compound of formula ii, use of the compound and pharmaceutical composition comprising said compound

专利摘要:
THERAPEUTIC ACTIVE COMPOSITIONS AND THEIR METHOD OF USE. Methods of treating a cancer characterized by the presence of an IDH1 mutant allele comprising administering to a subject in need thereof a compound described herein are provided.
公开号:BR112013001122B1
申请号:R112013001122-0
申请日:2011-07-15
公开日:2021-06-08
发明作者:Janeta Popovici-Muller；Francesco G. Salituro；Jeffrey O. Saunders；Jeremy M Travins；Shunqi Yan
申请人:Agios Pharmaceuticals, Inc；
IPC主号:

专利说明:

BACKGROUND OF THE INVENTION
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (ie, α-ketoglutarate). These enzymes belong to two distinct subclasses, one uses NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been described: three NAD-dependent (+) isocitrate dehydrogenases, which are located in 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. This contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in NADPH regeneration 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 alpha-hydroxylation of pitanic acid. The cytoplasmic enzyme plays a significant role in the production of cytoplasmic NADPH.
The human IDH1 gene encodes a 414 amino acid protein. The nucleotide and amino acid sequences for human IDH1 can be found as entries in GenBank NM_005896.2 and NP_005887.2 respectively. Nucleotide and amino acid sequences for IDH1 are also described in, for example, Nekrutenko et al., Mol. Biol. Evolution 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 (DEC-2008) for UniProtKB; Kullmann et al., Submitted (JUN-1996) to EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science 314:268-274(2006).
Non-mutant IDH1, eg wild type, catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, reducing NAD+ (NADP+) to NADP (NADPH), for example, in the direct reaction: Isocitrate + NAD+ (NADP+) → α-KG + CO2 + NADH (NADPH) + H+. IDH1 mutations present in certain cancer cells have been found to result in a novel ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG production is believed to contribute to cancer formation and progression (Dang, L et al, Nature 2009, 462:739-44).
Inhibition of the mutant IDH1 and its new activity is therefore a potential therapeutic treatment for cancer. In this regard, there is a continuing need for mutant IDH1 inhibitors having new alpha hydroxyl activity. SUMMARY OF THE INVENTION
Described here are methods of treating a cancer characterized by the presence of a mutant allele of IDH1. The methods comprise the step of administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:
V and W are independently =O or CF3;
R1 is selected from C2-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), carbocyclyl, -(C1-C2 alkylene)-(carbocyclyl), aryl, -(C1-C2 alkylene)- (aryl), -(C1-C2 alkylene)-(heteroaryl), and -(C1-C2 alkylene)-(heterocyclyl);
R2 is selected from C4-C8 alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(C1-C4 alkylene)-(aryl), and -(C1-C4 alkylene)-(heteroaryl);
R3 is selected from C2-C6 alkyl optionally substituted by =O or -OH; C2-C6 alkenyl; -(C1-C3 alkylene)-O-(C1-C3 alkyl); carbocyclyl; aryl, heterocyclyl, heteroaryl, -(C1C2 alkylene)-(carbocyclyl), -(C1-C2 alkylene)-(aryl), -(C1-C2 alkylene)-(heterocyclyl), and -(C1-C2 alkylene)-( heteroaