 (M+H)+
A mixture of above (R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (60 mg, 0.13 mmol), potassium vinylfluoborate (25 mg, 0.2 mmol), Pd(PPh3)4 (3 mg, 0.1 eq), and CsF (40 mg, 0.26 mmol) were suspended in 5 mL of dioxane and 1 mL of water, the resulting mixture was refluxed for 1 h. After the reaction was complete, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to afford 40 mg of title compound as yellow solid. (70% yield)
LC-MS: m/z 460.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 7.92 (s, 1H), 6.87 (s, 1H), 6.65 (dd, J=17.3, 10.6 Hz, 1H), 6.39 (d, J=17.5 Hz, 1H), 5.69 (d, J=10.7 Hz, 1H), 5.44 (br. s., 2H), 4.61 (d, J=13.2 Hz, 1H), 4.48 (d, J=12.1 Hz, 1H), 4.07 (d, J=7.5 Hz, 1H), 3.87-3.98 (m, 2H), 3.63-3.84 (m, 2H), 3.17-3.31 (m, 2H), 3.00-3.17 (m, 1H), 2.50-2.66 (m, 2H), 2.30-2.45 (m, 1H), 1.17-1.28 (m, 3H), 0.97-1.13 (m, 2H), 0.61 (br. s., 1H), 0.54 (br. s., 1H), 0.46 (br. s., 2H).
LC-MS: m/z 460.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.19-9.32 (m, 1H), 8.01 (s, 1H), 7.46-7.59 (m, 1H), 6.82 (dd, J=17.3, 10.8 Hz, 1H), 6.51-6.63 (m, 1H), 5.80 (d, J=11.3 Hz, 1H), 5.32 (s, 1H), 4.66 (d, J=13.1 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 4.08 (d, J=9.8 Hz, 1H), 3.88-3.97 (m, 2H), 3.67-3.82 (m, 2H), 3.32 (br. s., 1H), 3.20-3.29 (m, 2H), 3.02-3.20 (m, 2H), 2.49-2.66 (m, 2H), 2.34-2.45 (m, 1H), 1.22-1.29 (m, 3H), 1.02-1.10 (m, 2H), 0.63 (d, J=7.8 Hz, 1H), 0.55 (br. s., 1H), 0.47 (br. s., 2H).
LC-MS: m/z 445.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.97-8.12 (m, 1H), 7.51 (br. s., 1H), 6.21 (br. s., 2H), 4.71 (d, J=12.8 Hz, 1H), 4.57 (d, J=11.0 Hz, 1H), 4.06 (s, 1H), 3.52 (br. s., 3H), 3.31 (br. s., 3H), 3.22 (br. s., 2H), 2.38 (br. s., 1H), 1.71 (br. s., 1H), 1.19-1.28 (m, 3H), 0.96-1.14 (m, 4H), 0.75-0.87 (m, 2H), 0.62 (br. s., 1H), 0.51 (br. s., 2H), 0.38-0.48 (m, 1H).
LC-MS: m/z 473.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 7.95 (s, 1H), 6.88 (s, 1H), 6.66 (dd, J=17.5, 10.7 Hz, 1H), 6.47 (d, J=17.6 Hz, 1H), 5.71 (d, J=11.2 Hz, 1H), 5.27 (br. s., 2H), 4.64 (d, J=13.2 Hz, 2H), 4.50 (d, J=12.6 Hz, 2H), 4.16 (br. s., 3H), 4.01 (br. s., 1H), 3.90 (br. s., 1H), 3.65 (d, J=17.0 Hz, 1H), 3.46 (s, 3H), 3.18-3.32 (m, 2H), 3.02-3.18 (m, 1H), 2.32-2.47 (m, 1H), 1.18-1.32 (m, 3H), 1.00-1.11 (m, 2H), 0.63 (br. s., 2H), 0.46 (br. s., 2H)
LC-MS: m/z 460.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 7.51 (br. s., 1H), 6.66 (dd, J=16.7, 10.6 Hz, 1H), 6.35 (d, J=16.7 Hz, 1H), 5.88 (br. s., 1H), 5.66-5.83 (m, 1H), 4.44 (d, J=12.6 Hz, 1H), 4.25-4.38 (m, 2H), 4.19 (br. s., 1H), 3.98-4.10 (m, 1H), 3.91 (br. s., 2H), 3.84 (br. s., 1H), 3.60-3.79 (m, 3H), 3.08-3.25 (m, 2H), 2.89-3.08 (m, 1H), 2.47-2.65 (m, 2H), 2.40 (br. s., 2H), 2.01-2.08 (m, 1H), 1.27 (br. s., 1H), 1.14 (br. s., 2H), 0.98-1.10 (m, 2H), 0.62 (br. s., 1H), 0.53 (br. s., 1H), 0.34-0.50 (m, 2H).
LC-MS: m/z 476.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 7.44-7.56 (m, 1H), 6.49-6.74 (m, 1H), 6.35 (d, J=16.7 Hz, 1H), 5.88 (br. s., 1H), 5.67-5.82 (m, 1H), 4.46 (d, J=12.9 Hz, 1H), 4.25-4.39 (m, 2H), 4.07-4.23 (m, 3H), 3.98 (d, J=8.5 Hz, 1H), 3.84 (t, J=5.1 Hz, 1H), 3.73 (t, J=5.4 Hz, 1H), 3.45 (s, 3H), 3.10-3.21 (m, 1H), 3.02 (t, J=11.9 Hz, 1H), 2.39 (br. s., 2H), 2.00-2.16 (m, 1H), 1.69 (br. s., 1H), 1.30-1.37 (m, 1H), 1.14 (br. s., 2H), 0.97-1.09 (m, 2H), 0.64 (br. s., 1H), 0.51 (br. s., 1H), 0.45 (br. s., 1H).
LC-MS: m/z 476.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 6.65 (d, J=10.0 Hz, 1H), 6.36 (d, J=16.8 Hz, 1H), 5.65-5.84 (m, 2H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.25-4.38 (m, 0.5H), 4.01-4.25 (m, 4H), 3.87-4.01 (m, 1H), 3.67-3.86 (m, 4H), 3.39 (s, 3H), 3.09-3.22 (m, 1H), 2.95-3.09 (m, 1H), 2.54-2.71 (m, 2H), 2.36-2.48 (m, 5H), 2.03 (br. s., 1H), 1.20-1.35 (m, 4H), 0.84-1.08 (m, 4H).
LC-MS: m/z 478.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 6.67 (dd, J=16.3, 10.4 Hz, 1H), 6.36 (d, J=16.1 Hz, 1H), 5.65-5.85 (m, 2H), 4.13-4.34 (m, 3H), 4.03-4.11 (m, 1H), 3.95 (d, J=18.8 Hz, 1H), 3.78-3.89 (m, 1H), 3.62-3.78 (m, 4H), 3.38 (s, 3H), 3.27 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 1H), 2.36-2.47 (m, 5H), 1.96-2.08 (m, 1H), 1.23-1.39 (m, 3H), 0.81-1.07 (m, 4H), 0.60 (br. s., 1H), 0.52 (br. s., 1H), 0.43 (br. s., 2H).
LC-MS: m/z 504.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 6.67 (dd, J=16.7, 10.9 Hz, 1H), 6.36 (d, J=16.7 Hz, 1H), 5.64-5.85 (m, 1H), 4.10-4.38 (m, 3H), 4.04 (br. s., 1H), 3.98 (br. s., 1H), 3.91 (br. s., 2H), 3.61-3.83 (m, 3H), 3.04-3.34 (m, 2H), 2.59 (br. s., 1H), 2.52 (d, J=10.3 Hz, 1H), 2.37-2.48 (m, 5H), 2.06 (br. s., 1H), 1.34-1.50 (m, 1H), 1.16 (br. s., 1H), 0.93-1.10 (m, 3H), 0.62 (br. s., 1H), 0.27-0.56 (m, 3H)
LC-MS: m/z 490.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 6.36 (d, J=16.7 Hz, 1H), 5.68-5.98 (m, 2H), 4.33 (d, J=11.7 Hz, 1H), 4.22 (d, J=13.2 Hz, 2H), 4.04 (br. s., 1H), 3.92 (t, J=5.0 Hz, 3H), 3.64-3.78 (m, 2H), 3.47 (d, J=7.9 Hz, 1H), 2.96-3.09 (m, 2H), 2.52-2.65 (m, 2H), 2.38-2.48 (m, 5H), 2.04 (br. s., 2H), 0.95-1.07 (m, 6H), 0.83-0.95 (m, 4H)
LC-MS: m/z 492.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.60 (m, 1H), 7.64 (s, 1H), 7.37 (s, 1H), 7.19-7.27 (m, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=11.0 Hz, 1H), 5.17-5.42 (m, 1H), 4.89 (m, 0.5H), 4.73 (q, J=7.0 Hz, 1H), 4.46-4.62 (m, 1.5H), 4.34 (m, 2H), 4.28 (d, J=13.3 Hz, 0.5H), 3.85 (t, J=13.3 Hz, 0.5H), 3.50-3.67 (m, 0.5H), 3.21-3.32 (m, 1H), 2.99-3.20 (m, 1.5H), 2.76-2.94 (m, 3H), 2.46-2.60 (m, 1H), 1.87-2.09 (m, 1H), 1.24-1.32 (m, 3H), 1.14-1.23 (m, 2H), 0.93-1.10 (m, 3H).
LC-MS: m/z 444.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.65 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.38 (s, 1H), 7.13-7.27 (m, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.13-6.40 (m, 1H), 5.56 (d, J=11.5 Hz, 1H), 5.18-5.34 (m, 1H), 4.81-5.03 (m, 0.5H), 4.65-4.79 (m, 1H), 4.48-4.65 (m, 1.5H), 4.30-4.42 (m, 2H), 4.26 (d, J=12.8 Hz, 0.5H), 3.86 (d, J=13.3 Hz, 0.5H), 3.49-3.66 (m, 0.5H), 3.23-3.40 (m, 1H), 3.01-3.20 (m, 1.5H), 2.71-3.01 (m, 3H), 2.37-2.64 (m, 1H), 1.90-2.10 (m, 1H), 1.24-1.34 (m, 3H), 1.13-1.24 (m, 2H), 0.93-1.09 (m, 2H)
LC-MS: m/z 444.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.70 (d, J=4.8 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J=4.8 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.30 (d, J=17.3 Hz, 1H), 5.58 (d, J=11.3 Hz, 1H), 4.90 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.07-4.26 (m, 2.5H), 3.93 (br. s., 2H), 3.66-3.79 (m, 0.5H), 3.58 (t, J=11.0 Hz, 0.5H), 3.46 (br. s., 1H), 3.13-3.29 (m, 1.5H), 2.95-3.13 (m, 1H), 2.47-2.75 (m, 2H), 2.22 (s, 3H), 1.74 (br. s., 1H), 1.50-1.63 (m, 1H), 1.37-1.46 (m, 1.5H), 1.33 (d, J=6.8 Hz, 1.5H), 1.01-1.14 (m, 2H), 0.79-0.95 (m, 2H).
LC-MS: m/z 431.5 (M+H)+
1H NMR (CHLOROFORM-d) δ: 7.94-8.05 (m, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.60 (d, J=3.5 Hz, 1H), 7.43-7.48 (m, 1H), 7.14 (dd, J=17.6, 10.8 Hz, 1H), 6.55 (dd, J=17.6, 1.8 Hz, 1H), 5.81 (d, J=11.0 Hz, 1H), 4.60 (d, J=13.1 Hz, 1.5H), 4.48 (d, J=13.1 Hz, 1H), 4.13 (d, J=6.0 Hz, 0.5H), 3.86-3.99 (m, 2H), 3.82 (br. s., 1.5H), 3.28 (br. s., 1.5H), 3.15 (dd, J=15.7, 8.2 Hz, 2H), 2.56-2.68 (m, 2H), 1.13-1.23 (m, 2H), 0.80-0.97 (m, 3H), 0.68 (br. s., 1H), 0.59 (br. s., 1H), 0.51 (br. s., 2H).
LC-MS: m/z 495.1 (M+H)+
1H NMR (CHLOROFORM-d) δ9.20 (d, J=11.0 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.96-8.04 (m, 1H), 7.68 (dd, J=4.4, 2.9 Hz, 1H), 7.49-7.59 (m, 1H), 7.06-7.23 (m, 1H), 6.86 (d, J=17.1 Hz, 1H), 5.94 (d, J=10.5 Hz, 1H), 4.62-4.80 (m, 1.5H), 4.43-4.54 (m, 1.5H), 3.87-4.03 (m, 2H), 3.73-3.86 (m, 1H), 2.91-3.31 (m, 3H), 2.54-2.67 (m, 2H), 2.09-2.25 (m, 1H), 1.54 (td, J=8.0, 4.1 Hz, 1H), 1.11 (dd, J=13.7, 6.4 Hz, 4H), 0.79-0.94 (m, 6H).
LC-MS: m/z 497.3 (M+H)+
1H NMR (CHLOROFORM-d) δ9.17 (d, J=3.3 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.97 (dd, J=8.4, 7.2 Hz, 1H), 7.68 (s, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.08 (dd, J=17.3, 10.5 Hz, 1H), 6.74-6.90 (m, 1H), 5.89 (dd, J=10.5, 1.5 Hz, 1H), 4.93 (br. s., 0.5H), 4.57 (d, J=12.5 Hz, 0.5H), 4.28-4.47 (m, 2H), 4.21 (br. s., 0.5H), 3.94 (s, 2H), 3.71-3.84 (m, 0.5H), 3.50-3.68 (m, 0.5H), 3.29-3.44 (m, 1H), 3.06-3.26 (m, 2H), 2.49-2.78 (m, 2H), 1.50-1.62 (m, 1H), 1.45 (t, J=7.2 Hz, 1H), 1.35 (t, J=6.4 Hz, 2H), 1.14-1.22 (m, 2H), 0.83-0.98 (m, 2H)
LC-MS: m/z 469.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.08 (d, J=8.3 Hz, 1H), 7.97 (td, J=7.8, 1.3 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.47-7.56 (m, 1H), 7.09 (dd, J=17.1, 10.5 Hz, 1H), 6.82 (d, J=17.1 Hz, 1H), 5.90 (dd, J=10.7, 1.6 Hz, 1H), 4.61 (dd, J=13.1, 7.3 Hz, 1H), 4.41-4.55 (m, 1H), 4.12 (d, J=6.5 Hz, 1H), 3.94 (s, 2H), 3.67-3.82 (m, 1H), 3.10-3.40 (m, 3H), 2.49-2.68 (m, 2H), 1.56 (td, J=8.1, 4.1 Hz, 1H), 1.32-1.41 (m, 1H), 1.14-1.24 (m, 2H), 0.84-0.95 (m, 2H), 0.51-0.69 (m, 4H)
LC-MS: m/z 495.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.00 (s, 1H), 8.08-8.18 (m, 1H), 7.79-7.90 (m, 1H), 7.65-7.76 (m, 2H), 7.07 (dd, J=17.8, 11.0 Hz, 1H), 6.51 (d, J=17.6 Hz, 1H), 5.84 (d, J=11.0 Hz, 1H), 4.51 (d, J=13.1 Hz, 1H), 4.40 (d, J=12.8 Hz, 1H), 4.13 (q, J=7.0 Hz, 1.5H), 3.86-3.99 (m, 2.5H), 3.76 (d, J=19.8 Hz, 2H), 3.37 (d, J=7.8 Hz, 1H), 3.22-3.33 (m, 1H), 3.17 (d, J=12.3 Hz, 1H), 3.09 (br. s., 1H), 2.55-2.69 (m, 2H), 1.58-1.69 (m, 1H), 1.17-1.37 (m, 3H), 1.08 (br. s., 2H), 0.83 (br. s., 2H), 0.66 (br. s., 1H), 0.55 (br. s., 1H), 0.48 (d, J=5.8 Hz, 3H).
LC-MS: m/z 495.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 10.15 (br. s., 1H), 7.69-7.87 (m, 1H), 7.36-7.45 (m, 1H), 7.23 (s, 1H), 6.97 (dd, J=17.3, 11.2 Hz, 1H), 6.43 (d, J=3.2 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H), 4.58 (d, J=12.9 Hz, 1H), 4.45 (d, J=12.6 Hz, 1H), 4.12 (d, J=8.5 Hz, 1H), 3.94 (br. s., 2H), 3.63-3.87 (m, 2H), 3.13-3.27 (m, 2H), 2.54-2.69 (m, 2H), 1.95-2.02 (m, 1H), 1.54-1.74 (m, 1H), 1.22 (br. s., 2H), 0.97 (dd, J=7.6, 3.5 Hz, 2H), 0.67 (br. s., 1H), 0.57 (br. s., 1H), 0.50 (br. s., 2H)
LC-MS: m/z 483.6 (M+H)+
1H NMR (CHLOROFORM-d) δ9.53 (s, 1H), 8.54 (d, J=3.2 Hz, 1H), 7.88-8.00 (m, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.09 (dd, J=17.8, 11.0 Hz, 1H), 6.41 (d, J=17.6 Hz, 1H), 5.81 (d, J=11.2 Hz, 1H), 4.59 (d, J=13.2 Hz, 1H), 4.47 (d, J=12.6 Hz, 1H), 4.1-4.2 (m, 0.5H), 3.93 (br. s., 2H), 3.82 (m, 1.5H), 3.44 (m, 1H), 3.05-3.35 (m, 3H), 2.54-2.70 (m, 2H), 1.47-1.64 (m, 2H), 1.13-1.23 (m, 2H), 0.90-0.96 (m, 2H), 0.68 (br. s., 1H), 0.58 (br. s., 1H), 0.51 (br. s., 2H)
LC-MS: m/z 495.2 (M+H)+
1H NMR (CHLOROFORM-d) δ7.90 (s, 1H), 7.77 (s, 1H), 7.21 (s, 1H), 6.99 (dd, J=17.5, 10.7 Hz, 1H), 6.41 (d, J=17.3 Hz, 1H), 5.58-5.73 (m, 1H), 4.60 (d, J=13.2 Hz, 1H), 4.48 (d, J=12.6 Hz, 1H), 4.20 (s, 3H), 4.11 (d, J=8.8 Hz, 1H), 3.93 (br. s., 2H), 3.65-3.85 (m, 1H), 3.44 (br. s., 1H), 3.18-3.36 (m, 2H), 3.13 (d, J=10.0 Hz, 1H), 2.46-2.70 (m, 2H), 1.88-2.01 (m, 1H), 1.31-1.42 (m, 1H), 1.24 (dt, J=7.0, 3.5 Hz, 2H), 0.93-1.04 (m, 2H), 0.66 (br. s., 1H), 0.57 (br. s., 1H), 0.32-0.53 (m, 2H)
LC-MS: m/z 498.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.09 (d, J=8.3 Hz, 1H), 7.86-7.97 (m, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.58 (td, J=7.7, 1.0 Hz, 1H), 7.09 (dd, J=17.2, 10.4 Hz, 1H), 6.82 (dd, J=17.3, 1.8 Hz, 1H), 5.76-5.93 (m, 1H), 4.65 (d, J=13.1 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 4.11 (d, J=9.3 Hz, 0.5H), 3.93 (br. s., 2H), 3.7-3.85 (m, 1.5H), 3.48 (br. s., 1H), 3.26 (d, J=13.1 Hz, 2H), 3.17 (m, 1H), 2.52-2.68 (m, 2H), 1.88 (br. s., 1H), 1.66-1.80 (m, 1H), 0.81-0.99 (m, 4H), 0.62-0.79 (m, 1H), 0.57 (br. s., 1H), 0.50 (d, J=5.8 Hz, 2H)
LC-MS: m/z 495.2 (M+H)+
1H NMR (CHLOROFORM-d) δ8.08 (d, J=8.5 Hz, 1H), 7.87-7.97 (m, 2H), 7.83 (d, J=8.3 Hz, 1H), 7.54-7.66 (m, 1H), 7.08 (dd, J=17.2, 10.4 Hz, 1H), 6.74-6.90 (m, 1H), 5.78-5.94 (m, 1H), 4.66 (d, J=11.3 Hz, 1H), 4.46-4.62 (m, 1H), 4.15-4.35 (m, 1H), 3.53-3.77 (m, 1H), 3.48 (d, J=4.5 Hz, 1H), 3.30 (m, 1H), 3.19 (m, 1H), 1.60-1.83 (m, 2H), 1.43 (br. s., 1H), 1.16-1.29 (m, 2H), 1.04 (d, J=18.8 Hz, 2H), 0.77-0.97 (m, 4H), 0.59-0.77 (m, 1H), 0.37-0.59 (m, 3H)
LC-MS: m/z 491.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.15-8.23 (m, 1H), 8.08-8.15 (m, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.72-7.79 (m, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.1, 1.6 Hz, 1H), 7.07 (dd, J=17.6, 10.9 Hz, 1H), 6.34 (d, J=17.7 Hz, 1H), 5.73 (d, J=11.0 Hz, 1H), 4.69 (d, J=9.4 Hz, 0.5H), 4.54 (d, J=13.2 Hz, 1H), 4.42 (d, J=12.6 Hz, 1H), 4.10 (d, J=8.3 Hz, 0.5H), 3.93 (br. s., 2H), 3.69-3.86 (m, 1H), 3.16-3.36 (m, 2H), 2.99-3.16 (m, 1H), 2.48-2.69 (m, 2H), 2.11-2.20 (m, 1H), 1.16-1.31 (m, 3H), 0.93-1.05 (m, 2H), 0.66 (br. s., 1H), 0.56 (br. s., 1H), 0.39-0.52 (m, 2H)
LC-MS: m/z 494.9 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.17 (d, J=8.5 Hz, 1H), 8.11 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.3, 1.5 Hz, 1H), 7.06 (dd, J=17.7, 10.9 Hz, 1H), 6.33 (d, J=17.8 Hz, 1H), 5.71 (d, J=10.8 Hz, 1H), 4.56 (d, J=12.8 Hz, 1H), 4.43 (d, J=12.3 Hz, 1H), 4.09 (m, 1H), 3.72 (m, 1H), 3.29 (br. s., 2H), 3.12 (br. s., 1H), 2.10-2.20 (m, 1H), 1.73 (br. s., 1H), 1.44 (br. s., 1H), 1.18-1.25 (m, 2H), 1.06 (t, J=4.4 Hz, 1H), 0.94-1.04 (m, 3H), 0.81 (dd, J=7.8, 2.3 Hz, 2H), 0.67 (br. s., 1H), 0.41-0.58 (m, 3H).
LC-MS: m/z 490.9 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.58 (br. s., 1H), 8.57 (br. s., 1H), 7.67 (d, J=7.3 Hz, 1H), 7.21-7.34 (m, 2H), 7.10 (dd, J=17.6, 10.9 Hz, 1H), 6.42 (dd, J=17.6, 2.6 Hz, 1H), 5.82 (d, J=10.9 Hz, 1H), 4.38-4.49 (m, 1H), 4.34 (d, J=12.6 Hz, 1H), 4.14 (d, J=7.0 Hz, 1H), 3.89 (br. s., 1H), 3.69-3.82 (m, 2H), 3.40 (s, 3H), 3.23 (d, J=13.8 Hz, 2H), 3.02-3.17 (m, 1H), 2.72 (br. s., 1H), 2.67 (br. s., 1H), 2.11 (d, J=1.8 Hz, 3H), 1.45 (br. s., 1H), 1.06-1.18 (m, 2H), 0.79-0.90 (m, 1H), 0.69-0.79 (m, 2H), 0.64 (br. s., 1H), 0.57 (br. s., 1H), 0.41-0.55 (m, 2H).
LC-MS: m/z 522.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.58 (s, 1H), 8.60 (br. s., 1H), 7.79 (d, J=10.9 Hz, 1H), 7.63-7.71 (m, 1H), 7.50-7.63 (m, 1H), 7.12 (dd, J=17.6, 10.9 Hz, 1H), 6.47 (d, J=17.6 Hz, 1H), 5.83-5.94 (m, 1H), 4.63-4.80 (m, 1.5H), 4.37-4.58 (m, 2H), 4.04-4.26 (m, 2H), 3.93 (d, J=13.5 Hz, 1H), 3.10-3.33 (m, 2H), 2.09-2.30 (m, 0.5H), 1.92-2.08 (m, 1H), 1.11 (dd, J=16.3, 6.6 Hz, 4H), 0.85-0.98 (m, 6H).
LC-MS: m/z 496.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.56 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 7.72 (d, J=3.2 Hz, 1H), 7.68 (s, 1H), 7.45 (dd, J=9.5, 5.7 Hz, 1H), 7.10 (dd, J=17.8, 11.0 Hz, 1H), 6.42 (dd, J=17.6, 2.1 Hz, 1H), 5.72-5.90 (m, 1H), 4.63 (d, J=13.2 Hz, 1H), 4.45-4.55 (m, 1H), 4.18 (br. s., 2H), 4.06 (br. s., 1H), 3.96 (br. s., 1H), 3.60-3.85 (m, 1H), 3.44-3.49 (m, 3H), 3.23-3.34 (m, 1H), 3.16 (br. s., 1H), 1.97 (br. s., 1H), 1.48-1.56 (m, 1H), 1.22 (dd, J=7.9, 3.8 Hz, 2H), 0.86-0.94 (m, 2H), 0.70 (br. s., 1H), 0.57 (br. s., 1.5H), 0.51 (br. s., 1.5H).
LC-MS: m/z 494.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.58 (br. s., 1H), 8.61 (br. s., 1H), 7.77 (d, J=3.0 Hz, 1H), 7.64-7.73 (m, 1H), 7.54 (br. s., 1H), 7.12 (dd, J=17.6, 10.8 Hz, 1H), 6.45 (dd, J=17.7, 2.1 Hz, 1H), 5.85 (d, J=11.0 Hz, 1H), 4.64 (d, J=10.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.25 (br. s., 1H), 3.69-3.81 (br. s., 1H), 3.38 (d, J=15.3 Hz, 1.5H), 3.21 (br. s., 1.5H), 1.75 (br. s., 1H), 1.50 (br. s., 1H), 1.26-1.37 (m, 1H), 1.23 (br. s., 2H), 0.99-1.14 (m, 2H), 0.87-0.96 (m, 2H), 0.84 (dd, J=7.8, 2.3 Hz, 2H), 0.71 (br. s., 1H), 0.52-0.62 (m, 2H), 0.43-0.52 (m, 1H).
LC-MS: m/z 490.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.59 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.54-7.63 (m, 1H), 7.12 (dd, J=17.6, 10.8 Hz, 1H), 6.48 (dd, J=17.7, 2.1 Hz, 1H), 5.88 (d, J=11.0 Hz, 1H), 4.63 (d, J=12.5 Hz, 1H), 4.52 (d, J=7.5 Hz, 1H), 4.13 (d, J=9.3 Hz, 1H), 3.87-3.99 (m, 2H), 3.67-3.87 (m, 1H), 3.30 (br. s., 2H), 3.18 (br. s., 1H), 2.57-2.68 (m, 2H), 1.43-1.54 (m, 1H), 1.32-1.41 (m, 1H), 1.19-1.26 (m, 2H), 0.87-0.97 (m, 2H), 0.67 (br. s., 1H), 0.60 (br. s., 1H), 0.40-0.55 (m, 2H).
LC-MS: m/z 494.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.57 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 7.76 (d, J=3.5 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.49-7.60 (m, 1H), 7.11 (dd, J=17.6, 11.0 Hz, 1H), 6.45 (dd, J=17.6, 1.8 Hz, 1H), 5.85 (d, J=11.3 Hz, 1H), 4.55-4.68 (m, 1H), 4.50 (dd, J=12.8, 2.3 Hz, 1H), 4.15 (br. s., 0.5H), 3.92 (br. s., 0.5H), 3.66-3.84 (m, 3H), 3.40 (s, 3H), 3.30 (br. s., 1H), 3.22 (br. s., 1H), 3.15 (d, J=7.5 Hz, 1H), 2.66 (br. s., 1H), 2.56 (br. s., 1H), 1.46-1.54 (m, 1H), 1.32 (d, J=16.1 Hz, 1H), 1.19-1.24 (m, 2H), 0.84-0.99 (m, 2H), 0.66 (br. s., 1H), 0.60 (br. s., 1H), 0.49 (br. s., 2H).
LC-MS: m/z 508.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.55 (s, 1H), 8.59 (dd, J=5.3, 3.0 Hz, 1H), 7.73 (d, J=11.5 Hz, 1H), 7.67 (dd, J=4.5, 2.8 Hz, 1H), 7.45 (dd, J=12.5, 5.5 Hz, 1H), 7.10 (ddd, J=17.6, 10.9, 1.1 Hz, 1H), 6.42 (d, J=17.6 Hz, 1H), 5.82 (d, J=10.8 Hz, 1H), 4.61-4.79 (m, 1H), 4.41-4.60 (m, 2H), 3.86-4.01 (m, 2H), 3.82 (d, J=13.6 Hz, 0.5H), 3.53-3.60 (m, 0.5H), 3.10-3.30 (m, 2H), 3.01 (d, J=12.8 Hz, 0.5H), 2.73-2.84 (m, 0.5H), 2.56-2.68 (m, 2H), 2.09-2.37 (m, 1H), 1.47-1.55 (m, 1H), 1.05-1.17 (m, 4H), 0.80-1.01 (m, 6H).
LC-MS: m/z 496.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.61 (d, J=5.8 Hz, 1H), 8.30 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.65-7.72 (m, 1H), 7.58-7.65 (m, 1H), 6.64 (d, J=16.1 Hz, 1H), 5.84 (d, J=10.3 Hz, 1H), 4.58 (d, J=11.5 Hz, 1H), 4.46 (d, J=11.8 Hz, 1H), 4.01-4.31 (m, 1H), 3.61-3.89 (m, 1H), 3.33 (d, J=17.3 Hz, 1.5H), 3.15 (br. s., 1.5H), 2.02-2.09 (m, 1H), 1.42-1.47 (m, 1H), 1.34 (d, J=8.5 Hz, 1H), 1.25-1.30 (m, 3H), 1.06-1.11 (m, 1H), 0.98-1.02 (m, 2H), 0.90 (t, J=6.7 Hz, 1H), 0.80-0.84 (m, 2H), 0.68 (br. s., 1H), 0.52-0.56 (m, 1H), 0.46-0.49 (m, 1H)
LC-MS: m/z 492.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.33 (d, J=5.0 Hz, 1H), 7.49 (s, 1H), 7.12 (s, 1H), 6.98-7.06 (m, 1H), 4.47 (d, J=12.5 Hz, 1H), 4.30-4.50 (m, 2.5H), 4.20-4.30 (m, 1H), 4.04 (s, 1H), 3.60-3.90 (s, 1H), 2.90-3.45 (m, 1H), 2.01 (s, 1H), 1.80-1.91 (m, 1H), 1.72 (s, 1H), 1.09-1.17 (m, 2H), 0.93-1.09 (m, 4H), 0.74-0.86 (m, 2H), 0.37-0.65 (m, 4H)
LC-MS: m/z 462.2 (M+H)+
1H NMR (CHLOROFORM-d) □: 8.50 (d, J=5.0 Hz, 1H), 7.47 (s, 1H), 7.12 (s, 1H), 6.89-6.99 (m, 1H), 6.80 (dd, J=17.6, 10.8 Hz, 1H), 6.16-6.29 (m, 1H), 5.44-5.57 (m, 1H), 4.25-4.60 (m, 2.5H), 4.12-4.20 (m, 1H), 4.03 (s, 2H), 3.49-3.90 (m, 1H), 2.95-3.29 (m, 2.5H), 1.85-1.98 (m, 1H), 1.71 (s, 1H), 1.35-1.45 (m, 1H), 1.07-1.17 (m, 2H), 0.92-1.07 (m, 4H), 0.76-0.82 (m, 2H), 0.30-0.63 (m, 4H)
LC-MS: m/z 454.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.34 (d, J=5.3 Hz, 1H), 7.49 (s, 1H), 7.11 (s, 1H), 7.03 (d, J=5.0 Hz, 1H), 4.39-4.52 (m, 2H), 4.33 (d, J=12.3 Hz, 1H), 4.04 (s, 2H), 3.85-3.97 (m, 2H), 3.66-3.81 (m, 1H), 3.01-3.22 (m, 3H), 2.51-2.65 (m, 2H), 1.79-1.92 (m, 1H), 1.31-1.39 (m, 1H), 1.08-1.15 (m, 2H), 0.93-1.03 (m, 2H), 0.46-0.63 (m, 4H)
LC-MS: m/z 466.2 (M+H)+
A mixture of (R)-5-((2-chloropyridin-4-yl)methyl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (80 mg, 0.172 mmol), potassium vinyltrifluoroborate (46 mg, 0.343 mmol), Pd(dppf)Cl2 (7 mg, 0.009 mmol) and CsF (79 mg, 0.515 mmol) in dioxane/H2O was stirred at 100° C. for 16 hours. The mixture was diluted with EtOAc (30 mL) and filtered. The filtrated was partitioned between EtOAc (30 mL) and water (10 mL), the organic layer was washed with water (10 mL), brine and dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 25 mg of the product.
1H NMR (CHLOROFORM-d) □□: 8.47 (d, J=5.0 Hz, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 6.87-6.97 (m, 1H), 6.76 (dd, J=17.3, 10.8 Hz, 1H), 6.18 (dd, J=17.6, 1.0 Hz, 1H), 5.41-5.53 (m, 1H), 4.39 (d, J=12.8 Hz, 1H), 4.27 (d, J=12.5 Hz, 1H), 4.01 (m, 2H), 3.80-3.92 (m, 2H), 3.51-3.79 (m, 2H), 2.99-3.18 (m, 3H), 2.42-2.66 (m, 2H), 1.85-1.97 (m, 1H), 1.30-1.40 (m, 1H), 1.03-1.12 (m, 2H), 0.88-1.00 (m, 2H), 0.30-0.59 (m, 4H)
LC-MS: m/z 458.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 9.48 (s, 1H), 8.59 (d, J=5.8 Hz, 1H), 7.90 (br. s., 1H), 7.68-7.77 (m, 1H), 7.35-7.48 (m, 1H), 6.91 (dd, J=17.4, 10.9 Hz, 1H), 6.56 (s, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.67 (d, J=11.0 Hz, 1H), 4.86-4.98 (m, 0.5H), 4.51-4.62 (d, 0.5H) 4.14-4.38 (m, 3H), 3.94 (br. s., 2H), 3.70-3.81 (m, 0.5H), 3.59 (t, J=10.8 Hz, 0.5H), 3.27-3.41 (m, 1H), 3.01-3.24 (m, 2H), 2.48-2.78 (m, 2H), 1.97-2.09 (m, 1H), 1.44 (d, J=6.5 Hz, 1.5H), 1.34 (d, J=6.8 Hz, 1.5H), 1.10-1.20 (m, 2H), 0.94-1.06 (m, 2H).
LC-MS: m/z 483.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 6.57-6.47 (m, 2H), 6.08 (s, 1H), 4.75-4.64 (m, 0.5H), 4.49 (t, J=11.8 Hz, 1H), 4.37 (t, J=10.9 Hz, 1H), 4.14-4.09 (m, 0.5H), 3.89 (ddd, J=7.5, 3.5, 2.5 Hz, 0.5H), 3.81-3.64 (m, 2.5H), 3.39 (s, 3H), 3.31-3.17 (m, 1.5H), 3.10 (td, J=12.8, 3.4 Hz, 1H), 2.69 (ddd, J=22.8, 14.8, 9.9 Hz, 2H), 2.52 (dd, J=20.7, 9.1 Hz, 0.5H), 2.06 (ddd, J=7.5, 4.5, 1.6 Hz, 1H), 1.28 (m, J=4.7 Hz, 1H), 1.15 (m, 2H), 1.08-0.99 (m, 2H), 0.72-0.52 (m, 2H), 0.52-0.39 (m, 2H).
LC-MS: m/z NB250-076-2 481.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.26 (d, J=5.7 Hz, 1H), 7.62 (s, 1H), 6.72 (dd, J=17.4, 10.8 Hz, 1H), 6.58 (s, 1H), 6.46 (d, J=4.1 Hz, 1H), 6.20 (d, J=17.4 Hz, 1H), 5.94 (s, 1H), 5.49 (d, J=10.8 Hz, 1H), 4.70 (dd, J=14.5, 4.5 Hz, 0.5H), 4.46 (t, J=11.4 Hz, 1H), 4.33 (d, J=10.6 Hz, 1H), 4.13-4.07 (m, 0.5H), 3.92-3.85 (m, 0.5H), 3.83-3.62 (m, 2.5H), 3.39 (s, 3H), 3.31-3.16 (m, 1.5H), 3.09 (td, J=13.2, 3.7 Hz, 1H), 2.82-2.58 (m, 2H), 2.58-2.45 (m, 0.5H), 2.10 (dt, J=4.5, 3.0 Hz, 1H), 1.28 (s, 1H), 1.18-1.10 (m, 2H), 1.02 (ddd, J=9.9, 6.4, 3.2 Hz, 2H), 0.73-0.53 (m, 2H), 0.53-0.39 (m, 2H).
LC-MS: m/z 473.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.8 Hz, 1H), 7.60 (s, 1H), 6.54 (s, 1H), 6.51 (dd, J=5.8, 2.0 Hz, 1H), 6.15 (s, 1H), 4.90 (s, 0.5H), 4.54 (d, J=13.4 Hz, 0.5H), 4.35-4.16 (m, 2.5H), 3.93 (s, 2H), 3.74 (d, J=13.4 Hz, 0.5H), 3.58 (d, J=11.0 Hz, 0.5H), 3.30 (dd, J=10.8, 6.4 Hz, 1H), 3.15 (t, J=12.2 Hz, 1H), 3.08-3.01 (m, 0.5H), 2.74-2.51 (m, 2H), 2.07 (ddd, J=12.6, 8.0, 4.7 Hz, 1H), 1.42 (d, J=6.6 Hz, 1.5H), 1.32 (d, J=6.7 Hz, 1.5H), 1.13 (dt, J=7.2, 3.6 Hz, 2H), 1.05 (ddd, J=10.3, 6.6, 3.5 Hz, 2H).
LC-MS: m/z 441.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.01 (d, J=5.7 Hz, 1H), 7.59 (s, 1H), 6.49 (d, J=1.8 Hz, 1H), 6.46 (dd, J=5.7, 2.0 Hz, 1H), 6.41 (s, 1H), 4.66 (d, J=13.6 Hz, 0.5H), 4.45 (d, J=12.9 Hz, 1H), 4.33 (d, J=12.7 Hz, 1H), 4.06 (d, J=9.3 Hz, 0.5H), 3.91 (s, 2H), 3.80 (d, J=13.2 Hz, 0.5H), 3.72 (d, J=11.6 Hz, 0.5H), 3.56 (m, 0.5H), 3.27-3.01 (m, 2.5H), 2.59 (dd, J=17.2, 5.2 Hz, 1.5H), 2.11-2.04 (m, 1H), 1.98 (m, 0.5H), 1.43-1.27 (m, 1H), 1.18-1.09 (m, 2H), 1.07-0.98 (m, 2H), 0.63 (m, J=7.2, 4.7 Hz, 1H), 0.58-0.28 (m, 3H).
LC-MS: m/z 467.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.20 (d, J=6.1 Hz, 1H), 7.63 (s, 1H), 6.73 (dd, J=17.5, 10.9 Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 6.63 (d, J=3.1 Hz, 1H), 6.29 (d, J=17.5 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.69 (d, J=11.0 Hz, 0.5H), 4.46 (d, J=13.0 Hz, 1H), 4.35 (d, J=13.1 Hz, 1H), 4.10 (d, J=7.7 Hz, 0.5H), 3.92 (d, J=3.9 Hz, 2H), 3.74 (ddd, J=21.2, 17.7, 8.0 Hz, 1.5H), 3.30-3.17 (m, 1.5H), 3.13-3.03 (m, 1H), 2.69-2.48 (m, 2H), 2.15-2.06 (m, 1H), 1.28 (d, J=5.0 Hz, 1H), 1.14 (dt, J=7.3, 3.6 Hz, 2H), 1.08-0.98 (m, 2H), 0.76-0.62 (m, 1H), 0.62-0.32 (m, 3H).
LC-MS: m/z 459.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.7 Hz, 1H), 7.60 (s, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.46 (dd, J=5.7, 2.2 Hz, 1H), 5.79 (s, 1H), 4.43 (dd, J=52.6, 11.8 Hz, 2.5H), 4.16 (s, 2H), 4.00 (s, 1.5H), 3.67 (d, J=24.8 Hz, 1H), 3.46 (s, 3H), 3.21 (dd, J=13.0, 3.4 Hz, 1H), 3.09 (t, J=11.3 Hz, 1H), 2.07 (ddd, J=12.7, 8.0, 4.7 Hz, 1H), 1.38 (s, 1H), 1.15 (dt, J=7.5, 3.7 Hz, 2H), 1.08-1.00 (m, 2H), 0.67 (s, 1H), 0.63-0.39 (m, 3H).
LC-MS: m/z 467.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.26 (d, J=5.7 Hz, 1H), 7.62 (s, 1H), 6.71 (dd, J=17.4, 10.8 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 6.45 (dd, J=5.7, 2.3 Hz, 1H), 6.18 (dd, J=17.4, 1.0 Hz, 1H), 6.01 (s, 1H), 5.47 (dd, J=10.8, 0.9 Hz, 1H), 4.81-4.26 (m, 2.6H), 4.16 (s, 2H), 3.95 (d, J=43.6 Hz, 1.5H), 3.70 (s, 1H), 3.46 (s, 3H), 3.20 (dd, J=13.0, 3.4 Hz, 1H), 3.07 (t, J=11.4 Hz, 1H), 2.15-2.07 (m, 1H), 1.41 (s, 1H), 1.19-1.10 (m, 2H), 1.02 (ddd, J=10.2, 6.6, 3.4 Hz, 2H), 0.67 (s, 1H), 0.61-0.37 (m, 3H).
LC-MS: m/z NB295-002-01 459.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.8 Hz, 1H), 7.60 (d, J=3.1 Hz, 1H), 6.72 (dd, J=17.4, 10.8 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J=4.3 Hz, 1H), 6.37 (s, 1H), 6.23 (d, J=17.5 Hz, 1H), 5.52 (d, J=10.9 Hz, 1H), 4.68-4.47 (m, 1.5H), 4.37 (t, J=12.7 Hz, 1.5H), 4.28 (d, J=13.4 Hz, 0.5H), 4.22-4.13 (m, 1H), 4.08 (d, J=13.5 Hz, 0.5H), 3.88 (d, J=13.6 Hz, 0.5H), 3.56 (d, J=10.6 Hz, 0.5H), 3.47 (d, J=2.5 Hz, 3H), 3.42 (dd, J=13.3, 2.9 Hz, 0.5H), 3.24-2.95 (m, 2.5H), 2.19-2.04 (m, 2H), 1.28 (d, J=4.7 Hz, 1H), 1.19-1.11 (m, 1H), 1.07 (d, J=6.5 Hz, 3H), 1.05-0.97 (m, 2H), 0.91 (dd, J=15.7, 6.8 Hz, 3H).
LC-MS: m/z NB295-018-01 461.4 (M+H)+
To a solution of (R)-tert-butyl 4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate (1.5 g, 3.363 mmol) and 2-chloropyridin-4-amine (518.6 mg, 4.036 mmol) in 1,4-dioxane (20 mL) was added Pd(OAc)2 (76 mg, 0.34 mmol), BINAP (314.3 mg, 0.505 mmol) and Cs2CO3 (2.2 g, 6.726 mmol) at r.t. under N2. The resulting mixture was heated and stirred at 155° C. under N2 in microwave for 1 h. The solvent was removed in vacuum and the residue was purified via column chromatography (petroleum ether: EtOAc) to afford the title compound (1.1 g, 66.2%) as a yellow solid.
LC-MS: m/z 495.0 (M+H)+
To a solution of (R)-tert-butyl 4-(5-(2-chloropyridin-4-ylamino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate (550 mg, 1.1 mmol) in anhydrous THF (10 mL) was added NaH (89 mg, 2.22 mmol) and iodomethane (2 drops) at r.t. The reaction mixture was stirred at r.t. for 3 hrs. The reaction mixture was quenched by water at 0° C. The mixture was extracted with EtOAc (15 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. The organic phase was filtered and the filtrate was concentrated in vacuum to give out the title compound (crude, 567 mg) as a yellow solid.
LC-MS: m/z 509.1 (M+H)+
To a solution of (R)-tert-butyl 4-(5-((2-chloropyridin-4-yl)(methyl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-carboxylate (567 mg, 1.1 mmol) in anhydrous DCM (5 mL) was added TFA (5 mL) at r.t. The reaction mixture was stirred at r.t. for 2 hrs. The solvent was removed in vacuum and the residue was adjusted to pH>7.0. The residue mixture was extracted with EtOAc (15 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. The organic phase was filtered and the filtrate was concentrated in vacuum to give out the title compound (crude, 432 mg) as a yellow solid.
LC-MS: m/z 409.1 (M+H)+
To a solution of (R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile (410 mg, 1.0 mmol) in DMF (8 mL) was added sodium 3-hydroxypropanoate (203.5 mg, 1.5 mmol), HATU (572.3 mg, 1.5 mmol) and DIPEA (194 mg, 1.5 mmol) at r.t. The reaction mixture was stirred at r.t. for 3 hrs. The solvent was removed in vacuum and the residue was purified via silica gel column chromatography (DCM: MeOH) to afford the title compound (270 mg, 56.3%) as a pale yellow solid.
1H NMR (CHLOROFORM-d) δ: 8.03 (d, J=5.8 Hz, 1H), 7.56 (s, 1H), 6.45 (s, 1H), 6.35 (d, J=3.5 Hz, 1H), 4.70 (d, J=11.2 Hz, 0.5H), 4.51 (d, J=13.0 Hz, 1H), 4.39 (d, J=13.4 Hz, 1H), 4.10 (d, J=9.2 Hz, 0.5H), 3.93 (d, J=4.5 Hz, 2H), 3.86-3.65 (m, 1.5H), 3.40 (s, 1H), 3.30 (s, 3H), 3.28-3.15 (m, 1.5H), 3.15-3.01 (m, 1H), 2.69-2.44 (m, 2H), 1.89-1.78 (m, 1H), 1.28 (d, J=5.0 Hz, 1H), 1.13 (s, 2H), 1.01 (d, J=11.8 Hz, 2H), 0.82-0.65 (m, 1H), 0.64-0.32 (m, 3H)
LC-MS: m/z 481.0 (M+H)+
To a solution of (R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (270 mg, 0.563 mmol) in isopropanol (10 mL) and H2O (3 mL) was added Vinyltrifluoroboric acid potassium salt (113.1 mg, 0.844 mmol), Pd(dppf)Cl2 (49.0 mg, 0.06 mmol) and DIPEA (145.3 mg, 1.126 mmol) at r.t. under N2. The reaction mixture was heated and stirred at reflux under N2 overnight. The solvent was removed in vacuum and the residue was purified via silica gel column chromatography (DCM: MeOH) to afford the title compound (121 mg, 45.5%) as a pale yellow solid.
1H NMR (CHLOROFORM-d) δ: 8.25 (d, J=5.9 Hz, 1H), 7.58 (s, 1H), 6.71 (dd, J=17.4, 10.7 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 6.20 (d, J=17.3 Hz, 1H), 5.45 (d, J=11.2 Hz, 1H), 4.69 (d, J=13.4 Hz, 0.4H), 4.49 (d, J=13.0 Hz, 1H), 4.37 (d, J=12.7 Hz, 1H), 4.10 (d, J=8.6 Hz, 0.6H), 3.92 (s, 2H), 3.86-3.65 (m, 1.5H), 3.42 (s, 1H), 3.31 (s, 3H), 3.22 (m, 1.5H), 3.15-3.00 (m, 1H), 2.69-2.45 (m, 2H), 1.88 (ddd, J=12.7, 8.1, 4.7 Hz, 1H), 1.40-1.31 (m, 1H), 1.12 (s, 2H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).
LC-MS: m/z 473.4 (M+H)+
To a solution of (R)-5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (675 mg, 1.487 mmol) in anhydrous THF (15 mL) was added iodomethane (0.5 mL) and NaH (119 mg, 2.974 mmol) at r.t. The reaction mixture was stirred at r.t. for 3 hrs. The reaction mixture was quenched by water at 0° C. The mixture was extracted with EtOAc (15 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. The organic phase was filtered and the filtrate was concentrated in vacuum. The residue was purified via silica gel column chromatography (DCM: MeOH) to afford the title compound (350 mg, 50.3%) as a white solid.
1H NMR (CHLOROFORM-d) δ: 8.04 (d, J=5.7 Hz, 1H), 7.54 (s, 1H), 6.42 (d, J=44.6 Hz, 2H), 4.92 (s, 0.5H), 4.55 (d, J=13.0 Hz, 0.5H), 4.40-4.25 (m, 2H), 4.22 (d, J=13.9 Hz, 0.5H), 3.83 (d, J=13.7 Hz, 0.5H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (t, J=11.5 Hz, 0.5H), 3.39 (s, 3H), 3.37-3.33 (m, 0.5H), 3.31 (s, 3H), 3.28-2.97 (m, 2H), 2.85-2.65 (m, 1H), 2.64-2.51 (m, 1H), 1.80 (ddd, J=12.5, 8.0, 4.6 Hz, 1H), 1.36 (dd, J=41.2, 6.2 Hz, 3H), 1.12 (s, 2H), 1.07-0.93 (m, 2H).
LC-MS: m/z 469.2 (M+H)+
To a solution of (R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (330 mg, 0.71 mmol) in isopropanol (30 mL) and H2O (3 mL) was added Vinyltrifluoroboric acid potassium salt (142.1 mg, 1.06 mmol), Pd(dppf)Cl2 (58.0 mg, 0.071 mmol) and DIPEA (182 mg, 1.41 mmol) at r.t. under N2. The reaction mixture was heated and stirred at reflux under N2 overnight. The solvent was removed in vacuum and the residue was purified via silica gel column chromatography (DCM:MeOH) to afford the title compound (89 mg, 27.5%) as a white solid.
1H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.9 Hz, 1H), 7.55 (s, 1H), 6.71 (dd, J=17.4, 10.8 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 6.20 (d, J=17.3 Hz, 1H), 5.46 (d, J=11.0 Hz, 1H), 4.91 (s, 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.34-4.16 (m, 2.5H), 3.89-3.68 (m, 2.5H), 3.56 (t, J=11.5 Hz, 0.5H), 3.39 (s, 3H), 3.31 (s, 3H), 3.29 (s, 1H), 3.10 (m, 1.5H), 2.80-2.52 (m, 2H), 1.88-1.83 (m, 1H), 1.41 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.6 Hz, 1.5H), 1.10 (m, 2H), 0.97 (m, 2H).
LC-MS: m/z 461.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.32 (d, J=5.8 Hz, 1H), 7.59 (s, 1H), 7.01 (s, 1H), 6.72 (d, J=3.8 Hz, 1H), 6.62 (s, 1H), 4.92 (s, 0.5H), 4.55 (d, J=12.7 Hz, 0.5H), 4.30 (t, J=11.2 Hz, 2H), 4.22 (d, J=12.7 Hz, 0.5H), 3.83 (d, J=13.8 Hz, 0.5H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (t, J=11.5 Hz, 0.5H), 3.39 (s, 3H), 3.33 (d, J=12.5 Hz, 1H), 3.21-3.04 (m, 1.5H), 2.73 (ddd, J=22.1, 14.2, 6.5 Hz, 1H), 2.64-2.53 (m, 1H), 2.05-1.99 (m, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.7 Hz, 1.5H), 1.18-1.10 (m, 2H), 1.09-0.98 (m, 2H).
LC-MS: m/z 446.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.62 (d, J=5.5 Hz, 2H), 7.53 (s, 1H), 7.28-7.20 (m, 4H), 4.95 (s, 0.5H), 4.58 (d, J=10.0 Hz, 0.5H), 4.37 (dd, J=42.6, 13.4 Hz, 2.5H), 3.89 (d, J=13.8 Hz, 0.5H), 3.77 (t, J=6.3 Hz, 2H), 3.66-3.57 (m, 0.5H), 3.44 (s, 0.5H), 3.40 (s, 3H), 3.35-3.13 (m, 1.5H), 2.87-2.67 (m, 1H), 2.62 (dd, J=13.7, 7.4 Hz, 1H), 1.68 (d, J=4.3 Hz, 1H), 1.44 (d, J=6.6 Hz, 1.5H), 1.34 (d, J=6.3 Hz, 1.5H), 1.11 (dt, J=6.9, 3.5 Hz, 2H), 0.97-0.88 (m, 2H).
LC-MS: m/z 548.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.7 Hz, 1H), 7.98 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 6.62 (dd, J=5.6, 2.3 Hz, 1H), 6.03 (s, 1H), 5.65 (s, 1H), 4.92 (s, 0.5H), 4.55 (d, J=13.9 Hz, 0.5H), 4.27 (t, J=11.1 Hz, 2H), 4.19 (d, J=13.0 Hz, 0.5H), 3.82 (d, J=13.0 Hz, 0.5H), 3.76 (t, J=6.2 Hz, 2H), 3.57 (t, J=11.5 Hz, 0.5H), 3.40 (s, 3H), 3.34-3.23 (m, 1H), 3.15 (t, J=12.1 Hz, 1H), 3.10-3.00 (m, 0.5H), 2.84-2.65 (m, 1H), 2.60 (m, 1H), 2.07 (ddd, J=12.6, 8.0, 4.6 Hz, 1H), 1.41 (d, J=6.2 Hz, 1.5H), 1.31 (d, J=6.7 Hz, 1.5H), 1.13 (dt, J=7.4, 3.6 Hz, 2H), 1.00 (td, J=6.6, 3.4 Hz, 2H).
LC-MS: m/z 464.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.24 (d, J=5.7 Hz, 1H), 6.70 (dd, J=17.4, 10.8 Hz, 1H), 6.49 (s, 1H), 6.35 (s, 1H), 6.19 (d, J=17.4 Hz, 1H), 5.79 (s, 1H), 5.48 (d, J=10.9 Hz, 1H), 4.68 (d, J=12.8 Hz, 0.5H), 4.51-4.38 (m, 0.5H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.08 (d, J=9.0 Hz, 0.5H), 3.93 (s, 2H), 3.82-3.70 (m, 1H), 3.31 (dd, J=19.9, 7.5 Hz, 0.5H), 3.24-3.12 (m, 1H), 3.11-2.97 (m, 1H), 2.56 (m, 2H), 2.39 (s, 3H), 2.11 (ddd, J=12.6, 8.0, 4.7 Hz, 1H), 1.35-1.25 (m, 1H), 1.10 (s, 2H), 0.97 (dd, J=7.9, 3.2 Hz, 2H), 0.78-0.34 (m, 4H).
LC-MS: m/z 473.4 (M+H)+
To a solution of (R)-5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinonitrile (300 mg, 0.761 mmol) in DMF (3 mL) was added (R)-2-(oxetan-2-yl)acetic acid (115 mg, 0.99 mmol), HATU (436.0 mg, 1.142 mmol) and DIPEA (196.4 mg, 1.53 mmol) at r.t. The reaction mixture was stirred at r.t. for 3 hs. The solvent was removed in vacuum and the residue was purified via silica gel column chromatography (DCM:MeOH) to afford the title compound (182 mg, 48.5%) as a pale yellow solid.
1H NMR (CHLOROFORM-d) δ: 8.06 (d, J=5.7 Hz, 1H), 7.60 (s, 1H), 6.50 (d, J=1.8 Hz, 1H), 6.47 (dd, J=5.7, 2.0 Hz, 1H), 5.80 (s, 1H), 5.27 (dt, J=13.0, 6.5 Hz, 1H), 4.72 (dd, J=14.0, 8.0 Hz, 1H), 4.65-4.43 (m, 2H), 4.37 (d, J=13.2 Hz, 1H), 4.09 (d, J=7.2 Hz, 0.5H), 3.95 (d, J=15.5 Hz, 0.5H), 3.80-3.67 (m, 1H), 3.28 (ddd, J=9.8, 9.1, 5.3 Hz, 1H), 3.16 (d, J=11.2 Hz, 0.5H), 3.13-3.03 (m, 1H), 2.98 (dd, J=15.2, 6.8 Hz, 1H), 2.93-2.78 (m, 2H), 2.78-2.66 (m, 0.5H), 2.66-2.47 (m, 1H), 2.10-2.02 (m, 1H), 1.28 (d, J=4.9 Hz, 1H), 1.15 (dt, J=7.3, 3.5 Hz, 2H), 1.04 (dt, J=7.0, 3.2 Hz, 2H), 0.77-0.38 (m, 4H).
LC-MS: m/z 494.0 (M+H)+
A solution of (R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-vinylpyridin-4-ylamino)nicotinonitrile (200 mg, 0.448 mmol) in acetic anhydride (5 mL) was heated and stirred at 135° C. overnight. The solvent was removed in vacuum and the residue was purified via reverse phase silica gel column chromatography (MeOH:H2O) to afford the title compound (16 mg, 7.3%) as a pale yellow solid.
1H NMR (CHLOROFORM-d) δ: 8.52 (d, J=5.5 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=5.3 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 6.78 (dd, J=17.4, 10.8 Hz, 1H), 6.23 (d, J=17.3 Hz, 1H), 5.52 (d, J=10.9 Hz, 1H), 4.92 (s, 1H), 4.55 (d, J=11.4 Hz, 1H), 4.40-4.23 (m, 3H), 3.84 (d, J=12.8 Hz, 1H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (t, J=11.0 Hz, 1H), 3.39 (s, 3H), 3.35 (s, 1H), 3.17 (dt, J=24.0, 11.2 Hz, 2H), 2.73 (ddd, J=23.2, 13.8, 6.3 Hz, 1H), 2.59 (dd, J=13.3, 7.2 Hz, 1H), 2.20-2.06 (m, 3H), 2.01 (dt, J=12.8, 6.2 Hz, 1H), 1.40 (d, J=5.9 Hz, 2H), 1.29 (d, J=6.7 Hz, 2H), 1.16 (d, J=4.3 Hz, 3H), 1.03 (d, J=7.5 Hz, 1H).
LC-MS: m/z 489.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.12 (d, J=5.4 Hz, 1H), 7.82 (d, J=5.7 Hz, 1H), 6.83 (d, J=5.4 Hz, 1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.40 (s, 2H), 5.90 (d, J=17.5 Hz, 1H), 5.47 (d, J=10.9 Hz, 1H), 4.71 (d, J=12.5 Hz, 0.5H), 4.45 (dd, J=16.5, 9.9 Hz, 1.5H), 4.33-4.22 (m, 1H), 3.85 (d, J=13.3 Hz, 0.5H), 3.82-3.70 (m, 2H), 3.57 (d, J=10.5 Hz, 0.5H), 3.49-3.41 (m, 0.5H), 3.39 (d, J=3.3 Hz, 3H), 3.05 (dddd, J=21.0, 19.1, 13.7, 2.9 Hz, 2H), 2.82-2.54 (m, 2H), 2.27 (dd, J=16.7, 6.8 Hz, 0.5H), 2.18 (ddd, J=12.8, 8.2, 4.8 Hz, 1H), 1.35-1.27 (m, 1H), 1.18-0.97 (m, 7H), 0.91 (d, J=6.8 Hz, 1.5H), 0.86 (d, J=6.8 Hz, 1.5H).
LC-MS: m/z 475.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.10 (d, J=5.3 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 6.82 (d, J=5.4 Hz, 1H), 6.69 (s, 1H), 6.58 (dd, J=17.6, 10.8 Hz, 1H), 6.39 (s, 1H), 5.89 (d, J=17.5 Hz, 1H), 5.46 (d, J=10.9 Hz, 1H), 5.32-5.24 (m, 1H), 4.83-4.61 (m, 1.5H), 4.56 (dtd, J=7.7, 5.8, 1.8 Hz, 1H), 4.48 (d, J=13.5 Hz, 0.5H), 4.46-4.39 (m, 1H), 4.27 (d, J=11.9 Hz, 1H), 3.88 (d, J=13.4 Hz, 0.5H), 3.56 (d, J=10.0 Hz, 0.5H), 3.45 (dd, J=13.4, 3.2 Hz, 0.5H), 3.13-2.92 (m, 3H), 2.92-2.75 (m, 2H), 2.65-2.44 (m, 1H), 2.31-2.24 (m, 0.5H), 2.21-2.10 (m, 2H), 1.16-1.07 (m, 2H), 1.05 (dd, J=6.5, 3.0 Hz, 3H), 1.04-0.98 (m, 2H), 0.92 (d, J=6.8 Hz, 1H), 0.86 (d, J=6.8 Hz, 2H).
LC-MS: m/z 487.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.08 (d, J=5.6 Hz, 1H), 7.81 (s, 1H), 6.87 (d, J=5.6 Hz, 1H), 6.59 (dd, J=17.5, 10.9 Hz, 1H), 6.43 (s, 1H), 5.94 (d, J=17.6 Hz, 1H), 5.53 (d, J=10.9 Hz, 1H), 5.31-5.22 (m, 1H), 4.77-4.68 (m, 1H), 4.59-4.51 (m, 1H), 4.41 (s, 1H), 4.29-4.31 (m, 1H), 4.10-4.03 (m, 1H), 3.96-3.89 (m, 0.5H), 3.74-3.76 (m, 1H), 3.10-3.41 (m, 3H), 2.83-2.90 (m, 2.5H), 2.54-2.55 (m, 1H), 2.18-2.20 (m, 1H), 1.35-1.36 (m, 1H), 1.14-1.16 (m, 2H), 1.04-1.06 (m, 2H), 0.38-0.49 (m, 4H).
LC-MS: m/z 485.6 (M+H)+
To a solution of (R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile (180 mg, 0.46 mmol) in 10 mL DMF was added sodium 3-hydroxypropanoate (104 mg, 0.92 mmol), and triethylamine (1 mL), HATU (350 mg, 0.92 mmol). The resulting reaction mixture was stirred at r.t. for overnight. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by Prep-HPLC (50% EtOAc/petroleum ether) to get 100 mg title compound.
1H NMR (CHLOROFORM-d) δ8.11 (d, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 6.82 (dd, 1H), 6.53-6.62 (m, 1H), 6.40 (s, 1H), 5.89 (d., 1H), 5.45 (s, 1H), 4.75 (m, 0.5H), 4.37-4.32 (dd, 2H), 3.92 (m, 0.5H), 3.39-3.05 (m, 3H), 2.61-2.60 (m, 2H), 2.20-1.69 (m, 1H), 1.28-1.26 (m, 1H), 1.40-1.00 (m, 4H), 0.47-0.45 (m, 4H).
LC-MS: m/z 4 459 (M+H)+
To a solution of (R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)pyridin-3-yl)benzoic acid (450 mg, 1 mmol) and N,O-dimethylhydroxylammonium chloride (146 mg, 1.5 mmol) in DCM (10 mL) was added HATU (570 mg, 1.5 mmol) and DIPEA (516 mg, 4 mmol). The resulting mixture was stirred at r.t. for 2 h. The organic phase was washed with 1N HCl (10 mL×3), sat. NaHCO3 (20 mL×1) and brine, dried over Na2SO4 and concentrated under vacuum to give 390 mg of the title compound as a white solid.
1H NMR (CHLOROFORM-d) δ: 7.71-7.85 (m, J=8.3 Hz, 2H), 7.64 (s, 1H), 7.39-7.50 (m, J=8.3 Hz, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=12.3 Hz, 0.5H), 4.13-4.39 (m, 2.5H), 3.78-3.87 (m, 0.5H), 3.76 (br. s., 2H), 3.63 (s, 3H), 3.58 (d, J=10.3 Hz, 0.5H), 3.35-3.46 (m, 6H), 3.23-3.34 (m, 1H), 3.13 (br. s., 1H), 3.06 (d, J=12.5 Hz, 0.5H), 2.73 (br. s., 1H), 2.61 (br. s., 1H), 2.00-2.12 (m, 1H), 1.35-1.47 (m, 1.5H), 1.24-1.35 (m, 1.5H), 1.12-1.24 (m, 2H), 0.87-1.02 (m, 2H)
LC-MS: m/z 492.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.29 (d, J=5.1 Hz, 2H), 7.59 (s, 1H), 7.12 (br. s., 2H), 7.03 (dd, J=5.1, 1.1 Hz, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.2 Hz, 0.5H), 4.14-4.36 (m, 2.5H), 3.76 (t, J=6.2 Hz, 2.5H), 3.49-3.66 (m, 0.5H), 3.39 (s, 3H), 3.20-3.35 (m, 3H), 3.14 (d, J=11.3 Hz, 1H), 3.06 (d, J=11.3 Hz, 0.5H), 2.65-2.84 (m, 1H), 2.52-2.65 (m, 1H), 1.86-1.99 (m, 1H), 1.22-1.38 (m, 3H), 0.95-1.08 (m, 2H), 0.68-0.82 (m, 2H)
LC-MS: m/z 546.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.12 (d, J=5.4 Hz, 1H), 7.78 (s, 1H), 6.82 (dd, J=5.4, 1.1 Hz, 1H), 6.61 (br. s., 1H), 6.52 (s, 1H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.4 Hz, 0.5H), 4.07-4.32 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.39 (s, 3H), 3.18-3.33 (m, 2H), 2.92-3.17 (m, 1.5H), 2.64-2.83 (m, 1H), 2.53-2.64 (m, 1H), 2.08-2.22 (m, 1H), 1.41 (d, J=6.2 Hz, 1.5H), 1.31 (d, J=6.4 Hz, 1.5H), 1.07-1.18 (m, 2H), 0.96-1.07 (m, 2H)
LC-MS: m/z 445.5 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.00 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 6.88 (dd, J=5.9, 1.2 Hz, 1H), 6.64 (s, 1H), 4.51 (d, J=13.2 Hz, 1H), 4.37 (d, J=12.9 Hz, 1H), 4.17 (br. s., 2H), 4.01 (br. s., 0.5H), 3.89 (br. s., 0.5H), 3.71 (br. s., 0.5H), 3.40-3.52 (m, 4.5H), 3.22 (d, J=9.7 Hz, 1H), 3.02-3.16 (m, 1H), 2.09-2.20 (m, 1H), 1.03-1.22 (m, 4H), 0.67 (br. s., 2H), 0.47 (br. s., 4H)
LC-MS: m/z 457.5 (M+H)+
To a solution of (R)-5-amino-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl) nicotinonitrile (140 mg, 0.41 mmol) and 2-chloro-4-vinylpyridine (57 mg, 0.41 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (56 mg, 0.061 mmol) and Xantphos (59 mg, 0.1 mmol) and Cs2CO3 (267 mg, 0.82 mmol) and the mixture was heated at 110° C. under N2. for 16 h. After TLC showed the complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (DCM:MeOH=20:1) to afford 25 mg of title compound COMPOUND 647 and 20 mg compound COMPOUND 646.
1H NMR (CHLOROFORM-d) δ: 7.94-7.93 (d, 1H), 7.68 (s, 1H), 6.84-6.82 (d, 1H), 6.58-6.51 (q, 1H), 6.38 (s, 1H), 5.95-5.90 (d, 1H), 5.55-5.52 (d, 1H), 4.87 (s, 0.5H), 4.54-4.51 (d, 0.5H); 4.48-4.13 (m, 3H) 3.79-3.70 (m, 2H) 3.44-3.35 (m, 1H) 3.25 (s, 3H), 3.11-2.98 (m, 3H), 2.77-2.56 (m, 2H), 2.17-2.12 (m, 1H), 1.38-1.13 (m, 3H), 1.09-1.00 (m, 2H), 0.99-0.98 (m, 2H).
LC-MS: m/z 447 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.15-8.14 (d, 1H), 7.58 (s, 1H), 7.26-7.23 (d, 1H), 6.97-6.94 (dd, 1H), 6.79-6.72 (q, 1H), 6.03-5.98 (dd, 1H), 5.58 (s, 1H), 5.36-5.33 (dd, 1H), 4.88 (s, 0.5H), 4.54-4.51 (d, 0.5H); 4.20-4.09 (dd, 2H) 3.93 (s, 2H) 3.75-3.52 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.50 (m, 2H), 2.18-2.10 (m, 1H), 1.41-1.26 (m, 3H), 1.43-1.30 (m, 2H), 1.13-1.11 (m, 2H), 1.03-1.09 (m, 2H).
LC-MS: m/z 433 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.13 (d, 1H), 7.85 (s, 1H), 6.83 (dd, 1.2 Hz, 1H), 6.58 (dd, 10.7 Hz, 1H), 6.41 (s, 1H), 6.33 (br. s., 1H), 5.90 (d, 1H), 5.46 (d, 0.5H), 4.36 (d, 1H), 4.26 (d, Hz, 1H), 4.00-4.15 (m, 0.5H), 3.87 (d, 0.5H), 3.74 (t, 3H), 3.39 (s, 3H), 3.74-3.04 (m, 3H), 2.48-2.77 (m, 2H), 2.14-2.25 (m, 1H), 1.39 (br. s., 1H), 1.14 (t, 2H), 0.98-1.06 (m, 2H), 0.62-0.46 (d, 4H).
LC-MS: m/z 473 (M+H)+
1H NMR (DMSO-d6) δ: 8.08-8.20 (m, 1H), 7.92 (d, J=5.3 Hz, 1H), 6.67-6.84 (m, 2H), 6.64 (br. s., 1H), 6.25 (d, J=16.7 Hz, 1H), 5.63 (br. s., 1H), 4.56 (t, J=5.3 Hz, 1.5H), 4.08-4.52 (m, 4.5H), 3.94 (d, J=13.5 Hz, 1H), 3.59-3.72 (m, 3.5H), 3.07-3.20 (m, 2H), 1.91-2.11 (m, 3H), 0.91-1.06 (m, 8H), 0.74 (d, J=6.7 Hz, 3H)
LC-MS: m/z 461.6 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.11 (d, 1H), 7.84 (s, 1H), 7.28 (s, 1H), 6.74-6.92 (m, 1H), 6.67 (br. s., 1H), 6.58 (dd, 10.8 Hz, 1H), 6.41 (s, 1H), 5.90 (d, 1H), 5.47 (d, 1H), 4.89 (br. s., 0.5H), 4.53 (d, 0.5H), 4.07-4.36 (m, 2H), 3.93 (br. s., 2H), 3.72-3.65 (m, 1H), 2.98-3.27 (m, 2.5H), 2.44-2.74 (m, 2.5H), 2.14-2.44 (m, 1H), 1.83-2.11 (m, 1.5H), 1.21-1.50 (m, 1.5H), 0.96-1.20 (m, 2H), 0.90 (t, 2H).
LC-MS: m/z 433 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.07 (d, J=5.3 Hz, 1H), 6.88 (br. s., 1H), 6.79 (dd, J=5.3, 1.2 Hz, 1H), 6.41-6.57 (m, 1H), 6.10 (s, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.43 (d, J=10.9 Hz, 1H), 4.71-4.62 (m, 2-0.5H), 4.16-4.34 (m, 2H), 4.07 (d, J=8.8 Hz, 0.5H), 3.92 (br. s., 3H), 3.77 (br. s., 1H), 3.21-3.12 (d, 2H), 2.54-2.68 (m, 2H), 2.41 (s, 3H), 2.14-2.31 (m, 1H), 1.03-1.13 (m, 2H), 0.89-1.01 (m, 2H), 0.32-0.57 (m, 4H).
LC-MS: m/z 473 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 6.41-6.41 (d, 1H), 6.06 (s, 1H), 5.05 (m, 0.5H), 4.51-4.58 (m, 0.5H), 4.14 (s, 3H), 4.12 (m, 0.5H), 3.85 (m, 2H), 3.54-3.52 (m, 0.5H); 3.28 (s, 3H) 3.12-3.03 (m, 2H), 2.72-2.70 (m, 2H), 2.57-2.55 (m, 1H), 1.38-1.36 (m, 1.5H), 1.32 (m, 1.5H), 1.26-1.25 (m, 2H), 1.09-1.05 (m, 2H).
LC-MS: m/z 451 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.35 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 6.82 (s, 1H), 5.32-5.31 (m, 0.5H), 4.28-4.26 (m, 0.5H), 4.25-4.22 (m, 3H), 3.96 (s, 3H), 4.12 (m, 3H), 3.37 (s, 3H), 3.03-3.28 (m, 2H), 2.61-2.58 (m, 2H) 2.05-2.03 (m, 1H), 1.40-1.38 (m, 1.5H), 1.33-1.29 (m, 1.5H), 1.27-1.25 (m, 2H), 1.11-0.99 (m, 2H).
LC-MS: m/z 479 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.36 (d, 1H), 8.30 (s, 1H), 7.02-7.13 (m, 1H), 6.75 (d, 1H), 6.63 (dd, 10.6 Hz, 1H), 6.40 (d, 1H), 5.67 (d, 1H), 4.91 (br. s., 0.5H), 4.54 (d, 0.5H), 4.23 (br. s., 0.5H), 4.00-4.17 (m, 2H), 3.66-3.82 (m, 2H), 3.37-3.42 (m, 4H), 2.93-3.23 (m, 2H), 2.53-2.79 (m, 2H), 2.08-2.20 (m, 1H), 1.38-1.45 (m, 1.5H), 1.31 (d, 1.5H), 1.09-1.17 (m, 2H), 1.03 (dd, 2H).
LC-MS: m/z 448 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.99 (br. s., 1H), 8.55 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.39 (dd, J=8.3, 4.3 Hz, 1H), 6.82 (dd, J=17.1, 10.8 Hz, 1H), 6.38 (br. s., 1H), 6.30 (d, J=17.6 Hz, 1H), 5.59 (d, J=10.8 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.26 (d, J=11.3 Hz, 2H), 4.16 (d, J=13.3 Hz, 1H), 3.70-3.89 (m, 3H), 3.50-3.09 (m, 7H), 3.04 (d, J=12.3 Hz, 1H), 2.52-2.82 (m, 2.5H), 1.98-2.13 (m, 1.5H), 1.28-1.44 (m, 5H), 0.93-1.02 (m, 2H)
LC-MS: m/z 498.1 (M+H)+
To a solution of (R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (406 mg, 1 mmol) and pyridin-4-amine (94 mg, 1 mmol) in 1,4-dioxane (5 mL) was added Pd(dba)3 (136 mg, 0.15 mmol) and X-phos (72 mg, 0.15 mmol) and Cs2CO3 (752 mg, 2 mmol) at room temperature under N2. The resulting mixture was heated and stirred at 120° C. under N2 in microwave for 1.5 h. The solvent was removed in vacuum and the residue was purified by column chromatography (MeOH/DCM=1/15) afforded 168 mg of title compound as a yellow solid.
LC-MS: m/z 471.4 (M+H)+
To a solution of (R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyridin-4-ylamino) nicotinonitrile (41 mg, 0.1 mmol) and N,N-Diisopropylethylamine (26 mg, 0.2 mmol) in 5 mL of DCM was added Acryloyl chloride (10 mg, 0.1 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 3 h. After LC-MS showed the completion of reaction, the mixture was poured into water and extracted with methylene chloride. The combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (MeOH/DCM=1/15) afforded 12.6 mg of title compound as a colorless oil.
1H NMR (CHLOROFORM-d) δ: 8.60 (d, J=4.8 Hz, 2H), 7.53 (s, 1H), 7.28 (s, 2H), 6.58 (d, J=16.7 Hz, 1H), 6.16 (d, J=5.1 Hz, 1H), 5.82 (d, J=10.5 Hz, 1H), 4.92 (m, 0.5H), 4.56 (m, 0.5H), 4.20-4.42 (m, 2H), 3.69-3.91 (m, 2H), 3.58 (m, 1H), 3.37-3.41 (m, 3H), 3.36 (br. s., 1H), 3.14 (br. s., 2H), 2.59 (d, J=5.9 Hz, 2H), 1.82-1.94 (m, 1H), 1.37-1.44 (m, 2H), 1.20-1.36 (m, 5H).
LC-MS: m/z 475.5 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.96 (d, J=4.5 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 7.93-8.03 (m, 1H), 7.84 (t, J=7.5 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.44 (br. s., 1H), 7.30 (br. s., 1H), 6.61 (d, J=16.8 Hz, 1H), 6.16 (d, J=5.10 Hz, 1H), 5.82 (d, J=10.48 Hz, 1H), 4.88 (m, J=10.48 Hz, 0.5H), 4.52 (m, J=6.48 Hz, 0.5H), 4.27 (t, J=12.9 Hz, 2H), 3.74 (t, J=6.1 Hz, 2H), 3.52 (m, J=9.1 Hz, 1H), 3.37 (s, 3H), 3.29 (d, J=10.8 Hz, 1H), 3.12 (br. s., 2H), 2.72 (t, J=9.8 Hz, 1H), 2.58 (t, J=5.8 Hz, 1H), 2.23 (t, J=7.7 Hz, 1H), 1.31-1.40 (m, 2H), 1.21-1.31 (m, 3H), 1.14 (br. s., 2H).
LC-MS: m/z 525.5 (M+H)+
To a solution of (R)-5-amino-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (34 mg, 0.1 mmol) and 7-bromo-2-vinylquinoline (23 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was added Pd(dba)3 (13.6 mg, 0.015 mmol) and X-phos (7.2 mg, 0.15 mmol) and Cs2CO3 (75.2 mg, 0.2 mmol) at room temperature under N2. The resulting mixture was heated and stirred at 120° C. under N2 in microwave for 1.5 h. The solvent was removed in vacuum and the residue was purified by column chromatography (MeOH/DCM=1/15) afforded 17.2 mg of title compound as a colorless oil.
1H NMR (CHLOROFORM-d) δ: 8.08 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.31 (br. s., 1H), 7.03-7.18 (m, 2H), 6.32 (d, J=17.6 Hz, 1H), 6.18 (br. s., 1H), 5.74 (d, J=10.9 Hz, 1H), 4.92 (m, 0.5H), 4.54 (m, 0.5H), 4.09-4.33 (m, 2H), 3.71-3.86 (m, 2H), 3.57 (br. s., 1H), 3.40 (s, 3H), 3.25 (t, J=11.4 Hz, 1H), 3.13 (br. s., 2H), 2.75 (br. s., 1H), 2.53-2.64 (m, 1H), 2.14-2.27 (m, 1H), 1.40-1.47 (m, 1H), 1.24-1.35 (m, 2H), 1.12 (t, J=3.7 Hz, 2H), 0.97 (dd, J=7.9, 3.5 Hz, 2H).
LC-MS: m/z 497.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.12 (d, J=7.5 Hz, 2H), 7.63 (br. s., 1H), 7.48 (d, J=7.5 Hz, 2H), 4.47-4.61 (d, J=12.5 Hz, 0.5H), 4.19-4.37 (m, 2.5H), 3.96 (br. s., 3H), 3.75 (br. s., 2H), 3.47-3.61 (m, 1H), 3.38 (br. s., 3H), 3.28 (br. s., 1H), 3.01-3.18 (m, 1H), 2.65-2.79 (m, 1H), 2.60 (br. s., 1H), 1.96-2.10 (m, 1H), 1.72-1.91 (m, 1H), 1.38 (br. s., 1H), 1.28 (br. s., 2H), 1.18 (br. s., 2H), 0.97 (br. s., 2H)
LC-MS: m/z 463.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.29 (d, J=5.7 Hz, 1H), 7.47 (s, 1H), 6.83-6.77 (m, 2H), 4.90-4.91 (m, 1H), 4.53-4.55 (m, 1H), 4.20 (t, J=12.8 Hz, 3H), 3.92 (s, 2H), 3.79-3.70 (m, 1H), 3.55 (d, J=10.9 Hz, 1H), 3.31-3.20 (m, 1H), 3.14-2.99 (m, 1H), 2.55 (s, 2H), 2.01 (t, J=4.6 Hz, 1H), 1.87 (d, J=3.4 Hz, 1H), 1.43 (d, J=6.4 Hz, 1H), 1.32 (d, J=6.4 Hz, 2H), 1.12 (dd, J=7.9, 3.1 Hz, 2H), 1.03 (dt, J=7.9, 3.1 Hz, 2H).
LC-MS: m/z 442.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.29 (d, J=5.6 Hz, 1H), 7.46 (s, 1H), 6.83-6.76 (m, 2H), 4.69-4.72 (m, 0.5H), 4.40 (d, J=12.6 Hz, 1H), 4.28 (d, J=12.7 Hz, 1H), 4.13 (dd, J=14.3, 7.2 Hz, 1H), 3.88 (d, J=12.0 Hz, 1H), 3.78-3.64 (m, 3H), 3.38 (s, 3H), 3.18 (d, J=13.1 Hz, 1H), 3.04 (d, J=26.4 Hz, 1H), 2.74-2.57 (m, 2H), 2.48-2.50 (m, 0.5H), 1.98-2.04 (m, 1H), 1.35 (t, J=10.7 Hz, 1H), 1.13 (dd, J=7.4, 3.1 Hz, 2H), 1.02 (dt, J=7.9, 3.1 Hz, 2H), 0.59 (d, J=30.2 Hz, 2H), 0.45-0.48 (m, 2H).
LC-MS: m/z 482.1 (M+H)+
A mixture of (R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl) nicotinonitrile (3, general procedure 8 scheme) (0.35 g, 0.88 mol), sodium 3-hydroxypropanoate (0.10 g, 0.88 mol), HATU (0.5 g, 1.32 mmol) and 0.23 g DIEA (1.76 mmol) was stirred in 8 mL DMF for 4 hrs. Then the mixture was quenched by adding 6 mL water and extracted with EtOAc (15 mL×2), the organic phase was combined and concentrated to give a yellow oil, which was further purified by silica gel chromatography (DCM:MeOH=20:1) to give 0.10 g of product as yellow solid (52% yield).
1H NMR (CHLOROFORM-d) δ: 8.30 (d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H), 6.81 (dt, J=5.6, 2.0 Hz, 2H), 4.70 (s, 1H), 4.41 (d, J=13.0 Hz, 1H), 4.29 (d, J=13.0 Hz, 1H), 4.12 (dd, J=18.6, 7.4 Hz, 1H), 3.93 (s, 2H), 3.84-3.67 (m, 1H), 3.18 (d, J=12.8 Hz, 1H), 3.13-2.99 (m, 1H), 2.61 (s, 2H), 2.32-2.22 (m, 0.5H), 2.02 (t, J=4.6 Hz, 1H), 1.35 (s, 1H), 1.29 (d, J=9.4 Hz, 3H), 1.14 (dd, J=7.4, 3.0 Hz, 2H), 1.04 (dt, J=7.9, 3.1 Hz, 2H), 0.66-0.67 (m, 2H), 0.46-0.51 (m, 2H).
LC-MS: m/z 468.1 (M+H)+
A mixture of (R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxy propanoyl) piperazin-1-yl)nicotinonitrile (4) 0.35 g, (0.75 mmol), potassium trifluoro(vinyl)borate (0.15 g, 1.1 mmol), PdCl2dppf (80 mg, 0.075 mmol) and DIEA (0.24 mL, 1.5 mmol) was heated in isopropanol at reflux at 85° C. under nitrogen for 5 hrs. The mixture was then concentrated under reduced pressure to give a yellow solid which was further purified by silica chromatography (PE/EA/MeOH=150/120/8) to give 0.19 g of product as a white solid (55% yield).
1H NMR (CHLOROFORM-d) δ: 8.47 (d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H), 6.86 (d, J=2.3 Hz, 1H), 6.77 (dd, J=17.4, 10.8 Hz, 1H), 6.66 (dd, J=5.6, 2.4 Hz, 1H), 6.22 (dd, J=17.4, 0.9 Hz, 1H), 5.53 (dd, J=10.8, 0.8 Hz, 1H), 4.68 (d, J=11.7 Hz, 1H), 4.38 (d, J=12.9 Hz, 1H), 4.30-4.22 (m, 1H), 4.15-4.04 (m, 1H), 3.92 (s, 2H), 3.75 (d, J=20.7 Hz, 1H), 3.47 (d, J=21.7 Hz, 1H), 3.25-3.12 (m, 1H), 3.09-2.95 (m, 1H), 2.60 (s, 2H), 2.32-2.22 (m, 0.5H), 2.11-2.05 (m, 1H), 1.37 (d, J=20.5 Hz, 1H), 1.27 (d, J=2.0 Hz, 1H), 1.16-1.10 (m, 2H), 1.01 (ddd, J=10.1, 6.7, 3.3 Hz, 2H), 0.65 (t, J=33.7 Hz, 2H), 0.45-0.48 (m, 2H).
LC-MS: m/z 460.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.46 (d, J=5.6 Hz, 1H), 7.46 (s, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.77 (dd, J=17.4, 10.8 Hz, 1H), 6.66 (dd, J=5.6, 2.4 Hz, 1H), 6.22 (d, J=17.4 Hz, 1H), 5.53 (d, J=10.9 Hz, 1H), 4.54-4.71 (m, 0.5H), 4.37 (d, J=12.4 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.11 (s, 1H), 3.88 (d, J=11.9 Hz, 1H), 3.80-3.68 (m, 3H), 3.38 (s, 3H), 3.20 (t, J=23.2 Hz, 1H), 3.05 (s, 1H), 2.68 (dd, J=15.1, 12.2 Hz, 2H), 2.47-2.53 (m, 0.5H), 2.06 (dd, J=8.6, 3.9 Hz, 1H), 1.38-1.28 (m, 1H), 1.13 (dd, J=7.4, 3.1 Hz, 2H), 1.01 (dt, J=7.9, 3.2 Hz, 2H), 0.73-0.51 (m, 2H), 0.43-0.46 (m, 2H).
LC-MS: m/z 476.1 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.47 (s, 1H), 6.85 (s, 2H), 4.93-5.05 (m, 0.5H), 4.56-4.58 (m, 0.5H), 4.33-4.09 (m, 3H), 3.88-3.68 (m, 3H), 3.57 (s, 1H), 3.40 (s, 3H), 3.30 (s, 1H), 3.10 (dd, J=36.0, 11.2 Hz, 1H), 2.82-2.48 (m, 1H), 1.42 (d, J=6.5 Hz, 2H), 1.36-1.29 (m, 2H), 1.14 (s, 2H), 1.03-1.05 (m, 2H).
LC-MS: m/z 456.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.47 (s, 1H), 6.85 (s, 2H), 4.92-4.96 (m, 0.5H), 4.55-4.58 (m, 0.5H), 4.33-4.09 (m, 3H), 3.88-3.68 (m, 2H), 3.57 (s, 1H), 3.40 (s, 3H), 3.30 (s, 1H), 3.10 (dd, J=36.0, 11.2 Hz, 1H), 2.82-2.48 (m, 1H), 1.42 (d, J=6.5 Hz, 2H), 1.36-1.29 (m, 2H), 1.14 (s, 2H), 1.03 (d, J=4.1 Hz, 2H).
LC-MS: m/z 449.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.07 (d, J=6.0 Hz, 1H), 7.54 (s, 1H), 7.09-7.05 (m, 2H), 4.60-4.68 (m, 1H), 4.31-4.35 (m, 1H), 4.21 (d, J=13.0 Hz, 1H), 4.07 (d, J=9.8 Hz, 1H), 3.92 (s, 2H), 3.74 (d, J=11.5 Hz, 1H), 3.48 (d, J=24.4 Hz, 1H), 3.21-3.07 (m, 1H), 3.03 (d, J=10.9 Hz, 1H), 2.58 (d, J=17.5 Hz, 2H), 2.15-2.00 (m, 1H), 1.44 (s, 1H), 1.13 (dd, J=7.3, 3.6 Hz, 2H), 0.98 (dt, J=6.8, 2.7 Hz, 2H), 0.65 (s, 2H), 0.45-0.48 (m, 2H).
LC-MS: m/z 469.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.10 (d, J=5.3 Hz, 1H), 7.53 (s, 1H), 7.07 (dd, J=5.3, 1.1 Hz, 1H), 6.97 (s, 1H), 6.70 (dd, J=17.6, 10.9 Hz, 1H), 6.01 (d, J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H), 4.69-4.71 (m, 0.5H), 4.28 (d, J=12.4 Hz, 1H), 4.18 (d, J=12.5 Hz, 1H), 4.09 (d, J=8.0 Hz, 1H), 3.80-3.90 (m, 0.5H), 3.72 (dd, J=13.7, 7.8 Hz, 3H), 3.39 (d, J=5.9 Hz, 3H), 3.27 (s, 1H), 3.09 (d, J=12.5 Hz, 1H), 2.97 (s, 1H), 2.73-2.59 (m, 2H), 2.18-2.10 (m, 1H), 1.12 (d, J=4.0 Hz, 2H), 0.96 (ddd, J=9.2, 8.5, 5.1 Hz, 3H), 0.89 (dd, J=13.9, 6.8 Hz, 2H), 0.62 (s, 2H), 0.45-0.47 (m, 2H).
LC-MS: m/z 474.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.47 (d, J=5.6 Hz, 1H), 7.44 (d, J=3.5 Hz, 1H), 6.88 (s, 1H), 6.84-6.74 (m, 1H), 6.69 (d, J=3.5 Hz, 1H), 6.28 (d, J=17.4 Hz, 1H), 5.58 (d, J=10.7 Hz, 1H), 4.89-4.91 (m, 0.5H), 4.50-4.54 (m, 0.5H), 4.23-4.06 (m, 2H), 3.82-3.68 (m, 2H), 3.50-3.53 (m, 0.5H), 3.37 (s, 3H), 3.26 (d, J=12.7 Hz, 1H), 3.05-3.10 (m, 1.5H), 2.78-2.52 (m, 2H), 2.05-1.93 (m, 1H), 1.39 (d, J=6.0 Hz, 1H), 1.32-1.25 (m, 3H), 1.14-1.08 (m, 2H), 0.99 (dt, J=11.5, 3.3 Hz, 2H).
LC-MS: m/z 448.0 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.61 (d, J=5.0 Hz, 1H), 7.39 (s, 1H), 7.21-7.26 (m, 1H), 7.18 (s, 1H), 6.85 (dd, J=17.4, 10.9 Hz, 1H), 6.26 (dd, J=17.4, 1.1 Hz, 1H), 5.47-5.61 (m, 1H), 5.06 (s, 2H), 4.88 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.21 (d, J=6.8 Hz, 0.5H), 3.85-4.05 (m, 2H), 3.67-3.81 (m, 2.5H), 3.54 (d, J=6.8 Hz, 0.5H), 3.37 (s, 3H), 3.04-3.18 (m, 1.5H), 2.84-3.04 (m, 1H), 2.63-2.80 (m, 1H), 2.44-2.63 (m, 2H), 1.22-1.36 (m, 3H), 1.03-1.17 (m, 4H)
LC-MS: m/z 461.6 (M+H)+
1H NMR (CHLOROFORM-d) □ 6.67 (dd, J=16.7, 10.6 Hz, 1H), 6.35 (dd, J=16.7, 7.0 Hz, 1H), 5.64-5.85 (m, 2H), 5.26 (m, 6.6 Hz, 1H), 4.66-4.79 (m, 1H), 4.56 (br. s., 1H), 4.23-4.39 (m, 2H), 4.18 (d, J=12.6 Hz, 1H), 3.95-4.11 (m, 2H), 3.90 (d, J=17.9 Hz, 1H), 3.63-3.83 (m, 2H), 3.27 (br. s., 1H), 3.08 (br. s., 1H), 2.96 (d, J=10.3 Hz, 2H), 2.79-2.92 (m, 2H), 2.53 (d, J=7.9 Hz, 1H), 2.31-2.48 (m, 5H), 2.04 (dd, J=13.4, 6.0 Hz, 1H), 1.44 (d, J=8.2 Hz, 1H), 1.15 (br. s., 1H), 0.85-1.07 (m, 3H), 0.60 (br. s., 1H), 0.52 (br. s., 1H), 0.44 (br. s., 2H)
LC-MS: m/z 516.6 (M+H)
1H NMR (CHLOROFORM-d) □ 7.86-7.94 (s, 1H), 7.71-7.81 (s, 1H), 7.22 (s, 1H), 6.99 (dd, J=17.6, 10.9 Hz, 1H), 6.28-6.48 (m, 1H), 5.66 (dd, J=10.9, 0.9 Hz, 1H), 5.28 (t, J=6.7 Hz, 1H), 4.68-4.78 (m, 1H), 4.54-4.68 (m, 2H), 4.48 (d, J=14.1 Hz, 1H), 4.21 (s, 3H), 3.75-4.17 (m, 2H), 2.77-3.35 (m, 6H), 2.45-2.65 (m, 1H), 1.85-2.01 (m, 2H), 1.18-1.25 (m, 2H), 0.95-1.05 (m, 2H), 0.61-0.81 (m, 1H), 0.57 (br. s., 1H), 0.48 (br. s., 2H)
LC-MS: m/z 524.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=5.7 Hz, 1H), 6.93-6.75 (m, 2H), 6.65 (d, J=3.7 Hz, 1H), 6.30 (d, J=17.4 Hz, 1H), 5.60 (d, J=10.7 Hz, 1H), 4.60-4.71 (m, 0.5H), 4.27-4.28 (m, 1H), 4.23-4.14 (m, 1H), 4.10-4.15 (m, 0.5H), 3.92-3.93 (m, 2H), 3.78-3.79 (m, 1H), 3.44-3.45 (m, 1H), 3.26-3.10 (m, 1H), 3.04-3.05 (m, 1H), 2.61-2.62 (m, 2H), 2.31 (s, 3H), 2.01-1.94 (m, 1H), 1.44-1.45 (m, 1H), 1.13-1.07 (m, 2H), 1.01-0.94 (m, 2H), 0.91-0.86 (m, 1H), 0.65-0.66 (m, 1H), 0.46-0.52 (m, 2H). MS (ES) M+H expected 474.0. found 474.6
1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.76 (s, 1H), 6.58 (dd, J=17.6, 11.0 Hz, 2H), 6.05 (d, J=17.6 Hz, 1H), 5.66 (d, J=11.0 Hz, 1H), 4.65-4.70 (m, 0.5H), 4.43-4.46 (m, 1H), 4.33 (d, J=12.4 Hz, 1H), 4.16-4.07 (m, 1H), 3.87-3.88 (m, 0.5H), 3.71-3.74 (m, 3H), 3.39 (s, 3H), 3.20 (s, 1H), 3.07-3.09 (m, 1H), 2.65-2.66 (m, 2H), 2.55-2.47 (m, 1H), 2.18 (d, J=10.1 Hz, 1H), 1.30-1.25 (m, 1H), 1.15 (s, 2H), 1.07-0.98 (m, 2H), 0.50-0.60 (m, 2H), 0.45-0.47 (m, 2H). MS (ES) M+H expected 474.0. found 474.6
1H NMR (400 MHz, CHLOROFORM-d) δ: 8.31 (d, J=5.0 Hz, 1H), 7.80-7.69 (m, 1H), 6.94 (dd, J=1.3, 5.1 Hz, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 4.34 (d, J=12.6 Hz, 2H), 4.14-3.65 (m, 4H), 3.39 (s, 3H), 2.61-3.23 (m, 5H), 2.15-2.05 (m, 1H), 1.20-1.11 (m, 2H), 1.04 (td, J=3.0, 7.8 Hz, 2H), 0.45 (d, J=5.3 Hz, 5H)
LC_MS (M+1)+ 472.5
1H NMR (400 MHz, CHLOROFORM-d) δ: 8.30 (d, J=5.9 Hz, 1H), 7.59 (s, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.77-6.62 (m, 2H), 5.27 (t, J=6.7 Hz, 1H), 4.75-4.65 (m, 1H), 4.62-4.51 (m, 1H), 4.47 (d, J=12.6 Hz, 1H), 4.37 (d, J=12.6 Hz, 1H), 4.07 (d, J=7.9 Hz, 1H), 3.65-3.75 (m, 1H), 3.30-3.04 (m, 2H), 2.98 (s, 1H), 2.92-2.72 (m, 3H), 2.62-2.44 (m, 1H), 2.05-1.98 (m, 1H), 1.08-0.99 (m, 2H), 0.93-0.80 (m, 4H), 0.63 (br. s., 1H), 0.52 (br. s., 1H), 0.48-0.36 (m, 1H)
LC_MS (M+1)+ 484.6
1H NMR (CHLOROFORM-d) δ 8.23 (d, J=5.9 Hz, 1H), 7.62 (s, 1H), 6.72 (dd, J=17.4, 10.9 Hz, 1H), 6.63 (s, 1H), 6.55 (s, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.54 (d, J=10.7 Hz, 1H), 5.34-5.22 (m, 1H), 4.73 (dd, J=14.6, 8.2 Hz, 1H), 4.56 (dt, J=9.1, 5.8 Hz, 1H), 4.47 (d, J=12.9 Hz, 1H), 4.34 (d, J=13.2 Hz, 1H), 4.09 (d, J=10.0 Hz, 0.5H), 3.89 (d, J=13.3 Hz, 0.5H), 3.80-3.64 (m, 1H), 3.42-3.15 (m, 2H), 3.15-2.78 (m, 3H), 2.75-2.34 (m, 2H), 2.10 (ddd, J=12.7, 8.1, 4.7 Hz, 1H), 1.29 (dd, J=6.7, 4.8 Hz, 1H), 1.18-1.10 (m, 2H), 1.03 (dd, J=7.7, 3.2 Hz, 2H), 0.81-0.53 (m, 2H), 0.52-0.38 (m, 2H).
LC-MS: m/z NB295-063-01 485.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.10 (d, J=5.3 Hz, 1H), 7.81 (s, 1H), 6.90 (tt, J=14.6, 7.3 Hz, 1H), 6.82 (d, J=5.3 Hz, 1H), 6.79-6.63 (m, 1H), 6.58 (dd, J=17.6, 10.8 Hz, 1H), 6.41 (d, J=14.1 Hz, 2H), 5.89 (d, J=17.5 Hz, 1H), 5.46 (d, J=10.8 Hz, 1H), 4.76-4.64 (m, 0.5H), 4.55-4.37 (m, 1.5H), 4.26 (t, J=11.6 Hz, 1H), 4.18 (d, J=5.2 Hz, 0.5H), 3.95 (d, J=13.7 Hz, 0.5H), 3.81 (t, J=6.0 Hz, 2H), 3.67 (d, J=9.3 Hz, 0.5H), 3.54-3.42 (m, 0.5H), 3.29-3.16 (m, 0.5H), 3.16-2.96 (m, 2.5H), 2.52 (dd, J=13.0, 6.4 Hz, 2H), 2.36-2.24 (m, 0.5H), 2.24-2.11 (m, 1.5H), 1.18-1.08 (m, 2H), 1.07 (d, J=6.5 Hz, 3H), 1.04-0.98 (m, 2H), 0.93-0.84 (m, 3H).
LC-MS: m/z NB295-055-02 487.7 (M+H)+
1H NMR (400 MHz, CHLOROFORM-d) δ: 9.02 (s, 1H), 8.19-8.09 (m, 1H), 7.91-7.80 (m, 1H), 7.76-7.67 (m, 2H), 7.08 (dd, J=11.2, 17.6 Hz, 1H), 6.98-6.82 (m, 0.5H), 6.57-6.37 (m, 1.5H), 5.97-5.73 (m, 2H), 4.70-4.35 (m, 3.5H), 4.23-4.16 (m, 1H), 3.86-3.75 (m, 1.5H), 3.60-3.42 (m, 1H), 3.32-3.05 (m, 4H), 2.58-2.48 (m, 1H), 2.37-2.18 (m, 1H), 1.32-1.23 (m, 2H), 1.16-1.05 (m, 3H), 0.98-0.72 (m, 6H)
LC_MS (M+1)+ 523.7
1H NMR (CHLOROFORM-d) δ 8.63 (d, J=5.3 Hz, 1H), 7.63 (s, 1H), 7.38 (s, 1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.86 (dd, J=17.3, 10.9 Hz, 1H), 6.26 (d, J=17.3 Hz, 1H), 5.55 (d, J=10.9 Hz, 1H), 4.86 (s, 1H), 4.60-4.74 (m, 1H), 4.46-4.60 (m, 2H), 4.40 (d, J=12.9 Hz, 1H), 4.07 (s, 1H), 3.82 (s, 1H), 3.69 (s, 1H), 3.12-3.42 (m, 2H), 2.99-3.10 (m, 1H), 2.48-2.63 (m, 3H), 1.96-2.24 (m, 3H), 1.19 (m, 2H), 0.93-1.02 (m, 2H), 0.33-0.54 (m, 4H)
LC-MS: m/z 484.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.01 (d, J=1.8 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.36 (d, J=17.9 Hz, 1H), 5.79 (d, J=11.2 Hz, 1H), 5.27 (t, J=6.7 Hz, 1H), 4.66-4.79 (m, 1H), 4.51-4.63 (m, 1H), 4.41 (d, J=12.6 Hz, 1H), 4.09 (d, J=7.6 Hz, 1H), 3.95 (d, J=12.6 Hz, 1H), 3.79 (d, J=10.9 Hz, 1H), 2.92-3.32 (m, 4H), 2.84-2.92 (m, 1H), 2.46-2.61 (m, 1H), 2.24 (s, 3H), 2.04 (dd, J=15.1, 7.5 Hz, 1H), 1.43-1.50 (m, 1H), 1.09-1.19 (m, 2H), 0.83-0.91 (m, 2H), 0.35-0.62 (m, 4H)
LC-MS: m/z 485.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.01 (s, 1H), 7.50 (s, 1H), 7.12 (dd, J=17.9, 11.2 Hz, 1H), 6.36 (d, J=17.9 Hz, 1H), 5.78 (d, J=11.2 Hz, 1H), 5.23-5.31 (m, 1H), 4.64-4.78 (m, 1H), 4.39-4.63 (m, 3H), 4.34 (d, J=12.6 Hz, 1H), 3.91 (d, J=13.5 Hz, 1H), 3.43-3.65 (m, 1H), 2.92-3.17 (m, 4H), 2.82-2.91 (m, 1H), 2.44-2.66 (m, 1H), 2.22 (s, 3H), 2.07-2.17 (m, 1H), 1.91-2.04 (m, 1H), 1.38-1.58 (m, 1H), 1.00-1.15 (m, 3H), 0.85-0.94 (m, 6H)
LC-MS: m/z 487.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.01 (d, J=1.8 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.37 (d, J=17.6 Hz, 1H), 5.80 (d, J=11.2 Hz, 1H), 4.41 (d, J=13.2 Hz, 1H), 4.32 (d, J=12.9 Hz, 1H), 4.09 (d, J=7.0 Hz, 1H), 3.93 (s, 2H), 3.68-3.84 (m, 2H), 3.13-3.37 (m, 2H), 3.09 (d, J=8.5 Hz, 1H), 2.54-2.67 (m, 2H), 2.24 (s, 3H), 1.45-1.49 (m, 1H), 1.07-1.19 (m, 2H), 0.92 (dd, J=12.5, 6.3 Hz, 2H), 0.47-0.67 (m, 4H)
LC-MS: m/z 459.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.27 (br. s., 1H), 7.43 (br. s., 1H), 6.73 (dd, J=17.6, 11.2 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 5.28 (m, 1H), 4.63-4.78 (m, 1H), 4.30-4.60 (m, 3.5H), 3.87 (d, J=13.2 Hz, 0.5H), 3.41-3.61 (m, 1H), 2.88-3.18 (m, 4H), 2.72-2.88 (m, 2H), 2.41-2.65 (m, 1H), 2.22 (s, 3H), 2.01-2.16 (m, 1H), 1.38-1.51 (m, 1H), 1.12 (d, J=16.4 Hz, 2H), 0.98-1.05 (m, 3H), 0.75-0.98 (m, 6H)
LC-MS: m/z 487.1 (M+H)
1H NMR (CHLOROFORM-d) δ 9.28 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 6.75 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.79 (d, J=11.2 Hz, 1H), 4.40-4.55 (m, 1.5H), 4.35 (d, J=11.2 Hz, 1H), 3.94 (t, J=4.8 Hz, 2H), 3.67-3.81 (m, 0.5H), 3.41-3.57 (m, 1H), 3.01-3.21 (m, 3H), 2.57-2.66 (m, 2H), 2.28 (s, 3H), 1.63-1.67 (m, 1H), 1.12-1.16 (m, 2H), 1.01-1.09 (m, 3H), 0.79-0.98 (m, 6H)
LC-MS: m/z 461.1 (M+H)
1H NMR (CHLOROFORM-d) δ 9.27 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 5.20-5.29 (m, 1H), 4.68-4.78 (m, 1H), 4.51-4.68 (m, 1H), 4.43 (d, J=12.9 Hz, 1H), 4.33 (d, J=12.0 Hz, 1H), 4.07 (d, J=9.1 Hz, 0.5H), 3.81-3.93 (m, 0.5H), 3.69-3.81 (m, 0.5H), 3.09-3.28 (m, 3.5H), 2.81-3.01 (m, 3H), 2.55 (m, 1H), 2.30 (s, 3H), 1.82 (br. s., 1H), 1.41-1.54 (m, 1H), 1.15 (br. s., 2H), 0.88 (m, 2H), 0.43-0.72 (m, 4H)
LC-MS: m/z 485.1 (M+H)
1H NMR (CHLOROFORM-d) δ 8.49 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.46 (dd, J=5.1, 1.3 Hz, 1H), 7.23-7.28 (m, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=10.3 Hz, 0.5H), 4.23-4.47 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.31-3.45 (m, 4H), 3.05-3.29 (m, 1.5H), 2.64-2.80 (m, 1H), 2.53-2.64 (m, 1H), 1.90-2.03 (m, 1H), 1.38 (d, J=6.2 Hz, 1.5H), 1.18-1.33 (m, 3.5H), 1.02-1.13 (m, 2H)
LC-MS: m/z 554.1 (M+H)
1H NMR (CHLOROFORM-d) δ 9.02 (s, 1H), 7.52 (s, 1H), 7.14 (dd, J=17.6, 11.2 Hz, 1H), 6.37 (d, J=17.9 Hz, 1H), 5.80 (d, J=11.2 Hz, 1H), 4.65-4.76 (m, 0.5H), 4.40-4.55 (m, 1.5H), 4.34 (t, J=10.4 Hz, 1H), 3.86-4.01 (m, 2H), 3.77 (d, J=13.5 Hz, 0.5H), 3.42-3.57 (m, 1H), 2.96-3.21 (m, 3H), 2.53-2.69 (m, 2H), 2.20 (s, 3H), 1.42-1.50 (m, 1H), 1.10-1.16 (m, 2H), 1.00-1.08 (m, 3H), 0.83-1.00 (m, 6H)
LC-MS: m/z 461.1 (M+H)
1H NMR (CHLOROFORM-d) δ 9.28 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 6.75 (dd, J=17.8, 11.0 Hz, 1H), 6.15-6.26 (m, 1H), 5.79 (d, J=10.9 Hz, 1H), 4.41 (d, J=12.9 Hz, 1H), 4.31 (d, J=12.6 Hz, 1H), 4.08 (d, J=14.4 Hz, 1H), 3.36-3.55 (m, 2H), 3.24 (dd, J=12.9, 3.5 Hz, 1H), 3.07 (td, J=12.5, 3.5 Hz, 1H), 2.24 (s, 3H), 1.54 (s, 9H), 1.41-1.47 (m, 1H), 1.31-1.39 (m, 1H), 1.16 (br. s., 2H), 0.79-0.96 (m, 2H), 0.42-0.66 (m, 3H), 0.28-0.42 (m, 1H)
LC-MS: m/z 487.1 (M+H)
1H NMR (CHLOROFORM-d) δ 1H NMR (CHLOROFORM-d) □: 9.27 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 4.41 (d, J=12.9 Hz, 1H), 4.30 (d, J=12.6 Hz, 1H), 4.02-4.22 (m, 1H), 3.36-3.53 (m, 2H), 3.18-3.30 (m, 1H), 3.07 (td, J=12.4, 3.4 Hz, 1H), 2.23 (s, 3H), 1.49 (s, 9H), 1.42-1.48 (m, 1H), 1.31-1.38 (m, 1H), 1.09-1.21 (m, 2H), 0.87 (dd, J=7.8, 3.1 Hz, 2H), 0.42-0.65 (m, 3H), 0.30-0.42 (m, 1H)
LC-MS: m/z 487.1 (M+H)
1H NMR (CHLOROFORM-d) δ 9.27 (d, J=2.1 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 6.87 (dt, J=14.8, 7.3 Hz, 1H), 6.73 (dd, J=17.8, 11.0 Hz, 1H), 6.26-6.49 (m, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 4.42 (d, J=12.9 Hz, 1H), 4.33 (d, J=12.6 Hz, 1H), 4.04-4.21 (m, 1H), 3.79 (t, J=6.0 Hz, 3H), 3.38 (br. s., 1H), 3.23 (d, J=10.0 Hz, 1H), 3.08 (td, J=12.5, 2.9 Hz, 1H), 2.50 (q, J=6.2 Hz, 2H), 2.27 (s, 3H), 1.35-1.52 (m, 2H), 1.15 (br. s., 2H), 0.88 (dd, J=7.6, 3.2 Hz, 2H), 0.65 (br. s., 1H), 0.51 (br. s., 1H), 0.44 (br. s., 2H)
LC-MS: m/z 485.1 (M+H)
1H NMR (CHLOROFORM-d) 8.69 (d, J=5.0 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J=5.0 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (dd, J=10.7, 1.0 Hz, 1H), 4.33 (d, J=12.9 Hz, 1H), 4.25 (d, J=12.6 Hz, 1H), 4.09 (d, J=7.6 Hz, 0.5H), 3.79-3.92 (m, 1H), 3.65-3.79 (m, 2.5H), 3.31 (br. s., 0.5H), 3.14 (d, J=12.0 Hz, 1H), 2.99-3.11 (m, 1.5H), 2.58 (br. s., 2H), 2.17-2.26 (m, 3H), 1.90-2.00 (m, 2H), 1.51-1.62 (m, 1H), 1.43 (d, J=10.3 Hz, 1H), 1.02-1.16 (m, 2H), 0.87 (dd, J=7.9, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.54 (br. s., 1H), 0.31-0.50 (m, 2H)
LC-MS: m/z 472.5 (M+H)+
1H NMR (CHLOROFORM-d) 8.70 (d, J=5.0 Hz, 1H), 7.21-7.28 (m, 1H), 7.09 (br. s., 1H), 6.89 (dd, J=17.3, 10.9 Hz, 1H), 6.30 (d, J=17.3 Hz, 1H), 5.59 (d, J=10.9 Hz, 1H), 5.26-5.33 (m, 1H), 4.67-4.78 (m, 1.5H), 4.56 (dt, J=9.1, 5.9 Hz, 1H), 4.38-4.48 (m, 1.5H), 4.29 (d, J=12.3 Hz, 1H), 3.89 (d, J=13.5 Hz, 0.5H), 3.45-3.61 (m, 1H), 2.92-3.15 (m, 3.5H), 2.78-2.91 (m, 2H), 2.44-2.65 (m, 1H), 2.26 (br. s., 0.5H), 2.19-2.23 (m, 3H), 2.11-2.18 (m, 0.5H), 1.56 (td, J=8.0, 4.5 Hz, 1H), 1.12 (br. s., 1H), 1.04 (d, J=6.5 Hz, 4H), 0.93 (d, J=6.7 Hz, 1H), 0.83-0.90 (m, 4H)
LC-MS: m/z 486.6 (M+H)+
1H NMR (CHLOROFORM-d) 8.68 (d, J=5.0 Hz, 1H), 7.23 (d, J=9.7 Hz, 1H), 7.07 (br. s., 1H), 6.81-6.94 (m, 2H), 6.40 (d, J=15.3 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.35-4.52 (m, 1.5H), 4.28 (d, J=9.4 Hz, 1H), 3.94 (d, J=12.9 Hz, 0.5H), 3.80 (t, J=5.9 Hz, 2H), 3.68 (d, J=9.7 Hz, 0.5H), 3.52 (t, J=11.9 Hz, 0.5H), 3.05-3.18 (m, 2H), 2.51 (q, J=6.4 Hz, 2H), 2.25-2.32 (m, 1H), 2.20 (s, 3H), 2.05 (d, J=7.3 Hz, 1H), 1.51-1.61 (m, 1H), 1.10 (br. s., 1H), 1.04 (d, J=6.5 Hz, 4H), 0.93 (d, J=6.7 Hz, 1H), 0.76-0.95 (m, 4H)
LC-MS: m/z 486.6 (M+H)+
1H NMR (CHLOROFORM-d) 8.69 (d, J=5.0 Hz, 1H), 7.24 (s, 1H), 7.08 (d, J=4.4 Hz, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.0 Hz, 1H), 4.13 (q, J=7.2 Hz, 1H), 3.70-3.91 (br. s., 1.5H), 3.23-3.39 (m, 0.5H), 3.09-3.21 (m, 1H), 3.03 (t, J=10.7 Hz, 1H), 2.33-2.51 (m, 2H), 2.24-2.32 (m, 1H), 2.17-2.24 (m, 3H), 1.80-1.95 (m, 2H), 1.61-1.72 (m, 2H), 1.50-1.61 (m, 3H), 1.43 (d, J=12.6 Hz, 1H), 1.14-1.24 (m, 2H), 1.11 (br. s., 2H), 0.82-0.91 (m, 2H), 0.51-0.75 (m, 2H), 0.44 (d, J=5.0 Hz, 2H)
LC-MS: m/z 496.7 (M+H)+
1H NMR (CHLOROFORM-d) 8.68 (d, J=5.0 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.07 (br. s., 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.23-6.33 (m, 1H), 5.48-5.66 (m, 1H), 4.69 (d, J=10.9 Hz, 0.5H), 4.37-4.48 (m, 1.5H), 4.23-4.31 (m, 1H), 3.82 (d, J=13.8 Hz, 0.5H), 3.41-3.53 (m, 3H), 3.22-3.38 (m, 3H), 2.92-3.15 (m, 3H), 2.39-2.56 (m, 2H), 2.25-2.33 (m, 0.5H), 2.17-2.24 (m, 3H), 2.09-2.17 (m, 0.5H), 1.90-2.00 (m, 2H), 1.52-1.60 (m, 1H), 1.09-1.15 (m, 1H), 1.03 (dd, J=6.5, 2.6 Hz, 4H), 0.91 (d, J=6.7 Hz, 1H), 0.80-0.89 (m, 4H)
LC-MS: m/z 488.7 (M+H)+
1H NMR (CHLOROFORM-d) 8.71 (d, J=5.0 Hz, 1H), 7.26 (br. s., 1H), 7.09 (d, J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.25 (d, J=17.6 Hz, 1H), 5.57 (d, J=11.2 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.25 (d, J=12.6 Hz, 1H), 4.04-4.16 (m, 0.5H), 3.68-3.86 (m, 1.5H), 3.16 (br. s., 1.5H), 3.03 (br. s., 1H), 2.36 (br. s., 1.5H), 2.26 (d, J=7.3 Hz, 2H), 2.20 (s, 3H), 1.50-1.59 (m, 1H), 1.05-1.11 (m, 3H), 0.86 (dd, J=7.9, 3.2 Hz, 2H), 0.55-0.61 (m, 4H), 0.44 (br. s., 1H), 0.16-0.23 (m, 3H)
LC-MS: m/z 468.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.36 (s, 1H), 8.41 (br. s., 1H), 8.07-8.19 (m, 1H), 7.65-7.76 (m, 2H), 7.46 (t, J=9.0 Hz, 1H), 4.96 (br. s., 0.5H), 4.58 (br. s., 0.5H), 4.11-4.38 (m, 2.5H), 3.73-3.89 (m, 2.5H), 3.58-3.64 (m, 0.5H), 3.41 (s, 3H), 3.04-3.32 (m, 2.5H), 2.56-2.84 (m, 2H), 2.10 (s, 3H), 1.42-1.51 (m, 1H), 1.31-1.41 (m, 3H), 1.03-1.14 (m, 2H), 0.63-0.83 (m, 2H)
LC-MS: m/z 470.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.48 (br. s., 1H), 8.58 (br. s., 1H), 8.13 (d, J=8.3 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.64 (d, J=7.0 Hz, 1H), 7.32 (d, J=10.3 Hz, 1H), 4.96 (br. s., 0.5H), 4.58 (d, J=12.3 Hz, 0.5H), 4.08-4.36 (m, 2.5H), 3.71-3.93 (m, 2.5H), 3.56-3.70 (m, 0.5H), 3.41 (s, 3H), 3.19-3.36 (m, 1.5H), 3.01-3.14 (m, 1H), 2.56-2.78 (m, 2H), 2.02-2.10 (m, 3H), 1.81 (br. s., 1H), 1.42-1.50 (m, 3H), 1.05-1.15 (m, 2H), 0.61-0.81 (m, 2H)
LC-MS: m/z 470.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.44 (t, J=7.8 Hz, 1H), 7.13-7.23 (m, 1H), 6.96-7.12 (m, 2H), 6.48-6.67 (m, 2H), 6.32 (d, J=16.3 Hz, 1H), 6.02 (d, J=10.0 Hz, 1H), 4.58 (br. s., H), 4.34 (d, J=12.5 Hz, 1H), 4.26 (d, J=12.3 Hz, 1H), 3.76 (br. s., 2H), 3.23 (br. s., 1H), 3.07 (br. s., 1H), 2.19 (s, 3H), 1.73 (br. s., 1H), 1.32 (d, J=11.5 Hz, 2H), 0.96-1.15 (m, 4H), 0.74-0.88 (m, 4H), 0.67 (br. s., 1H), 0.37-0.60 (m, 3H)
LC-MS: m/z 532.7 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.22-7.30 (m, 2H), 7.08 (ddd, J=8.2, 4.6, 2.0 Hz, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.00-4.29 (m, 2.5H), 3.66-3.85 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s, 3H), 3.01-3.25 (m, 2.5H), 2.63-2.84 (m, 1H), 2.48-2.63 (m, 1H), 2.18 (s, 3H), 1.51-1.61 (m, 1H), 1.31-1.40 (m, 2H), 1.01-1.14 (m, 2H), 0.80-0.90 (m, 2H)
LC-MS: m/z 471.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.65 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.43 (d, J=12.5 Hz, 1H), 4.17-4.33 (m, 2H), 3.96-4.17 (m, 1H), 3.79 (br. s., 1H), 3.71 (d, J=11.8 Hz, 1H), 3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48 (m, 1H), 2.04 (m, 1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br. s., 1H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H)
LC-MS: m/z 458.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.59 (d, J=4.8 Hz, 1H), 7.16 (s, 1H), 7.00 (d, J=4.8 Hz, 1H), 6.78 (dd, J=17.3, 10.8 Hz, 1H), 6.19 (d, J=17.6 Hz, 1H), 5.46 (dd, J=10.8, 1.0 Hz, 1H), 4.60 (d, J=10.5 Hz, 0.5H), 4.26 (d, J=12.8 Hz, 1H), 4.17 (d, J=12.5 Hz, 1H), 3.96-4.06 (m, 0.5H), 3.80 (d, J=12.3 Hz, 1H), 3.59-3.74 (m, 3H), 3.18-3.37 (m, 4H), 3.04-3.14 (m, 1H), 2.90-3.01 (m, 1H), 2.37-2.67 (m, 2H), 2.08-2.18 (m, 3H), 1.39-1.56 (m, 1H), 0.98-1.10 (m, 2H), 0.78 (dd, J=7.9, 3.1 Hz, 2H), 0.51 (br. s., 1H), 0.44 (br. s., 1H), 0.29-0.40 (m, 2H)
LC-MS: m/z 472.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.98 (s, 1H), 7.61-7.76 (m, 1H), 6.18 (s, 1H), 5.54 (s, 1H), 4.88 (br. s., 1H), 4.51 (d, J=9.8 Hz, 1H), 4.18-4.47 (m, 3H), 3.63-3.93 (m, 3H), 3.41-3.63 (m, 1H), 3.36 (s, 4H), 2.97-3.24 (m, 2H), 2.49-2.79 (m, 2H), 2.28-2.47 (m, 1H), 2.22 (s, 3H), 1.34 (d, J=6.3 Hz, 2H), 1.14-1.30 (m, 4H), 1.04 (dd, J=7.9, 2.9 Hz, 2H)
LC-MS: m/z 447.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.61 (s, 2H), 4.59 (s, 1H), 4.33 (d, J=12.5 Hz, 1H), 4.24 (d, J=12.5 Hz, 1H), 3.98-4.15 (m, 1H), 3.84 (s, 1H), 3.22 (d, J=15.1 Hz, 1H), 3.05 (s, 1H), 2.31 (s, 3H), 1.83-1.98 (m, 1H), 1.73 (s, 1H), 1.37-1.60 (m, 1H), 0.98-1.15 (m, 4H), 0.74-0.92 (m, 4H), 0.34-0.65 (m, 4H).
LC-MS: m/z 416.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.47-7.60 (m, 1H), 7.31-7.40 (m, 2H), 7.00-7.14 (m, 2H), 6.28 (s, 1H), 6.32 (s, 1H), 6.17 (d, J=9.8 Hz, 2H), 4.34 (d, J=12.8 Hz, 1H), 4.26 (d, J=12.5 Hz, 2H), 3.85 (s, 1H), 3.06 (br. s., 2H), 1.85 (br. s., 1H), 1.72 (br. s., 1H), 1.58 (td, J=8.2, 4.1 Hz, 2H), 0.95-1.18 (m, 4H), 0.72-0.95 (m, 5H), 0.65 (br. s., 1H), 0.32-0.59 (m, 3H)
LC-MS: m/z 622.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.27 (d, J=8.5 Hz, 1H), 8.11 (dd, J=11.5, 8.8 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.53-7.78 (m, 3H), 4.59 (dt, J=13.1, 2.3 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H), 4.04-4.34 (m, 1H), 3.81 (br. s., 1H), 3.21-3.51 (m, 3H), 3.15 (d, J=11.5 Hz, 2H), 1.68 (br. s., 2H), 1.37-1.48 (m, 3H), 1.14-1.36 (m, 13H), 0.77-1.04 (m, 4H), 0.71 (br. s., 1H), 0.60 (br. s., 1H), 0.31-0.57 (m, 2H)
LC-MS: m/z 513.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.25 (d, J=8.8 Hz, 1H), 8.13 (dd, J=10.3, 9.0 Hz, 1H), 7.85-8.04 (m, 1H), 7.56-7.76 (m, 3H), 4.59 (d, J=12.0 Hz, 1H), 4.47 (d, J=12.5 Hz, 2H), 4.13 (q, J=7.0 Hz, 1H), 3.72 (br. s., 1H), 3.42 (d, J=10.0 Hz, 1H), 3.09-3.36 (m, 2H), 1.66-1.86 (m, 1H), 1.52-1.66 (m, 1H), 1.36-1.52 (m, 2H), 1.00-1.30 (m, 8H), 0.75-1.00 (m, 6H), 0.71 (d, J=7.8 Hz, 1H), 0.34-0.63 (m, 4H)
LC-MS: m/z 489.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 7.53 (d, J=1.0 Hz, 1H), 6.00 (dt, J=19.1, 2.0 Hz, 1H), 4.61-4.91 (m, 2H), 4.52-4.61 (m, 1H), 4.40-4.52 (m, 2H), 4.19-4.40 (m, 2H), 3.50 (s, 1H), 3.43 (d, J=6.0 Hz, 1H), 3.02-3.32 (m, 3H), 2.09-2.31 (m, 2H), 1.75 (br. s., 2H), 1.37-1.48 (m, 1H), 1.11-1.37 (m, 7H), 0.95-1.11 (m, 2H), 0.66-0.95 (m, 2H).
LC-MS: m/z 430.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 7.70 (d, J=6.0 Hz, 2H), 7.61 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 4.50 (d, J=11.8 Hz, 1H), 4.38 (d, J=12.3 Hz, 1H), 3.73 (d, J=7.0 Hz, 1H), 3.25 (br. s., 1H), 3.07 (br. s., 1H), 2.38-2.51 (m, 2H), 1.98-2.22 (m, 1H), 1.73 (br. s., 1H), 1.21-1.45 (m, 6H), 1.16 (dt, J=7.8, 3.6 Hz, 3H), 0.87-1.11 (m, 5H), 0.76-0.86 (m, 2H), 0.65 (br. s., 1H), 0.29-0.59 (m, 3H).
LC-MS: m/z 484.3 (M+H)+
1H NMR (DEUTERIUM OXIDE) □ 9.35 (s, 1H), 8.54 (dd, J=5.9, 1.9 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.69-7.75 (m, 1H), 7.64-7.68 (m, 2H), 7.44 (dd, J=12.5, 6.0 Hz, 1H), 4.46-4.59 (m, 2.5H), 4.08-4.18 (m, 1H), 3.86 (br. s., 0.5H), 3.53-3.74 (m, 3H), 3.21-3.32 (m, 2H), 1.87-2.06 (m, 2H), 1.49-1.58 (m, 1H), 1.33 (d, J=5.8 Hz, 1H), 1.14-1.28 (m, 7H), 0.81-0.90 (m, 2H), 0.65 (br. s., 1H), 0.36-0.59 (m, 3H).
LC-MS: m/z 508.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.25 (d, J=5.9 Hz, 1H), 7.58 (s, 1H), 6.71 (dd, J=17.4, 10.7 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 6.20 (d, J=17.3 Hz, 1H), 5.45 (d, J=11.2 Hz, 1H), 4.69 (d, J=13.4 Hz, 0.4H), 4.49 (d, J=13.0 Hz, 1H), 4.37 (d, J=12.7 Hz, 1H), 4.10 (d, J=8.6 Hz, 0.6H), 3.92 (s, 2H), 3.86-3.65 (m, 1.5H), 3.42 (s, 1H), 3.31 (s, 3H), 3.22 (m, 1.5H), 3.15-3.00 (m, 1H), 2.69-2.45 (m, 2H), 1.88 (ddd, J=12.7, 8.1, 4.7 Hz, 1H), 1.40-1.31 (m, 1H), 1.12 (s, 2H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).
LC-MS: m/z 473.4 (M+H)+
1H NMR (CHLOROFORM-d) □ 8.64 (d, J=5.0 Hz, 1H), 7.46 (s, 1H), 7.34-7.42 (m, 1H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd, J=17.6, 10.9 Hz, 1H), 6.54 (s, 1H), 6.21-6.33 (m, 1H), 5.55 (dd, J=10.9, 0.9 Hz, 1H), 4.63-4.77 (m, 0.3H), 4.01-4.18 (m, 0.7H), 3.80-3.94 (m, 1H), 3.41-3.82 (m, 4H), 3.35 (s, 3H), 3.18-3.35 (m, 1H), 2.97-3.05 (m, 1H), 2.79-2.93 (m, 1H), 2.46 (d, J=7.3 Hz, 2H), 1.81-1.99 (m, 4H), 0.94-1.07 (m, 2H), 0.72-0.83 (m, 2H), 0.36-0.56 (m, 4H).
LC-MS: m/z 471.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.76 (s, 1H), 6.58 (dd, J=17.6, 11.0 Hz, 2H), 6.05 (d, J=17.6 Hz, 1H), 5.66 (d, J=11.0 Hz, 1H), 4.65-4.70 (m, 0.5H), 4.43-4.46 (m, 1H), 4.33 (d, J=12.4 Hz, 1H), 4.16-4.07 (m, 1H), 3.87-3.88 (m, 0.5H), 3.71-3.74 (m, 3H), 3.39 (s, 3H), 3.20 (s, 1H), 3.07-3.09 (m, 1H), 2.65-2.66 (m, 2H), 2.55-2.47 (m, 1H), 2.18 (d, J=10.1 Hz, 1H), 1.30-1.25 (m, 1H), 1.15 (s, 2H), 1.07-0.98 (m, 2H), 0.50-0.60 (m, 2H), 0.45-0.47 (m, 2H).
LC-MS: m/z 474.6 (M+H)+
The mixture of (R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (268 mg, 0.627 mmol), tert-butyl (5-chloropyridazin-3-yl)carbamate (120 mg, 0.523 mmol), Pd(dppf)Cl2 (20 mg, 0.026 mmol) and CsF (159 mg, 1.045 mmol) in dioxane/H2O (8 mL/2 mL) was stirred at 100° C. for 16 hours. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrated was partitioned between EtOAc (50 mL) and water (30 mL), the organic layer was washed with water (30 mL), brine and dried over Na2SO4 and concentrated to give the crude which was purified by prep-TLC to give 150 mg of the product.
1H NMR (CHLOROFORM-d) □: 8.97 (d, J=2.1 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.24 (br. s., 1H), 7.70 (s, 1H), 4.62 (d, J=13.2 Hz, 1H), 4.49 (d, J=12.9 Hz, 1H), 4.08 (d, J=8.8 Hz, 1H), 3.92 (t, J=4.5 Hz, 2H), 3.63-3.85 (m, 1H), 3.02-3.23 (m, 3H), 2.41-2.67 (m, 2H), 1.91-2.06 (m, 1H), 1.48-1.63 (m, 9H), 1.15-1.25 (m, 3H), 1.02-1.13 (m, 2H), 0.46-0.72 (m, 4H)
LC-MS: m/z 534.3 (M+H)+
1H NMR (MeOD): δ 8.797-8.790 (d, J=2.8 Hz, 1H), 8.059-8.037 (d, J=8.8 Hz, 1H), 7.985-7.962 (d, J=9.2 Hz, 1H), 7.926-7.920 (d, J=2.4 Hz, 1H), 7.861 (s, 1H), 7.795-7.710 (m, 2H), 4.797-4.783 (m, 0.5H), 4.451-4.416 (m, 1H), 4.227-4.112 (m, 2H), 3.972-3.932 (m, 0.5H), 3.694-3.613 (m, 2H), 3.608-3.577 (m, 0.5H), 3.334 (s, 3H), 3.284 (m, 0.5H), 3.211-3.137 (m, 1H), 3.045-3.007 (m, 0.5H), 2.852-2.704 (m, 1H), 2.700-2.578 (m, 1.5H), 2.240-2.177 (m, 1H), 1.401-1.384 (d, J=6.8 Hz, 1.5H), 1.284-1.267 (d, J=6.8 Hz, 1.5H), 1.188-1.170 (m, 2H), 0.992-0.965 (m, 2H);
LC-MS: m/z 471.5 (M+H)+
1H NMR (MeOD): δ 7.543 (s, 1H), 6.936-6.893 (t, J=8.6 Hz, 2H), 6.723-6.690 (q, J=4.4 Hz, 2H), 4.798-4.781 (m, 0.5H), 4.443-4.361 (m, 1H), 4.050-3.898 (m, 2.5H), 3.675-3.509 (m, 2.5H), 3.336 (s, 3H), 3.254-2.877 (m, 2.5H), 2.792-2.588 (m, 2H), 2.260-2.196 (m, 1H), 1.402-1.255 (m, 3H), 1.115-1.097 (m, 2H), 0.992-0.968 (m, 2H);
LC-MS: m/z 438.5 (M+H)+
1H NMR (MeOD): δ 8.593-8.572 (d, J=8.4 Hz, 1H), 8.440-8.422 (d, J=7.2 Hz, 1H), 8.065-8.026 (m, 1H), 7.983-7.962 (d, J=8.4 Hz, 1H), 7.931 (s, 1H), 7.854-7.813 (m, 2H), 6.552-6.535 (d, J=6.8 Hz, 1H), 4.792-4.783 (m, 0.5H), 4.451-4.420 (m, 1H), 4.329-4.207 (m, 2H), 3.982-3.948 (m, 0.5H), 3.414-3.338 (m, 4H), 3.257-3.068 (m, 1.5H), 2.829-2.610 (m, 2H), 2.091-2.026 (m, 1H), 1.389-1.256 (m, 3H), 1.199-1.181 (m, 2H), 1.050-0.988 (m, 2H);
LC-MS: m/z 471.5 (M+H)+
1H NMR (MeOD): δ 7.558 (s, 1H), 4.763-4.752 (m, 0.5H), 4.429-4.346 (m, 1H), 4.052-3.883 (m, 3H), 3.747-3.668 (m, 6H), 3.328 (s, 3H), 3.182-3.119 (m, 2H), 3.061-2.886 (m, 4.5H), 2.781-2.677 (m, 1H), 2.623-2.562 (m, 2H), 2.142 (s, 3H), 1.375-1.358 (m, 1.5H), 1.261-1.244 (m, 1.5H), 1.109-1.036 (m, 4H);
LC-MS: m/z 455.5 (M+H)+
1H NMR (MeOD): δ 7.551 (s, 1H), 4.762-4.748 (m, 0.5H), 4.428-4.352 (m, 1H), 4.039-3.975 (m, 2H), 3.941-3.827 (m, 5H), 3.681-3.667 (m, 2H), 3.574-3.501 (m, 1H), 3.327 (s, 3H), 3.173-3.116 (m, 2H), 3.046-2.991 (m, 1H), 2.940-2.882 (m, 4H), 2.744-2.522 (m, 2.5H), 1.378-1.361 (m, 1.5H), 1.264-1.247 (m, 1.5H), 1.097-1.012 (m, 4H);
LC-MS: m/z 414.5 (M+H)+
1H NMR (MeOD): δ 7.549 (s, 1H), 4.763-4.747 (m, 0.5H), 4.426-4.343 (m, 1H), 4.171-4.118 (m, 2H), 4.044-3.882 (m, 1.5H), 3.666-3.639 (m, 6H), 3.573-3.501 (m, 1H), 3.327 (s, 3H), 3.176-2.988 (m, 2H), 2.911-2.886 (m, 4.5H), 2.781-2.546 (m, 3H), 1.374-1.358 (m, 1.5H), 1.289-1.253 (m, 4.5H), 1.101-1.026 (m, 4H);
LC-MS: m/z 485.6 (M+H)+
1H NMR (MeOD): δ 7.587 (s, 1H), 4.765-4.749 (m, 0.5H), 4.426-4.348 (m, 1H), 4.055-3.882 (m, 1.5H), 3.669-3.457 (m, 7H), 3.329 (s, 3H), 3.152-3.066 (m, 4H), 3.004-2.888 (m, 4.5H), 2.742-2.538 (m, 3H), 1.373-1.335 (m, 4.5H), 1.261-1.245 (m, 1.5H), 1.094-1.036 (m, 4H);
LC-MS: m/z 505.6 (M+H)+
1H NMR (MeOD): δ 7.598 (s, 1H), 4.768-4.752 (m, 0.5H), 4.431-4.355 (m, 1H), 4.068-3.892 (m, 2.5H), 3.688-3.660 (m, 2H), 3.572-3.507 (m, 1H), 3.333 (s, 3H), 3.101-2.930 (m, 9H), 2.903-2.871 (m, 1H), 2.787-2.586 (m, 4H), 2.544-2.493 (m, 1H), 1.378-1.362 (m, 1.5H), 1.264-1.248 (m, 1.5H), 1.124-1.044 (m, 5H), 0.698-0.652 (m, 2H), 0.357-0.268 (m, 2H);
LC-MS: m/z 467.6 (M+H)+
1H NMR (MeOD): δ 7.588 (s, 1H), 7.492-7.451 (m, 5H), 4.780-4.768 (m, 0.5H), 4.430-4.346 (m, 1H), 4.053-3.881 (m, 4.5H), 3.667-3.630 (m, 2.5H), 3.536-3.477 (m, 2H), 3.326 (m, 4H), 3.180-3.085 (m, 1.5H), 3.023-2.923 (m, 5H), 2.756-2.709 (m, 1H), 2.619-2.567 (m, 2H), 1.373-1.357 (m, 1.5H), 1.259-1.243 (m, 1.5H), 1.113-1.033 (m, 4H);
LC-MS: m/z 517.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.41-7.51 (m, 1H), 7.12 (td, J=8.5, 2.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.02-4.22 (m, 2.5H), 3.70-3.92 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.40 (s, 3H), 2.92-3.31 (m, 2.5H), 2.61-2.84 (m, 21H), 2.16-2.25 (m, 3H), 1.57-1.65 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.33 (d, J=6.8 Hz, 1.5H), 1.08 (t, J=4.6 Hz, 2H), 0.79-0.90 (m, 2H)
LC-MS: m/z 437.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.15-7.25 (m, 1H), 6.94-7.06 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.05-4.34 (m, 2.5H), 3.70-3.85 (m, 2.5H), 3.52-3.67 (m, 0.5H), 3.40 (s, 3H), 2.93-3.31 (m, 2.5H), 2.73 (td, J=15.3, 7.3 Hz, 1H), 2.54-2.64 (m, 1H), 2.21 (s, 3H), 1.54-1.61 (m, 1H), 1.39-1.45 (m, 1.5H), 1.32 (t, J=5.8 Hz, 1.5H), 1.01-1.18 (m, 2H), 0.83-0.93 (m, 2H)
LC-MS: m/z 455.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.31-7.36 (m, J=8.0 Hz, 2H), 7.23-7.28 (m, J=8.3 Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.8 Hz, 0.5H), 4.00-4.22 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.36-3.44 (m, 3H), 3.12-3.31 (m, 1.5H), 2.94-3.12 (m, 1H), 2.64-2.83 (m, 1H), 2.61 (br. s., 1H), 2.16-2.22 (m, 3H), 1.52-1.63 (m, 1H), 1.39-1.47 (m, 1.5H), 1.32 (d, J=6.3 Hz, 1.5H), 1.03-1.15 (m, 2H), 0.78-0.90 (m, 2H)
LC-MS: m/z 503.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.32-7.40 (m, 5H), 7.18 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=12.5 Hz, 0.5H), 4.21 (br. s., 0.5H), 4.06 (d, J=14.1 Hz, 1H), 3.95-4.01 (m, 2.5H), 3.68-3.79 (m, 3H), 3.53-3.67 (m, 2.5H), 3.30-3.44 (m, 5H), 3.07-3.25 (m, 2H), 2.89-3.07 (m, 1H), 2.51-2.79 (m, 2.5H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.11-1.20 (m, 7H)
LC-MS: m/z 524.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.47 (dd, J=5.0, 3.0 Hz, 1H), 7.17 (dd, J=2.8, 1.3 Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H), 4.91 (br. s., 0.5H), 4.55 (d, J=10.8 Hz, 0.5H), 3.98-4.28 (m, 2.5H), 3.75 (q, J=6.0 Hz, 2.5H), 3.50-3.67 (m, 0.5H), 3.36-3.46 (m, 3H), 3.10-3.30 (m, 1.5H), 2.89-3.10 (m, 1H), 2.65-2.81 (m, 2H), 2.25 (s, 3H), 1.71-1.79 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.05-1.12 (m, 2H), 0.81-0.90 (m, 2H)
LC-MS: m/z 425.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 6.91 (d, J=8.0 Hz, 1H), 6.60-6.74 (m, 2H), 6.01-6.11 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.6 Hz, 0.5H), 4.24 (br. s., 0.5H), 4.02-4.20 (m, 2H), 3.70-3.85 (m, 2.5H), 3.59 (t, J=11.7 Hz, 0.5H), 3.39 (s, 3H), 3.19 (t, J=13.7 Hz, 1.5H), 2.92-3.08 (m, 1H), 2.65-2.83 (m, 1H), 2.55-2.64 (m, 1H), 2.19-2.27 (m, 3H), 1.67-1.76 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.31-1.38 (m, 1.5H), 1.06 (t, J=5.3 Hz, 2H), 0.79-0.91 (m, 2H)
LC-MS: m/z 463.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.87 (br. s., 2H), 7.86 (br. s., 2H), 4.90-5.00 (m, 0.5H), 4.57 (br. s., 0.5H), 4.33 (d, J=12.5 Hz, 2.5H), 3.71-3.82 (m, 2.5H), 3.58 (br. s., 0.5H), 3.40 (s, 3H), 3.09-3.28 (m, 2.5H), 2.68 (br. s., 1H), 2.61 (br. s., 1H), 2.23-2.28 (m, 3H), 1.62-1.66 (m, 1H), 1.32-1.38 (m, 3H), 1.20 (br. s., 2H), 0.98 (br. s., 2H)
LC-MS: m/z 420.5 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.84-8.00 (m, 3H), 7.71 (s, 1H), 7.53-7.60 (m, 2H), 7.34 (dd, J=8.4, 1.4 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d, J=13.3 Hz, 0.5H), 4.06-4.34 (m, 2.5H), 3.71-3.85 (m, 2.5H), 3.52-3.69 (m, 0.5H), 3.37-3.45 (m, 3H), 3.14-3.30 (m, 1.5H), 2.94-3.12 (m, 1H), 2.67-2.85 (m, 1H), 2.54-2.66 (m, 1H), 2.19-2.28 (m, 3H), 1.62-1.70 (m, 1H), 1.45 (d, J=5.8 Hz, 1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.03-1.16 (m, 2H), 0.74-0.84 (m, 2H)
LC-MS: m/z 469.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.38 (s, 1H), 4.29 (d, J=12.8 Hz, 1H), 4.18 (d, J=12.5 Hz, 1H), 4.09 (d, J=7.5 Hz, 0.5H), 3.70-3.81 (m, 1.5H), 3.46-3.55 (m, 4.5H), 3.30 (q, J=9.8 Hz, 2H), 2.92-3.14 (m, 8.5H), 2.38-2.53 (m, 1H), 1.38-1.49 (m, 3H), 1.29-1.36 (m, 1H), 1.02-1.17 (m, 4H), 0.42-0.67 (m, 4H)
LC-MS: m/z 555.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.37 (s, 1H), 3.42-4.57 (m, 9H), 2.90-3.22 (m, 8H), 2.40-2.52 (m, 1H), 1.73 (br. s., 1H), 1.39-1.50 (m, 4H), 1.10-1.17 (m, 2H), 0.95-1.09 (m, 4H), 0.76-0.85 (m, 2H), 0.35-0.58 (m, 4H)
LC-MS: m/z 513.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.55 (d, J=5.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.67-7.78 (m, 2H), 7.51-7.63 (m, 1H), 6.32 (d, J=5.3 Hz, 1H), 4.50 (d, J=12.3 Hz, 1H), 4.38 (d, J=12.3 Hz, 1H), 3.12-4.18 (m, 5H), 2.05-2.13 (m, 1H), 1.03-1.22 (m, 5H), 0.95-1.01 (m, 3H), 0.83 (dd, J=7.9, 2.4 Hz, 2H), 0.39-0.62 (m, 4H)
LC-MS: m/z 479.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 9.48 (s, 1H), 8.58 (d, J=5.9 Hz, 1H), 7.87 (br. s., 1H), 7.74 (s, 1H), 6.91 (dd, J=17.6, 10.9 Hz, 1H), 6.57 (s, 1H), 6.27 (d, J=17.6 Hz, 1H), 5.69 (d, J=10.9 Hz, 1H), 4.52 (d, J=12.9 Hz, 1H), 4.40 (d, J=12.3 Hz, 1H), 4.11 (d, J=7.9 Hz, 1H), 3.94 (br. s., 2H), 3.64-3.88 (m, 1H), 3.33 (br. s., 1H), 3.24 (d, J=13.5 Hz, 1H), 3.03-3.19 (m, 1H), 2.48-2.69 (m, 2H), 1.98-2.09 (m, 1H), 1.37 (d, J=16.1 Hz, 1H), 1.10-1.22 (m, 2H), 0.95-1.08 (m, 2H), 0.66 (br. s., 1H), 0.57 (br. s., 1H), 0.49 (br. s., 2H)
LC-MS: m/z 430.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.69 (d, J=4.7 Hz, 1H), 7.23 (br. s., 1H), 7.07 (d, J=4.4 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (d, J=11.7 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.25 (d, J=12.0 Hz, 1H), 4.09 (br. s., 1H), 3.80 (br. s., 1H), 3.13 (br. s., 2H), 3.02 (br. s., 1H), 2.73 (dt, J=15.6, 7.8 Hz, 1H), 2.51 (br. s., 2H), 2.21 (s, 3H), 2.10-2.20 (m, 2H), 1.67-1.97 (m, 5H), 1.50-1.66 (m, 1H), 1.43 (d, J=15.8 Hz, 1H), 1.11 (br. s., 2H), 0.83-0.93 (m, 2H), 0.61 (br. s., 1H), 0.52 (br. s., 1H), 0.31-0.48 (m, 2H)
LC-MS: m/z 482.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.70 (d, J=5.0 Hz, 1H), 7.25 (s, 1H), 7.09 (d, J=3.8 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz, 1H), 6.31 (d, J=17.3 Hz, 1H), 5.92 (br. s., 1H), 5.59 (d, J=11.2 Hz, 1H), 4.35 (d, J=12.9 Hz, 1H), 4.27 (d, J=12.6 Hz, 1H), 3.91-4.19 (m, 1H), 3.78 (br. s., 1H), 3.10-3.31 (m, 3H), 3.04 (td, J=12.4, 3.4 Hz, 1H), 2.84 (t, J=8.4 Hz, 2H), 2.43-2.55 (m, 1H), 2.22 (s, 3H), 1.98-2.17 (m, 2H), 1.53-1.63 (m, 1H), 1.45 (br. s., 1H), 1.04-1.18 (m, 2H), 0.82-0.96 (m, 2H), 0.64 (br. s., 1H), 0.50 (br. s., 1H), 0.31-0.48 (m, 2H)
LC-MS: m/z 480.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.25-7.31 (m, 1H), 6.85-6.92 (m, 2H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.00-4.23 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.51-3.63 (m, 0.5H), 3.39 (s, 3H), 3.10-3.27 (m, 1.5H), 2.94-3.09 (m, 1H), 2.64-2.82 (m, 1H), 2.55-2.64 (m, 1H), 2.32-2.39 (m, 3H), 2.20 (s, 3H), 1.60-1.70 (m, 1H), 1.39-1.47 (m, 1.5H), 1.30-1.35 (m, 1.5H), 1.07 (t, J=4.6 Hz, 2H), 0.83 (dt, J=7.5, 3.5 Hz, 2H)
LC-MS: m/z 451.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.28-7.42 (m, 5H), 6.97 (d, J=3.3 Hz, 1H), 5.15 (q, J=6.3 Hz, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J=13.1 Hz, 0.5H), 4.15 (br. s., 0.5H), 3.76-3.94 (m, 2H), 3.64-3.76 (m, 2.5H), 3.41-3.57 (m, 0.5H), 3.36 (s, 3H), 2.96-3.13 (m, 1.5H), 2.77-2.96 (m, 1H), 2.61-2.77 (m, 1H), 2.48-2.61 (m, 2H), 1.67 (d, J=6.3 Hz, 3H), 1.26 (d, J=5.3 Hz, 3H), 0.97-1.15 (m, 4H)
LC-MS: m/z 449.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.64 (d, J=4.5 Hz, 1H), 7.82 (t, J=7.3 Hz, 1H), 7.51-7.62 (m, 1H), 7.29-7.39 (m, 1H), 7.23 (s, 1H), 5.22 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=12.8 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.82-4.03 (m, 2H), 3.63-3.81 (m, 2.5H), 3.44-3.61 (m, 0.5H), 3.37 (s, 3H), 3.09 (t, J=13.2 Hz, 1.5H), 2.82-3.01 (m, 1H), 2.62-2.79 (m, 1H), 2.45-2.61 (m, 2H), 1.26 (d, J=5.3 Hz, 3H), 0.99-1.16 (m, 4H)
LC-MS: m/z 436.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.32 (t, J=7.9 Hz, 1H), 7.18 (s, 1H), 6.93-7.05 (m, 2H), 6.89 (dd, J=8.0, 2.3 Hz, 1H), 5.02 (s, 2H), 4.87 (br. s., 0.5H), 4.51 (d, J=13.3 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.92 (t, J=12.7 Hz, 2H), 3.83 (s, 3H), 3.73 (t, J=6.1 Hz, 2.5H), 3.53 (d, J=8.0 Hz, 0.5H), 3.37 (s, 3H), 3.01-3.18 (m, 1.5H), 2.81-3.00 (m, 1H), 2.62-2.78 (m, 1H), 2.45-2.62 (m, 2H), 1.27-1.44 (m, 3H), 0.97-1.15 (m, 4H)
LC-MS: m/z 465.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.28-7.39 (m, J=8.8 Hz, 2H), 7.20 (s, 1H), 6.88-6.97 (m, J=8.8 Hz, 2H), 4.96 (s, 2H), 4.88 (d, J=7.8 Hz, 0.5H), 4.51 (d, J=13.3 Hz, 0.5H), 4.18 (br. s., 1H), 3.92 (t, J=12.5 Hz, 2H), 3.83 (s, 3H), 3.67-3.78 (m, 2.5H), 3.46-3.60 (m, 0.5H), 3.37 (s, 3H), 3.00-3.16 (m, 1.5H), 2.80-2.99 (m, 1H), 2.61-2.80 (m, 1H), 2.42-2.61 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 0.92-1.14 (m, 4H)
LC-MS: m/z 465.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.11 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.19 (s, 1H), 5.07 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=13.6 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.94 (s, 3H), 3.83-4.02 (m, 2H), 3.64-3.80 (m, 2.5H), 3.52 (br. s., 0.5H), 3.37 (s, 3H), 3.09 (t, J=13.6 Hz, 1.5H), 2.82-3.01 (m, 1H), 2.62-2.80 (m, 1H), 2.41-2.62 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 0.98-1.15 (m, 4H)
LC-MS: m/z 493.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.01-8.14 (m, 2H), 7.44-7.56 (m, J=8.5 Hz, 2H), 7.18 (s, 1H), 5.10 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=13.6 Hz, 0.5H), 4.19 (br. s., 0.5H), 3.93 (s, 3H), 3.82-4.02 (m, 2H), 3.66-3.81 (m, 2.5H), 3.46-3.60 (m, 0.5H), 3.37 (s, 3H), 3.10 (t, J=13.7 Hz, 1.5H), 2.82-3.01 (m, 1H), 2.62-2.79 (m, 1H), 2.43-2.62 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.27-1.34 (m, 1.5H), 0.96-1.17 (m, 4H)
LC-MS: m/z 493.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.75 (s, 1H), 7.61-7.71 (m, 2H), 7.54 (t, J=7.9 Hz, 1H), 7.17 (s, 1H), 5.06 (s, 2H), 4.88 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.21 (br. s., 0.5H), 3.85-4.06 (m, 2H), 3.74 (br. s., 2.5H), 3.54 (br. s., 0.5H), 3.37 (s, 3H), 3.04-3.21 (m, 1.5H), 2.84-3.04 (m, 1H), 2.55-2.81 (m, 2H), 2.40-2.51 (m, 1H), 1.39 (d, J=5.5 Hz, 1.5H), 1.30 (d, J=6.3 Hz, 1.5H), 0.98-1.16 (m, 4H)
LC-MS: m/z 460.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.35-7.49 (m, 4H), 7.18 (s, 1H), 5.04 (s, 2H), 4.81-4.91 (m, 0.5H), 4.73 (s, 2H), 4.50 (d, J=13.3 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.81-4.00 (m, 2H), 3.64-3.81 (m, 2.5H), 3.45-3.60 (m, 0.5H), 3.37 (s, 3H), 3.00-3.17 (m, 1.5H), 2.81-2.99 (m, 1H), 2.61-2.79 (m, 1H), 2.43-2.61 (m, 2H), 1.92-2.08 (m, 1H), 1.31-1.41 (m, 3H), 0.97-1.14 (m, 4H)
LC-MS: m/z 465.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.27-7.39 (m, 5H), 6.87 (d, J=1.5 Hz, 1H), 4.84 (br. s., 0.5H), 4.66-4.74 (m, 1H), 4.47 (d, J=13.3 Hz, 0.5H), 4.14 (br. s., 0.5H), 3.63-3.90 (m, 4.5H), 3.40-3.57 (m, 0.5H), 3.35 (s, 3H), 2.93-3.12 (m, 1.5H), 2.76-2.93 (m, 1H), 2.47-2.75 (m, 3H), 2.18 (dq, J=13.3, 6.6 Hz, 1H), 1.19-1.39 (m, 3H), 1.00-1.11 (m, 7H), 0.87-0.97 (m, 3H)
LC-MS: m/z 477.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.27-7.42 (m, 5H), 6.91-7.00 (m, 1H), 5.15 (q, J=6.5 Hz, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J=13.6 Hz, 0.5H), 4.15 (br. s., 0.5H), 3.78-3.95 (m, 2H), 3.61-3.77 (m, 2.5H), 3.43-3.57 (m, 0.5H), 3.36 (s, 3H), 2.96-3.13 (m, 1.5H), 2.85 (td, J=12.4, 2.8 Hz, 1H), 2.48-2.76 (m, 3H), 1.67 (d, J=6.5 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H), 1.21-1.28 (m, 1.5H), 0.97-1.13 (m, 4H)
LC-MS: m/z 449.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.70 (s, 1H), 8.63 (d, J=3.8 Hz, 1H), 7.79 (dt, J=7.8, 1.9 Hz, 1H), 7.37 (dd, J=7.8, 4.8 Hz, 1H), 7.24 (s, 1H), 5.06 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=12.5 Hz, 0.5H), 4.20 (br. s., 0.5H), 3.83-4.04 (m, 2H), 3.63-3.83 (m, 2.5H), 3.53 (br. s., 0.5H), 3.37 (s, 3H), 3.03-3.17 (m, 1.5H), 2.84-3.02 (m, 1H), 2.62-2.78 (m, 1H), 2.51-2.62 (m, 1H), 2.39-2.51 (m, 1H), 1.36-1.43 (m, 2H), 1.27-1.34 (m, 2H), 0.91-1.15 (m, 4H)
LC-MS: m/z 436.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.27-7.42 (m, 5H), 6.92-6.98 (m, 1H), 5.15 (q, J=6.4 Hz, 1H), 4.84 (br. s., 0.5H), 4.49 (d, J=13.6 Hz, 0.5H), 4.15 (br. s., 0.5H), 3.77-3.95 (m, 2H), 3.72 (t, J=6.3 Hz, 2.5H), 3.43-3.56 (m, 0.5H), 3.36 (s, 3H), 2.97-3.13 (m, 1.5H), 2.78-2.95 (m, 1H), 2.48-2.78 (m, 3H), 1.67 (d, J=6.3 Hz, 3H), 1.36 (d, J=6.8 Hz, 1.5H), 1.26 (d, J=5.5 Hz, 1.5H), 0.97-1.14 (m, 4H)
LC-MS: m/z 449.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.28-7.42 (m, 5H), 6.92 (d, J=2.3 Hz, 1H), 4.78-4.95 (m, 1.5H), 4.48 (d, J=13.3 Hz, 0.5H), 4.14 (br. s., 0.5H), 3.77-3.93 (m, 2H), 3.65-3.77 (m, 2.5H), 3.48 (br. s., 0.5H), 3.36 (s, 3H), 2.95-3.12 (m, 1.5H), 2.76-2.95 (m, 1H), 2.46-2.76 (m, 3H), 2.00-2.13 (m, 1H), 1.84-1.98 (m, 1H), 1.36 (d, J=6.8 Hz, 1.5H), 1.25-1.29 (m, 1.5H), 0.92-1.12 (m, 7H)
LC-MS: m/z 463.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.67 (d, J=5.8 Hz, 2H), 7.39 (d, J=5.8 Hz, 2H), 7.17 (s, 1H), 5.07 (s, 2H), 4.79-4.95 (m, 0.5H), 4.51 (d, J=13.6 Hz, 0.5H), 4.19 (br. s., 0.5H), 3.86-4.04 (m, 2H), 3.62-3.81 (m, 2.5H), 3.45-3.59 (m, 0.5H), 3.37 (s, 3H), 3.03-3.18 (m, 1.5H), 2.83-3.02 (m, 1H), 2.62-2.79 (m, 1H), 2.43-2.61 (m, 2H), 1.39 (d, J=6.8 Hz, 1.5H), 1.27-1.31 (m, 1.5H), 0.99-1.15 (m, 4H)
LC-MS: m/z 436.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.33-7.38 (m, 1H), 7.27-7.33 (m, 3H), 7.19-7.25 (m, 1H), 6.96 (d, J=4.5 Hz, 1H), 5.11 (q, J=6.3 Hz, 1H), 4.85 (br. s., 0.5H), 4.49 (d, J=13.6 Hz, 0.5H), 4.16 (br. s., 0.5H), 3.78-3.97 (m, 2H), 3.63-3.78 (m, 2.5H), 3.49 (br. s., 0.5H), 3.36 (s, 3H), 2.98-3.14 (m, 1.5H), 2.79-2.97 (m, 1H), 2.60-2.77 (m, 1H), 2.46-2.60 (m, 2H), 1.65 (d, J=6.3 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H), 1.26 (d, J=7.8 Hz, 1.5H), 0.98-1.15 (m, 4H)
LC-MS: m/z 483.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.23-7.40 (m, 4H), 6.95 (d, J=3.8 Hz, 1H), 5.13 (q, J=6.1 Hz, 1H), 4.85 (br. s., 0.5H), 4.49 (d, J=13.1 Hz, 0.5H), 4.16 (br. s., 0.5H), 3.79-3.98 (m, 2H), 3.63-3.78 (m, 2.5H), 3.42-3.57 (m, 0.5H), 3.36 (s, 3H), 2.98-3.13 (m, 1.5H), 2.77-2.97 (m, 1H), 2.60-2.76 (m, 1H), 2.43-2.60 (m, 2H), 1.65 (d, J=6.3 Hz, 3H), 1.33-1.39 (m, 1.5H), 1.22-1.29 (m, 1.5H), 0.97-1.13 (m, 4H)
LC-MS: m/z 483.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.33 (s, 1H), 8.24 (dd, J=8.2, 1.2 Hz, 1H), 7.72-7.84 (m, 1H), 7.54-7.67 (m, 1H), 7.21 (s, 1H), 5.13 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=13.7 Hz, 0.5H), 4.19 (br. s., 0.5H), 3.86-4.03 (m, 2H), 3.63-3.84 (m, 2.5H), 3.53 (br. s., 0.5H), 3.37 (s, 3H), 3.04-3.18 (m, 1.5H), 2.84-3.04 (m, 1H), 2.62-2.78 (m, 1H), 2.42-2.61 (m, 2H), 1.39 (d, J=6.7 Hz, 1.5H), 1.29 (d, J=6.7 Hz, 1.5H), 0.97-1.19 (m, 4H)
LC-MS: m/z 480.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.13-7.24 (m, 2H), 6.79 (d, J=7.8 Hz, 1H), 6.74 (s, 1H), 6.67 (dd, J=8.0, 1.5 Hz, 1H), 4.95 (s, 2H), 4.87 (br. s., 0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.17 (br. s., 0.5H), 3.81-3.98 (m, 2H), 3.73 (t, J=6.1 Hz, 2.5H), 3.53 (d, J=8.8 Hz, 0.5H), 3.37 (s, 3H), 3.01-3.16 (m, 1.5H), 2.81-3.00 (m, 1H), 2.61-2.79 (m, 1H), 2.46-2.61 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.5 Hz, 1.5H), 0.95-1.14 (m, 4H)
LC-MS: m/z 450.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.11 (br. s., 1H), 7.82 (br. s., 1H), 7.52 (d, J=8.3 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.13-7.23 (m, 2H), 6.45 (dd, J=16.8, 1.3 Hz, 1H), 6.31 (dd, J=16.8, 10.0 Hz, 1H), 5.76 (dd, J=10.2, 1.4 Hz, 1H), 4.99 (s, 2H), 4.86 (br. s., 0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.81-3.99 (m, 2H), 3.72 (t, J=6.0 Hz, 2.5H), 3.45-3.59 (m, 0.5H), 3.35 (s, 3H), 3.00-3.16 (m, 1.5H), 2.81-2.99 (m, 1H), 2.62-2.79 (m, 1H), 2.41-2.62 (m, 2H), 1.39 (d, J=6.8 Hz, 1.5H), 1.25-1.32 (m, 1.5H), 0.94-1.15 (m, 4H)
LC-MS: m/z 504.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.52 (s, 1H), 7.73 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12-7.26 (m, 2H), 5.02 (s, 2H), 4.87 (br. s., 0.5H), 4.50 (d, J=13.3 Hz, 0.5H), 4.19 (d, J=8.5 Hz, 0.5H), 4.03 (s, 2H), 3.81-3.99 (m, 2H), 3.64-3.81 (m, 2.5H), 3.45-3.61 (m, 0.5H), 3.36 (s, 3H), 3.02-3.18 (m, 1.5H), 2.82-3.02 (m, 1H), 2.62-2.80 (m, 1H), 2.42-2.62 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.22-1.33 (m, 1.5H), 0.95-1.14 (m, 4H)
LC-MS: m/z 570.1 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.57-8.70 (m, 2H), 7.33 (d, J=6.0 Hz, 2H), 6.96 (d, J=3.3 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 4.86 (br. s., 0.5H), 4.49 (d, J=12.8 Hz, 0.5H), 4.17 (br. s., 0.5H), 3.81-4.05 (m, 2H), 3.63-3.81 (m, 2.5H), 3.51 (d, J=15.3 Hz, 0.5H), 3.36 (s, 3H), 3.07 (t, J=12.9 Hz, 1.5H), 2.81-3.00 (m, 1H), 2.60-2.78 (m, 1H), 2.46-2.60 (m, 2H), 1.67 (d, J=6.5 Hz, 3H), 1.36 (d, J=5.0 Hz, 1.5H), 1.24-1.28 (m, 1.5H), 0.99-1.16 (m, 4H)
LC-MS: m/z 450.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.03 (br. s., 1H), 7.56-7.64 (m, 2H), 7.30 (d, J=8.3 Hz, 2H), 6.90-7.05 (m, 1H), 6.43 (dd, J=16.8, 1.3 Hz, 1H), 6.29 (dd, J=16.8, 10.0 Hz, 1H), 5.74 (dd, J=10.0, 1.3 Hz, 1H), 5.05-5.19 (m, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J=12.5 Hz, 0.5H), 4.16 (br. s., 0.5H), 3.65-3.95 (m, 5.5H), 3.50 (d, J=11.3 Hz, 0.5H), 3.34 (s, 3H), 2.97-3.14 (m, 1.5H), 2.77-2.95 (m, 1H), 2.61-2.77 (m, 1H), 2.47-2.61 (m, 2H), 1.65 (d, J=6.3 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H), 1.26 (d, J=5.0 Hz, 1.5H), 0.97-1.15 (m, 4H)
LC-MS: m/z 518.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.75 (br. s., 1H), 7.47 (d, J=8.0 Hz, 1H), 7.30-7.40 (m, 2H), 7.10-7.23 (m, 2H), 6.88-7.09 (m, 1H), 5.96 (dd, J=15.1, 1.5 Hz, 1H), 5.01 (s, 2H), 4.87 (br. s., 0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.82-4.00 (m, 2H), 3.64-3.80 (m, 2.5H), 3.46-3.62 (m, 0.5H), 3.36 (s, 3H), 3.01-3.16 (m, 1.5H), 2.83-3.01 (m, 1H), 2.62-2.77 (m, 1H), 2.44-2.61 (m, 2H), 1.93 (dd, J=6.9, 1.6 Hz, 3H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=7.0 Hz, 1.5H), 0.95-1.13 (m, 4H)
LC-MS: m/z 518.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.75 (br. s., 1H), 7.63 (br. s., 1H), 7.46 (br. s., 1H), 7.34 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.94-7.01 (m, 1H), 6.46 (dd, J=16.8, 1.3 Hz, 1H), 6.28 (dd, J=16.9, 10.2 Hz, 1H), 5.79 (dd, J=10.3, 1.0 Hz, 1H), 5.13 (q, J=6.1 Hz, 1H), 4.86 (br. s., 0.5H), 4.49 (d, J=13.3 Hz, 0.5H), 4.17 (br. s., 0.5H), 3.78-3.95 (m, 2H), 3.63-3.78 (m, 2.5H), 3.52 (d, J=14.6 Hz, 0.5H), 3.37 (s, 3H), 2.98-3.14 (m, 1.5H), 2.79-2.97 (m, 1H), 2.63-2.78 (m, 1H), 2.48-2.63 (m, 2H), 1.68 (d, J=6.3 Hz, 3H), 1.38 (d, J=6.3 Hz, 1.5H), 1.24-1.30 (m, 1.5H), 1.00-1.14 (m, 4H)
LC-MS: m/z 518.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.69 (d, J=4.7 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J=4.7 Hz, 1H), 6.87 (dd, J=17.6, 10.9 Hz, 1H), 6.19-6.36 (m, 1H), 5.47-5.63 (m, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.10 (br. s., 0.65H), 3.64-3.91 (m, 1.35H), 2.88-3.38 (m, 2H), 2.37 (br. s., 2H), 2.21 (s, 3H), 1.61-1.73 (m, 2H), 1.51-1.61 (m, 1H), 1.44 (br. s., 1H), 1.35 (br. s., 4H), 1.04-1.17 (m, 2H), 0.90-0.98 (m, 3H), 0.87 (dd, J=8.1, 3.1 Hz, 2H), 0.60 (br. s., 1H), 0.55 (br. s., 1H), 0.23-0.50 (m, 2H)
LC-MS: m/z 484.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.70 (d, J=5.0 Hz, 1H), 7.25 (s, 1H), 7.09 (d, J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.51-5.64 (m, 1H), 4.34 (d, J=12.9 Hz, 1H), 4.26 (d, J=12.0 Hz, 1H), 4.09 (br. s., 0.6H), 3.63-3.92 (m, 1.4H), 3.01-3.13 (m, 2H), 2.25-2.38 (m, 2H), 2.22 (s, 3H), 2.00-2.13 (m, 4H), 1.82-1.90 (m, 2H), 1.75 (q, J=7.4 Hz, 2H), 1.61-1.69 (m, 2H), 1.56 (td, J=8.3, 4.0 Hz, 1H), 1.12 (br. s., 2H), 0.80-0.94 (m, 2H), 0.61 (br. s., 1H), 0.55 (br. s., 1H), 0.44 (br. s., 2H)
LC-MS: m/z 496.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.72 (d, J=5.0 Hz, 1H), 7.26 (s, 1H), 7.09 (d, J=4.7 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz, 1H), 6.27 (d, J=17.6 Hz, 1H), 5.52-5.65 (m, 1H), 4.34 (d, J=12.6 Hz, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.02-4.17 (m, 0.6H), 3.71-3.95 (m, 1.4H), 2.95-3.4 (m, 2H), 2.45-2.56 (m, 1H), 2.36 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 1.63-1.70 (m, 2H), 1.11 (br. s., 2H), 0.75-0.89 (m, 3H), 0.51-0.74 (m, 3H), 0.34-0.50 (m, 4H), 0.10 (d, J=4.1 Hz, 2H)
LC-MS: m/z 482.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.18-8.17 (d, 1H), 7.61 (s, 1H), 7.51-7.49 (d, 1H), 6.89-6.86 (dd, 1H), 6.38 (s, 1H), 4.87 (s, 0.5H), 4.53-4.50 (d, 0.5H); 4.27-4.16 (dd, 2H) 3.92 (s, 2H) 3.75-3.10 (m, 4H) 2.69-2.51 (m, 2H), 2.07-2.02 (m, 1H), 1.41-1.26 (m, 3H), 1.43-1.10 (m, 2H), 1.04-1.01 (m, 2H).
LC-MS: m/z 432.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.15-8.14 (d, 1H), 7.58 (s, 1H), 7.26-7.23 (d, 1H), 6.97-6.94 (dd, 1H), 6.79-6.72 (q, 1H), 6.03-5.98 (dd, 1H), 5.58 (s, 1H), 5.36-5.33 (dd, 1H), 4.88 (s, 0.5H), 4.54-4.51 (d, 0.5H); 4.20-4.09 (dd, 2H) 3.93 (s, 2H) 3.75-3.52 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.50 (m, 2H), 2.18-2.10 (m, 1H), 1.41-1.26 (m, 3H), 1.43-1.30 (m, 2H), 1.13-1.11 (m, 2H), 1.03-1.09 (m, 2H).
LC-MS: m/z 433.2 (M+H)+
1H NMR (CHLOROFORM-d) δ t: 7.21-7.27 (m, 2H), 7.11-7.19 (m, 2H), 4.85-4.95 (s, 0.5H), 4.45-4.57 (m, 0.5H), 4.05-4.27 (m, 4H), 3.74 (t, J=6.4 Hz, 2.5H), 3.57-3.63 (m, 0.5H), 3.35-3.40 (m, 3H), 3.29 (s, 3H), 3.09-3.26 (m, 2H), 2.59 (br. s., 1H), 1.60-1.70 (m, 1H), 1.38-1.44 (m, 1H), 1.30 (d, J=6.8 Hz, 2H), 1.25 (s, 1H), 1.04-1.10 (m, 2H), 0.81-0.88 (m, 2H).
LC-MS: m/z 487.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.57-8.87 (m, 1H), 7.25 (s, 1H), 7.02-7.16 (m, 1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.30 (d, J=17.3 Hz, 1H), 5.59 (d, J=10.9 Hz, 1H), 5.27 (t, J=6.6 Hz, 1H), 4.51-4.78 (m, 2H), 4.30-4.42 (m, 1H), 4.26 (d, J=11.4 Hz, 1H), 4.09 (d, J=9.1 Hz, 1H), 3.84-3.98 (m, 1H), 3.56-3.84 (m, 1H), 2.95-3.45 (m, 3H), 2.68-2.92 (m, 2H), 2.41-2.63 (m, 3H), 1.49-1.55 (m, 1H), 1.34 (d, J=8.2 Hz, 1H), 1.10 (t, J=7.6 Hz, 5H), 0.80-0.94 (m, 3H), 0.35-0.75 (m, 4H)
LC-MS: m/z 498.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.0 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J=5.0 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.22-6.40 (m, 1H), 5.57 (dd, J=10.9, 0.9 Hz, 1H), 4.60-4.70 (m, 0.5H), 4.18-4.41 (m, 3H), 4.02-4.15 (m, 0.5H), 3.89 (d, J=7.3 Hz, 1.5H), 3.63-3.82 (m, 1.5H), 2.90-3.45 (m, 3H), 2.64-2.85 (m, 1H), 2.53 (dd, J=14.8, 6.0 Hz, 1H), 2.08-2.32 (m, 4H), 1.88-2.00 (m, 2H), 1.51-1.69 (m, 2H), 1.43 (d, J=13.8 Hz, 1H), 1.11 (s, 2H), 0.87 (dd, J=7.9, 2.9 Hz, 2H), 0.35-0.66 (m, 4H)
LC-MS: m/z 498.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.71 (d, J=4.7 Hz, 1H), 7.25 (s, 1H), 7.09 (d, J=4.7 Hz, 1H), 6.90 (dd, J=17.3, 10.9 Hz, 1H), 6.31 (d, J=17.3 Hz, 1H), 5.60 (d, J=11.2 Hz, 1H), 4.94-5.08 (m, 1H), 4.17-4.45 (m, 2H), 4.08 (s, 1H), 3.79 (s, 2H), 2.80-3.45 (m, 4H), 2.51-2.73 (m, 4H), 2.19-2.28 (m, 3H), 1.57 (td, J=8.1, 4.0 Hz, 1H), 1.12 (s, 3H), 0.88 (dd, J=7.9, 3.2 Hz, 3H), 0.25-0.74 (m, 4H)
LC-MS: m/z 512.3 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.59 (d, J=4.7 Hz, 1H), 7.87-8.13 (m, 1H), 7.00-7.17 (m, 2H), 5.10-5.32 (m, 2H), 4.67-4.83 (m, 1H), 4.47-4.63 (m, 1H), 4.39 (d, J=11.7 Hz, 1H), 4.30 (d, J=12.3 Hz, 1H), 4.08 (d, J=7.3 Hz, 1H), 3.92 (d, J=12.9 Hz, 1H), 3.64-3.84 (m, 1H), 3.18-3.45 (m, 1H), 2.93-3.18 (m, 3H), 2.54 (d, J=6.7 Hz, 1H), 1.94-2.14 (m, 2H), 1.86 (br. s., 2H), 1.46 (d, J=8.2 Hz, 1H), 1.39 (br. s., 1H), 1.33 (br. s., 1H), 1.27 (s, 1H), 0.97-1.23 (m, 4H), 0.63 (br. s., 1H), 0.54 (br. s., 1H), 0.27-0.50 (m, 2H).
LC-MS: m/z 485.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.65 (d, J=5.3 Hz, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H), 6.20-6.35 (m, 1H), 5.51-5.65 (m, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.29-4.48 (m, 1H), 4.05-4.29 (m, 2H), 4.00 (br. s., 1H), 3.80 (br. s., 1H), 3.62-3.77 (m, 1H), 3.54 (br. s., 2H), 3.22 (d, J=12.6 Hz, 2H), 3.09 (t, J=10.9 Hz, 1H), 2.40-2.54 (m, 3H), 2.01-2.17 (m, 4H), 1.15-1.45 (m, 11H), 0.94-1.10 (m, 3H), 0.74-0.94 (m, 2H), 0.65 (br. s., 2H), 0.47 (br. s., 3H).
LC-MS: m/z 484.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.0 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J=3.8 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.45-5.62 (m, 1H), 4.88 (s, 1H), 4.64-4.74 (m, 1H), 4.54 (dt, J=8.8, 5.9 Hz, 1H), 4.33 (d, J=12.6 Hz, 1H), 4.18-4.29 (m, 1H), 4.03-4.15 (m, 1H), 3.60-3.90 (m, 1H), 3.09-3.39 (m, 2H), 2.94-3.09 (m, 1H), 2.66-2.78 (m, 1H), 2.25-2.60 (m, 3H), 2.21 (s, 3H), 2.01-2.14 (m, 2H), 1.51-1.68 (m, 1H), 1.43 (d, J=12.9 Hz, 1H), 1.00-1.16 (m, 2H), 0.87 (dd, J=7.9, 2.9 Hz, 2H), 0.25-0.65 (m, 4H)
LC-MS: m/z 498.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.67 (d, J=5.0 Hz, 1H), 7.60-7.71 (m, 1H), 7.40 (s, 1H), 7.21-7.27 (m, 1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.58 (d, J=10.9 Hz, 1H), 4.94-5.06 (m, 1H), 4.35-4.75 (m, 2.5H), 4.01-4.09 (m, 0.5H), 3.70-3.81 (m, 1.5H), 2.90-3.40 (m, 3.5H), 2.50-2.79 (m, 4H), 1.98-2.04 (m, 1H), 1.29-1.37 (m, 2H), 1.22 (dt, J=7.0, 3.5 Hz, 2H), 0.97-1.06 (m, 2H), 0.26-0.70 (m, 4H)
LC-MS: m/z 498.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.65 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.39 (s, 1H), 7.23 (d, J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz, 1H), 4.50-4.62 (m, 1H), 4.43 (d, J=12.9 Hz, 1H), 4.21-4.35 (m, 1H), 4.05-4.11 (m, 1H), 3.80-3.92 (m, 1.5H), 3.62-3.80 (m, 1.5H), 3.07-3.41 (m, 3H), 2.45-2.97 (m, 2H), 2.15-2.20 (m, 1H), 1.98-2.05 (m, 2H), 1.92 (dt, J=14.2, 6.9 Hz, 2H), 1.62 (d, J=7.3 Hz, 1H), 1.16-1.24 (m, 2H), 1.00 (dd, J=7.5, 3.4 Hz, 2H), 0.34-0.71 (m, 4H)
LC-MS: m/z 484.3 (M+H)+
1H NMR (400 MHz, MeOD) δ 8.08 (d, J=6.5 Hz, 1H), 7.80 (d, J=2.2 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.71 (dd, J=6.4, 2.3 Hz, 1H), 6.18-6.11 (m, 1H), 5.62 (dd, J=6.8, 5.5 Hz, 1H), 5.24 (s, 1H), 4.66 (d, J=7.0 Hz, 3H), 4.51 (d, J=13.1 Hz, 1H), 4.37 (s, 1H), 4.14-3.97 (m, 1H), 3.71 (dd, J=10.8, 4.4 Hz, 2H), 3.62 (s, 1H), 3.18-3.04 (m, 1H), 2.84 (s, 1H), 2.49 (d, J=6.5 Hz, 1H), 2.17-2.09 (m, 1H), 1.96 (s, 1H), 1.53-1.25 (m, 3H), 1.21-1.13 (m, 2H), 1.04 (dd, J=7.7, 3.4 Hz, 2H), 0.71-0.36 (m, 4H).
LC-MS: m/z 489.2 (M+H)+
1H NMR (400 MHz, D2O) δ 8.37 (d, J=5.0 Hz, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 6.74 (dd, J=17.5, 11.3 Hz, 1H), 6.04 (d, J=17.8 Hz, 1H), 5.51 (d, J=11.2 Hz, 1H), 4.47 (s, 1H), 4.35 (s, 2H), 3.91 (d, J=6.7 Hz, 3H), 3.82 (s, 1H), 3.56 (q, J=7.1 Hz, 2H), 3.20 (s, 1H), 2.78 (s, 1H), 2.71-2.63 (m, 1H), 1.92 (s, 1H), 1.55 (s, 4H), 1.18 (s, 2H), 0.89 (s, 1H), 0.45-0.46 (m, 2H), 0.37-0.22 (m, 2H).
LC-MS: m/z 568.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.07 (d, J=5.3 Hz, 1H), 7.81 (s, 1H), 7.02 (br. s., 1H), 6.71-6.84 (m, 1H), 6.55 (dd, J=17.6, 10.9 Hz, 1H), 6.38 (s, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.18-4.44 (m, 3H), 4.11 (q, J=7.0 Hz, 1H), 3.81-3.99 (m, 2H), 3.62-3.81 (m, 2H), 3.11 (d, J=12.9 Hz, 2H), 3.04 (m, 1H), 2.73 (d, J=6.5 Hz, 1H), 2.08-2.28 (m, 2H), 1.82-1.97 (m, 2H), 1.59 (dd, J=12.0, 7.9 Hz, 1H), 1.25 (t, J=7.0 Hz, 1H), 1.04-1.18 (m, 2H), 0.88-1.02 (m, 2H), 0.51-0.59 (m, 2H), 0.42-0.49 (m, 2H)
LC-MS: m/z 499.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.56 (s, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.11 (br, s, 1H), 5.79 (dd, J=7.3, 2.3 Hz, 1H), 5.58 (br. s., 1H), 5.26 (t, J=6.6 Hz, 1H), 4.71 (td, J=7.9, 6.2 Hz, 1H), 4.56 (m, 1H), 4.43 (d, J=12.3 Hz, 1H), 4.32 (d, J=12.6 Hz, 1H), 4.06 (d, J=9.1 Hz, 0.5H), 3.92 (d, J=12.3 Hz, 0.5H), 3.69-3.82 (m, 1H), 3.47 (s, 3H), 3.08-3.34 (m, 2H), 2.92-3.08 (m, 2.5H), 2.78-2.90 (m, 1.5H), 2.54 (d, J=7.3 Hz, 1H), 2.06-2.17 (m, 1H), 1.27 (s, 1H), 1.06-1.16 (m, 2H), 0.98-1.05 (m, 2H), 0.53-0.63 (m, 2H), 0.30-0.49 (m, 2H)
LC-MS: m/z 489.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.02 (d, J=4.4 Hz, 1H), 7.72 (s, 1H), 6.82 (d, J=5.3 Hz, 1H), 6.56 (dd, J=17.3, 10.9 Hz, 1H), 6.34 (s, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.49 (d, J=10.9 Hz, 1H), 4.40 (d, J=12.9 Hz, 1H), 4.29 (d, J=12.0 Hz, 1H), 4.11 (br. s., 1H), 3.80 (br. s., 2H), 3.16 (br. s., 2H), 2.90-3.11 (m, 1H), 2.25-2.45 (m, 5H), 1.56-1.73 (m, 4H), 1.20-1.48 (m, 4H), 1.07-1.20 (m, 2H), 0.82-1.07 (m, 2H).
LC-MS: m/z 485.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=4.7 Hz, 1H), 7.66 (s, 1H), 7.41 (s, 1H), 7.22-7.28 (m, 1H), 6.90 (dd, J=17.3, 10.9 Hz, 1H), 6.31 (d, J=17.3 Hz, 1H), 5.60 (d, J=10.9 Hz, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.43 (dd, J=12.9, 2.1 Hz, 1H), 4.14 (m, 2H), 3.72 (m, 1H), 3.43-3.63 (m, 2H), 3.22 (d, J=11.4 Hz, 2H), 3.01-3.16 (m, 2H), 2.06-2.11 (m, 1H), 1.79-2.09 (m, 1H), 1.65 (br. s., 1H), 1.40-1.53 (m, 1H), 1.17-1.25 (m, 2H), 0.96-1.08 (m, 2H), 0.66-0.75 (m, 2H), 0.39-0.61 (m, 2H)
LC-MS: m/z 483.7 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.3 Hz, 1H), 7.65 (s, 1H), 7.33-7.46 (m, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.5, 10.7 Hz, 1H), 6.24-6.39 (m, 1H), 5.57 (dd, J=10.9, 1.2 Hz, 1H), 5.01 (t, J=6.3 Hz, 1H), 4.56 (m, 1.5H), 4.44 (d, J=14.1 Hz, 1H), 3.79 (m, 1H), 3.22 (m, 1.5H), 2.70 (d, J=6.7 Hz, 1H), 2.49-2.65 (m, 3H), 1.90-2.14 (m, 4H), 1.35 (m, 1H), 1.21 (m, 3H), 0.92-1.08 (m, 2H), 0.48 (m, 4H)
LC-MS: m/z 498.7 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.64 (d, J=4.7 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd, J=17.6, 10.9 Hz, 1H), 6.18-6.36 (m, 1H), 5.49-5.62 (m, 1H), 4.67-4.71 (m, 0.5H), 4.54 (d, J=12.6 Hz, 1H), 4.36-4.46 (m, 1H), 4.28 (quin, J=6.5 Hz, 1H), 4.11 (d, J=7.9 Hz, 0.5H), 3.81-4.00 (m, 1.5H), 3.63-3.79 (m, 1.5H), 3.08-3.20 (m, 1H), 2.64-2.85 (m, 2H), 2.46-2.60 (m, 1H), 2.08-2.24 (m, 1H), 1.97-2.08 (m, 1H), 1.82-1.97 (m, 2H), 1.52-1.70 (m, 1H), 1.26-1.30 (m, 2H), 1.12-1.24 (m, 2H), 0.92-1.05 (m, 2H), 0.49-0.73 (m, 2H), 0.45 (m, 2H)
LC-MS: m/z 484.7 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.23 (s, 1H), 7.07 (dd, J=5.0, 1.2 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (dd, J=10.9, 1.2 Hz, 1H), 4.32 (d, J=12.9 Hz, 1H), 4.23 (dd, J=12.6, 2.1 Hz, 1H), 4.14 (m, 1H), 3.99 (br. s., 1H), 3.72 (br. s., 1.5H), 3.42-3.57 (m, 2.5H), 3.10-3.25 (m, 2H), 2.98-3.10 (m, 3H), 2.10-2.38 (m, 4H), 1.51-1.62 (m, 1H), 1.45 (dq, J=14.7, 7.3 Hz, 1H), 1.07-1.17 (m, 2H), 0.88 (dd, J=7.9, 3.2 Hz, 2H), 0.66 (br. s., 1H), 0.30-0.59 (m, 3H)
LC-MS: m/z 497.7 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.65 (d, J=5.3 Hz, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H), 6.20-6.35 (m, 1H), 5.51-5.65 (m, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.29-4.48 (m, 1H), 4.05-4.29 (m, 2H), 4.00 (br. s., 1H), 3.80 (br. s., 1H), 3.62-3.77 (m, 1H), 3.54 (br. s., 2H), 3.22 (d, J=12.6 Hz, 2H), 3.09 (t, J=10.9 Hz, 1H), 2.40-2.54 (m, 3H), 2.01-2.17 (m, 4H), 1.15-1.45 (m, 4H), 0.94-1.10 (m, 3H), 0.74-0.94 (m, 2H), 0.65 (br. s., 2H), 0.47 (br. s., 3H).
LC-MS: m/z 497.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 6.86 (dd, J=5.5, 1.1 Hz, 1H), 6.80 (s, 1H), 6.59 (dd, J=17.6, 10.9 Hz, 1H), 6.44 (s, 1H), 5.93 (d, J=17.5 Hz, 1H), 5.51 (d, J=10.9 Hz, 1H), 4.75-4.61 (m, 0.5H), 4.37 (d, J=12.8 Hz, 1H), 4.27 (d, J=12.6 Hz, 1H), 4.10 (d, J=7.2 Hz, 0.5H), 3.85 (d, J=10.0 Hz, 0.5H), 3.81-3.65 (m, 2.5H), 3.30 (dd, J=9.3, 5.7 Hz, 1H), 3.22-3.12 (m, 1H), 3.12-2.97 (m, 1H), 2.66-2.43 (m, 2H), 2.21-2.14 (m, 1H), 1.97 (dd, J=12.0, 6.2 Hz, 2H), 1.46 (dd, J=8.5, 6.8 Hz, 1H), 1.14 (dd, J=7.1, 4.0 Hz, 2H), 1.04 (ddd, J=9.5, 6.4, 3.0 Hz, 2H), 0.77-0.38 (m, 4H).
LC-MS: m/z 473.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=5.6 Hz, 1H), 7.83 (s, 1H), 7.19 (s, 1H), 6.87 (dd, J=5.7, 1.3 Hz, 1H), 6.60 (dd, J=17.5, 10.9 Hz, 1H), 6.44 (s, 1H), 5.95 (d, J=17.5 Hz, 1H), 5.54 (d, J=10.9 Hz, 1H), 4.55 (s, 0.5H), 4.39 (d, J=12.9 Hz, 1H), 4.28 (dd, J=12.7, 2.1 Hz, 1H), 4.19 (s, 1H), 4.00 (s, 0.5H), 3.75 (dd, J=30.5, 3.9 Hz, 2H), 3.55 (s, 2H), 3.33 (s, 1H), 3.18 (d, J=11.9 Hz, 1H), 3.05 (t, J=13.2 Hz, 1H), 2.47 (t, J=8.0 Hz, 2H), 2.21-2.16 (m, 1H), 2.12 (dt, J=15.4, 7.6 Hz, 2H), 1.28 (d, J=5.1 Hz, 1H), 1.19-1.10 (m, 2H), 1.05 (ddd, J=9.0, 6.6, 2.5 Hz, 2H), 0.78-0.41 (m, 4H).
LC-MS: m/z 513.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=5.6 Hz, 1H), 7.80 (s, 1H), 6.87 (dd, J=5.7, 1.2 Hz, 1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.43 (s, 1H), 5.95 (d, J=17.5 Hz, 1H), 5.54 (d, J=10.8 Hz, 1H), 4.65 (d, J=11.7 Hz, 0.4H), 4.41 (d, J=12.6 Hz, 1H), 4.30 (d, J=12.3 Hz, 1H), 4.09 (d, J=5.2 Hz, 0.6H), 3.91-3.59 (m, 1.5H), 3.34-3.10 (m, 1.5H), 3.09-2.94 (m, 1H), 2.74 (dt, J=15.5, 7.8 Hz, 1H), 2.52 (s, 2H), 2.25-2.12 (m, 3H), 1.98-1.82 (m, 2H), 1.82-1.63 (m, 2H), 1.28 (s, 1H), 1.19-1.09 (m, 2H), 1.04 (dt, J=6.9, 3.0 Hz, 2H), 0.78-0.34 (m, 4H).
LC-MS: m/z 483.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=5.4 Hz, 1H), 7.85 (s, 1H), 6.83 (dd, J=5.4, 1.3 Hz, 1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.41 (s, 1H), 6.39 (s, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.47 (d, J=11.0 Hz, 1H), 4.89 (s, 1H), 4.70 (dd, J=14.1, 7.8 Hz, 1H), 4.55 (dd, J=14.7, 5.8 Hz, 1H), 4.36 (d, J=12.8 Hz, 1H), 4.25 (dd, J=12.5, 1.8 Hz, 1H), 4.09 (dd, J=7.2, 2.6 Hz, 1H), 3.78 (ddd, J=23.5, 14.1, 6.1 Hz, 1.5H), 3.28 (s, 0.5H), 3.13 (d, J=12.4 Hz, 1H), 3.02 (dd, J=21.5, 9.8 Hz, 1H), 2.74 (ddd, J=14.2, 11.1, 8.0 Hz, 1H), 2.62-2.47 (m, 1H), 2.46-2.32 (m, 2H), 2.23-1.98 (m, 3H), 1.28 (d, J=4.8 Hz, 1H), 1.19-1.09 (m, 2H), 1.02 (ddd, J=9.4, 6.4, 3.0 Hz, 2H), 0.75-0.35 (m, 4H).
LC-MS: m/z 499.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=5.4 Hz, 1H), 7.84 (s, 1H), 6.84 (dd, J=5.4, 1.2 Hz, 1H), 6.59 (dd, J=17.5, 10.8 Hz, 1H), 6.46 (s, 1H), 6.41 (s, 1H), 5.91 (d, J=17.6 Hz, 1H), 5.47 (d, J=10.9 Hz, 1H), 4.69 (d, J=13.9 Hz, 0.5H), 4.46-4.33 (m, 1H), 4.28 (dd, J=15.4, 9.1 Hz, 2H), 4.11 (d, J=5.3 Hz, 0.5H), 3.98-3.83 (m, 1.5H), 3.75 (dt, J=22.2, 11.1 Hz, 1.5H), 3.40-3.09 (m, 2H), 3.09-2.93 (m, 1H), 2.83-2.47 (m, 2H), 2.47-2.29 (m, 0.5H), 2.26-2.12 (m, 2H), 2.11-1.99 (m, 0.5H), 1.93 (dt, J=13.7, 7.0 Hz, 2H), 1.28 (d, J=5.3 Hz, 1H), 1.19-1.09 (m, 2H), 1.02 (ddd, J=9.8, 6.6, 2.9 Hz, 2H), 0.77-0.32 (m, 4H).
LC-MS: m/z 499.3 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=6.1 Hz, 1H), 6.69 (dd, J=17.4, 10.9 Hz, 1H), 6.57 (s, 1H), 6.45 (s, 1H), 6.21 (d, J=17.6 Hz, 1H), 6.18-6.10 (m, 1H), 5.60 (d, J=11.1 Hz, 1H), 4.71 (d, J=13.2 Hz, 0.5H), 4.50-4.37 (m, 1.5H), 4.33-4.25 (m, 1H), 3.87 (d, J=13.1 Hz, 0.5H), 3.82-3.67 (m, 2H), 3.60 (d, J=10.2 Hz, 0.5H), 3.47 (dd, J=18.2, 7.7 Hz, 0.5H), 3.38 (d, J=4.2 Hz, 3H), 3.14 (ddd, J=13.3, 9.5, 5.2 Hz, 1.5H), 3.09-2.94 (m, 1H), 2.81-2.56 (m, 2H), 2.38 (s, 3H), 2.25 (dd, J=13.6, 6.4 Hz, 0.5H), 2.07 (ddd, J=15.8, 11.1, 6.8 Hz, 1.5H), 1.15-1.09 (m, 1H), 1.04 (dd, J=6.5, 2.9 Hz, 4H), 0.97 (dd, J=7.5, 5.0 Hz, 2H), 0.93 (d, J=6.8 Hz, 1.5H), 0.86 (d, J=6.8 Hz, 1.5H).
LC-MS: m/z 489.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=5.7 Hz, 1H), 6.70 (dd, J=17.4, 10.8 Hz, 1H), 6.50 (s, 1H), 6.33 (s, 1H), 6.16 (d, J=17.4 Hz, 1H), 5.74 (s, 1H), 5.48 (dd, J=10.8, 0.9 Hz, 1H), 4.69 (d, J=9.7 Hz, 0.5H), 4.41 (ddd, J=6.7, 6.1, 4.4 Hz, 1.5H), 4.27 (t, J=10.2 Hz, 1H), 4.00-3.86 (m, 2H), 3.76 (d, J=13.5 Hz, 0.5H), 3.60-3.52 (m, 1H), 3.50-3.44 (m, 1H), 3.17-3.05 (m, 2H), 3.01 (dd, J=11.6, 9.4 Hz, 0.5H), 2.61 (pd, J=11.7, 5.1 Hz, 2H), 2.38 (s, 3H), 2.33-2.22 (m, 0.5H), 2.11 (ddd, J=12.7, 9.3, 5.2 Hz, 1.5H), 1.11 (ddd, J=8.9, 6.6, 4.7 Hz, 1H), 1.05 (d, J=6.5 Hz, 4H), 0.97 (dt, J=7.8, 6.6 Hz, 2H), 0.93 (d, J=6.9 Hz, 1.5H), 0.86 (d, J=6.8 Hz, 1.5H).
LC-MS: m/z 475.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=5.3 Hz, 1H), 7.83 (s, 1H), 6.89-6.77 (m, 2H), 6.57 (dd, J=17.6, 10.8 Hz, 1H), 6.53-6.43 (m, 1H), 6.40 (s, 1H), 6.39-6.26 (m, 1H), 5.88 (d, J=17.5 Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 4.74-4.43 (m, 0.3H), 4.35 (t, J=11.7 Hz, 1H), 4.26 (d, J=12.5 Hz, 1H), 4.11-3.87 (m, 0.8H), 3.78 (dd, J=11.6, 5.5 Hz, 2H), 3.75-3.68 (m, 1H), 3.53 (m 0.5H), 3.45 (m 0.5H), 3.42-3.28 (m, 0.5H), 3.24-3.11 (m, 1.5H), 3.03 (td, J=12.6, 3.3 Hz, 1H), 2.49 (dd, J=12.5, 6.2 Hz, 2H), 2.22-2.15 (m, 1H), 1.45 (d, J=6.5 Hz, 1H), 1.17-1.08 (m, 2H), 1.00 (ddd, J=9.4, 6.5, 3.0 Hz, 2H), 0.73-0.32 (m, 4H).
LC-MS: m/z 485.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.7 Hz, 1H), 7.62 (s, 1H), 6.71 (dd, J=17.4, 10.8 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 6.45 (dd, J=5.7, 2.2 Hz, 1H), 6.19 (d, J=17.2 Hz, 1H), 5.90 (s, 1H), 5.48 (d, J=11.2 Hz, 1H), 4.90 (s, 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.23 (dd, J=31.3, 14.0 Hz, 2.5H), 3.94 (s, 2H), 3.74 (d, J=13.6 Hz, 0.5H), 3.57 (t, J=11.0 Hz, 0.5H), 3.29 (dd, J=10.5, 6.5 Hz, 1H), 3.15 (dd, J=23.7, 11.6 Hz, 1H), 3.09-2.99 (m, 0.5H), 2.62 (m, J=34.8, 15.8 Hz, 2H), 2.12 (td, J=8.1, 4.1 Hz, 1H), 1.43 (d, J=6.4 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.13 (dd, J=7.2, 4.2 Hz, 2H), 1.03 (ddd, J=10.0, 6.4, 3.3 Hz, 2H).
LC-MS: m/z 447.6 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=5.9 Hz, 1H), 7.61 (s, 1H), 6.72 (dd, J=17.5, 10.9 Hz, 1H), 6.62 (s, 1H), 6.53 (d, J=4.4 Hz, 1H), 6.24 (d, J=17.4 Hz, 1H), 5.53 (d, J=10.9 Hz, 1H), 4.92 (s, 1H), 4.55 (d, J=16.6 Hz, 1H), 4.25 (t, J=11.9 Hz, 2H), 4.17 (d, J=13.8 Hz, 1H), 3.82 (d, J=8.4 Hz, 1H), 3.76 (t, J=6.2 Hz, 2H), 3.58 (d, J=12.3 Hz, 1H), 3.39 (s, 3H), 3.30 (d, J=13.0 Hz, 1H), 3.15 (t, J=11.7 Hz, 1H), 3.06 (d, J=12.2 Hz, 1H), 2.73 (ddd, J=22.9, 14.3, 6.7 Hz, 1H), 2.64-2.53 (m, 1H), 2.09 (td, J=7.9, 4.1 Hz, 1H), 1.40 (d, J=5.7 Hz, 2H), 1.30 (d, J=7.1 Hz, 2H), 1.13 (dd, J=6.8, 4.1 Hz, 2H), 1.02 (dd, J=7.6, 3.3 Hz, 2H).
LC-MS: m/z 447.2 (M+H)+
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=4.9 Hz, 1H), 7.59 (s, 1H), 6.53 (s, 1H), 6.50 (s, 1H), 6.00 (s, 1H), 4.91 (s, 1H), 4.55 (d, J=10.6 Hz, 1H), 4.29 (d, J=11.2 Hz, 2H), 4.20 (d, J=12.9 Hz, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.73 (dt, J=9.5, 5.8 Hz, 2H), 3.57 (t, J=11.0 Hz, 1H), 3.39 (s, 3H), 3.30 (d, J=12.0 Hz, 1H), 3.15 (t, J=11.8 Hz, 1H), 3.07 (d, J=12.0 Hz, 1H), 2.83-2.65 (m, 1H), 2.60 (dd, J=13.4, 7.5 Hz, 1H), 2.07 (ddd, J=12.6, 7.0, 4.8 Hz, 1H), 1.40 (d, J=6.4 Hz, 2H), 1.34-1.27 (m, 1H), 1.13 (s, 2H), 1.09-0.99 (m, 2H).
LC-MS: m/z 455.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.69 (d, J=5.0 Hz, 1H), 7.31-7.38 (m, 1H), 7.23 (s, 1H), 7.07 (d, J=4.1 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.21-6.40 (m, 2H), 6.06 (d, J=2.9 Hz, 1H), 5.57 (d, J=11.4 Hz, 1H), 4.22 (d, J=12.6 Hz, 2H), 2.93-3.18 (m, 4H), 2.72 (br. s., 2H), 2.21 (s, 3H), 1.33-1.62 (m, 2H), 1.03-1.33 (m, 3H), 0.87 (dd, J=7.9, 3.2 Hz, 2H), 0.44 (br. s., 4H).
LC-MS: m/z 508.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.69 (d, J=4.7 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J=4.4 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.12-6.41 (m, 1H), 5.41-5.69 (m, 1H), 4.19-4.48 (m, 2H), 3.96-4.19 (m, 1H), 3.80 (br. s., 1H), 3.15 (br. s., 2H), 3.04 (br. s., 1H), 2.28-2.49 (m, 2H), 2.21 (s, 3H), 1.86 (br. s., 1H), 1.80 (br. s., 3H), 1.47-1.72 (m, 8H), 1.11 (br. s., 4H), 0.73-1.00 (m, 3H), 0.60 (br. s., 1H), 0.55 (br. s., 1H), 0.23-0.50 (m, 2H).
LC-MS: m/z 510.7 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.25 (dd, J=5.1, 1.6 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz, 1H), 6.30 (d, J=16.7 Hz, 1H), 5.58 (d, J=11.2 Hz, 1H), 4.56 (d, J=12.9 Hz, 1H), 4.35-4.49 (m, 1H), 3.99-4.20 (m, 3H), 3.71-3.84 (m, 1H), 2.99-3.22 (m, 2H), 2.53 (d, J=5.9 Hz, 1H), 2.00-2.07 (m, 3H), 1.66 (d, J=12.3 Hz, 3H), 1.52 (s, 18H), 1.18-1.25 (m, 2H), 0.98-1.06 (m, 2H), 0.62 (br. s., 1H), 0.56 (br. s., 1H), 0.47 (d, J=5.0 Hz, 2H)
LC-MS: m/z 650.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.55 (d, J=5.5 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.80 (t, J=7.3 Hz, 1H), 7.71 (s, 1H), 7.63 (t, J=7.7 Hz, 1H), 6.36 (d, J=5.5 Hz, 1H), 4.52 (d, J=13.3 Hz, 1H), 4.41 (d, J=13.8 Hz, 1H), 4.15 (br. s., 1H), 3.69-3.86 (m, 2H), 3.12-3.35 (m, 4H), 2.01-2.13 (m, 1H), 1.33-1.35 (m, 1H), 1.12-1.21 (m, 2H), 0.95-1.07 (m, 2H), 0.45-0.73 (m, 4H)
LC-MS: m/z 521.2 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.58-8.68 (m, 1H), 7.72-7.80 (m, 1H), 6.90-7.01 (m, 1H), 6.53-6.66 (m, 1H), 6.35-6.48 (m, 1H), 6.27 (s, 1H), 5.62 (dd, J=10.5, 1.3 Hz, 1H), 4.90 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.11-4.34 (m, 2.5H), 3.93 (br. s., 2H), 3.74 (d, J=13.6 Hz, 0.5H), 3.50-3.65 (m, 0.5H), 3.45 (br. s., 0.5H), 3.23-3.32 (m, 1H), 3.10-3.20 (m, 0.5H), 2.98-3.09 (m, 0.5H), 2.48-2.76 (m, 2H), 2.08-2.16 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.10-1.20 (m, 2H), 0.97-1.09 (m, 2H)
LC-MS: m/z 434.3 (M+H)+
1H NMR (CHLOROFORM-d) δ 7.97 (s, 1H), 6.89 (s, 1H), 6.66 (dd, J=17.3, 10.5 Hz, 1H), 6.52 (d, J=17.8 Hz, 1H), 5.74 (d, J=10.5 Hz, 1H), 5.41 (br. s., 2H), 4.66 (d, J=12.5 Hz, 1H), 4.52 (d, J=12.5 Hz, 1H), 3.16-4.28 (m, 5H), 2.33-2.49 (m, 1H), 1.72 (br. s., 2H), 1.21-1.26 (m, 2H), 0.98-1.15 (m, 4H), 0.82 (dd, J=7.8, 2.3 Hz, 2H), 0.63 (br. s., 1H), 0.36-0.58 (m, 3H)
LC-MS: m/z 456.4 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.24 (d, J=5.9 Hz, 1H), 7.62 (s, 1H), 6.70 (dd, J=17.3, 10.9 Hz, 1H), 6.61 (d, J=2.1 Hz, 1H), 6.49 (d, J=5.9 Hz, 1H), 6.19 (d, J=17.6 Hz, 1H), 6.04 (br. s., 1H), 5.53 (d, J=10.9 Hz, 1H), 5.27 (quin, J=6.7 Hz, 1H), 4.69-4.79 (m, 1H), 4.42-4.58 (m, 2H), 4.35 (d, J=12.9 Hz, 1H), 4.09 (d, J=8.8 Hz, 1H), 3.95 (d, J=13.8 Hz, 1H), 3.67-3.82 (m, 1H), 2.75-3.34 (m, 5H), 2.55 (d, J=9.1 Hz, 1H), 2.08 (td, J=8.1, 4.0 Hz, 1H), 1.33 (br. s., 1H), 1.10-1.18 (m, 2H), 1.03 (dd, J=7.8, 3.4 Hz, 2H), 0.63 (br. s., 1H), 0.55 (br. s., 1H), 0.47 (d, J=5.9 Hz, 2H)
LC-MS: m/z 485.6 (M+H)+
1H NMR (CHLOROFORM-d) δ 8.66 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.35-7.46 (m, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.88 (dd, J=17.5, 10.7 Hz, 1H), 6.21-6.36 (m, 1H), 5.49-5.61 (m, 1H), 5.27 (quin, J=6.6 Hz, 1H), 4.72 (td, J=7.9, 6.2 Hz, 1H), 4.50-4.65 (m, 2H), 4.44 (d, J=12.9 Hz, 1H), 4.09 (d, J=8.2 Hz, 0.6H), 3.84-4.02 (m, 0.7H), 3.74 (t, J=12.0 Hz, 0.7H), 3.25 (br. s., 1H), 2.91-3.23 (m, 3.5H), 2.55-2.9 (m, 2.5H), 2.55 (d, J=8.8 Hz, 1H), 1.97-2.11 (m, 1H), 1.33 (br. s., 1H), 1.18-1.26 (m, 2H), 0.94-1.07 (m, 2H), 0.63 (br. s., 1H), 0.56 (br. s., 1H), 0.47 (br. s., 2H)
LC-MS: m/z 470.2 (M+H)+
1H NMR (CHLOROFORM-d) δ: 8.63 (d, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.86 (dd, J=17.5, 10.7 Hz, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.54 (d, J=10.9 Hz, 1H), 4.53 (d, J=12.9 Hz, 1H), 4.41 (d, J=12.6 Hz, 1H), 4.00-4.22 (m, 1H), 3.85 (d, J=6.5 Hz, 3H), 3.62-3.77 (m, 2H), 3.08-3.29 (m, 3H), 2.31-2.60 (m, 2H), 1.83-2.11 (m, 5H), 1.68-1.83 (m, 1H), 1.46-1.58 (m, 1H), 1.20 (dt, J=7.3, 3.6 Hz, 2H), 0.93-1.07 (m, 2H), 0.49-0.76 (m, 2H), 0.43 (br. s., 2H)
LC-MS: m/z 498.7 (M+H)+
Having thus described several aspects of several embodiments, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and drawings are by way of example only.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2011 1 0172169 | Jun 2011 | CN | national |
This application is a continuation of U.S. Ser. No. 14/126,763, filed Mar. 10, 2014, which is a national stage application under 35 U.S.C. §371 of International Application No. PCT/CN2012/000841, filed Jun. 18, 2012, published as International Publication No. WO 2012/171337 on Dec. 20, 2012, which claims priority from Chinese Patent Application No. CN 201110172169.1, filed Jun. 17, 2011, U.S. Ser. No. 61/509,071, filed Jul. 18, 2011 and U.S. Ser. No. 61/584,210, filed Jan. 6, 2012, each of which is incorporated by reference in its entirety.
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| 2013107291 | Jul 2013 | WO |
| 2013107405 | Jul 2013 | WO |
| 2013133367 | Sep 2013 | WO |
| 2014015422 | Jan 2014 | WO |
| 2015003360 | Jan 2015 | WO |
| Entry |
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| Partial Machine Translation for WO 2010007756 (Jan. 2010). |
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| STN File CA, Registry No. 1023444-33-8, entered STN on May 29, 2008, Chemical Abstracts Index Name “Benzenesulfonamide, 3-[[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl]-N-(4-butylphenyl)-4-methyl-”. |
| STN File CA, Registry No. 1090629-29-0, entered STN on Dec. 28, 2008, Chemical Abstracts Index Name “Benzenesulfonamide, 3[[4-(2,5-dimethoxyphenyl)methyl]-1-piperazinyl]carbonyl]-N-(4-methoxypheny1)-4-methyl-”. |
| STN File CA, Registry No. 134538-28-6, entered STN on Jun. 28, 1991, Chemical Abstracts Index Name “1H-Pyrano[3,4-c]pyridine-5-carbonitrile, 3,4-dihydro-3,3-dimethyl-6[4-(1-oxobutyl)-1-piperazinyl]-8-phenyl-”, disclosed in Paronikyan et al. Armyanskii Khimicheskii Zhurnal, 1990, vol. 43, No. 8. |
| STN File CA, Registry No. 134538-29-7, entered STN on Jun. 28, 1991, Chemical Abstracts Index Name “1H-Pyrano[3,4-c]pyridine-5-carbonitrile, 3,4-dihydro-3,3-dimethyl-6[4-(2-methyl-1-oxopropyl)-1-piperazinyl]-8-phenyl-”, disclosed in Paronikyan et al. Armyanskii Khimicheskii Zhurnal, 1990, vol. 43, No. 8. |
| STN File CA, Registry No. 134538-30-0, entered STN on Jun. 28, 1991, Chemical Abstracts Index Name “1H-Pyrano[3,4-c]pyridine-5-carbonitrile,6-(4-benzoyl-1-piperazinyl)-3,4-dihydro-3,3-dimethyl-8-phenyl-”, disclosed in Paronikyan et al. Armyanskii Khimicheskii Zhurnal, 1990, vol. 43, No. 8. |
| STN File CA, Registry No. 134538-31-1, entered STN on Jun. 28, 1991, Chemical Abstracts Index Name “1H-Pyrano[3,4-c]pyridine-5-carbonitrile, 6-[4-(2-furanylcarbonyl)-1-piperazinyl]-3,4-dihydro-3,3-dimethyl-8-phenyl-”, disclosed in Paronikyan et al. Armyanskii Khimicheskii Zhurnal, 1990, vol. 43, No. 8. |
| STN File CA, Registry No. 380466-24-0 entered STN on Jan. 4, 2002, Chemical Abstracts Index Name “Benzenesulfonamide, N-methyl-N-phenyl-3-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]”. |
| STN File CA, Registry No. 713505-78-3, entered STN on Jul. 21, 2004, Chemical Abstracts Index Name “1-Piperazinecarboxylic acid, 4[4-methyl-3-[(phenylamino)sulfonyl]benzoyl], ethyl ester”. |
| STN File CA, Registry No. 736168-79-9 entered STN on Aug. 31, 2004, Chemical Abstracts Index Name “Benzenesulfonamide, 3,4-difluoro-N-[3-334-(phenylmethyl0-1-piperazinyl]carbonyl]phenyl”. |
| STN File CA, Registry No. 847757-57-7, entered STN on Apr. 1, 2005, Chemical Abstracts Index Name “Benzenesulfonamide, 3-[[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl]-N-(4-ethoxyphenyl)-N,4-dimethyl-” or “Piperazine, 1-(1,3-benzodioxol-5-ylmethyl)-4-[5-[[(4-ethoxyphenyl)methylamino]sulfonyl]-2-methylbenzoyl]-”. |
| STN Registry, L23 Answer 2 of 3 (CAS No. 1032450-21-7), Database: ASINEX Ltd.,Entered STN: Jul. 3, 2008 (Jul. 3, 2008). |
| STN Registry. L23 Answer 1 of 3 (CAS No. 1038821-72-5),Database: ChemDB (University of California Irvine), Entered STN: Aug. 5, 2008 (Aug. 5, 2008). |
| STN Tokyo, Registry No. 1001833-18-6, Entered STN on Feb. 6, 2008, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [(4-methyl-I-piperazinyl)carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 1030142-35-8, Entered STN on Jun. 24, 2008, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-[(5-methyl-3-isoxazolyl)methyl]-I-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 1031531-78-8, Entered STN on Jun. 29, 2008 Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, N-4[4-[(4-acetyl-1-piperazinyl)carbonyl]phenyl]-2,3-dihydro-”. |
| STN Tokyo, Registry No. 1057928-35-4, Entered STN on Oct. 7, 2008, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-(2-pyridinyl)-I-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 1240875-006, entered STN on Sep. 14, 2010, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4-[[4-(2-thiazolyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 748791-86-8, Entered STN on Sep. 21, 2004, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, N-[4- [[4-(2-furanylcarbonyl)-1-piperazinyl]carbonyl]phenyl]-2,3-dihydro-”. |
| STN Tokyo, Registry No. 878469-24-0, Entered STN on Mar. 29, 2006, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4-[[4-(2-pyrimidinyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 878474-39-6, Entered STN on Mar. 29, 2006, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4 [(4-phenyl-1-piperazinyl)carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 878590-33-1, Entered STN on Mar. 30, 2006, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4-{{4-(tetrahydro-2-furanyl)methyl]-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 878943-66-9 Entered STN on Apr. 2, 2006, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 3,4-dihydro-N-[[4-(2-pyrimidinyl)-1-piperazinyl)carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 878956-06-0, Entered STN on Apr. 2, 2006, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, N-[4- [[4-(cyclopropylcarbonyl)-1-piperazinyl]carbonyl]phenyl]-2,3-dihydro-”. |
| STN Tokyo, Registry No. 9200679-46-5, Entered STN on Feb. 13, 2007, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-(4-pyridinyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 920822-52-2, Entered STN on Feb. 14, 2007, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, N-[4- [[4-(4-fluoropheyl)-1-piperazinyl]carbonyl]phenyl]-2,3dihydro-”. |
| STN Tokyo, Registry No. 920824-56-2, Entered STN on Feb. 14, 2007, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-(3-thienylmethyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 920847-34-3, Entered STN on Feb. 14, 2007, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-(2-methylphenyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 920875-39-4, Entered STN on Feb. 14, 2007, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-(2-hydroxyphenyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 920902-88-1, Entered STN on Feb. 14, 2007, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-(2-thienylmethyl)-I-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 920921-09-1 Entered STN on Feb. 14, 2007, Chemical Abstracts Index Name “2H-1, 5-Benzodioxepin-7-sulfonamide, 3,4-dihydro-N-[4- [[4-(2pyridinyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 920924-42-1, Entered STN on Feb. 14, 2007, Chemical Abstracts Index Name “1,4-Benzodioxin-6-sulfonamide, 2,3-dihydro-N-[4- [[4-(2-pyridinylmethyl)-1-piperazinyl]carbonyl]phenyl]-”. |
| STN Tokyo, Registry No. 941220-77-5, Entered STN on Jul. 4, 2007, Chemical Abstracts Index Name “2H-1, 5-Benzodioxepin-7-sulfonamide, 3,4-dihydro-N-[4-[(4-methyl-I-piperazinyl)carbonyl]phenyl]-”. |
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| Number | Date | Country | |
|---|---|---|---|
| 20160229876 A1 | Aug 2016 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61584210 | Jan 2012 | US | |
| 61509071 | Jul 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14126763 | US | |
| Child | 15130358 | US |
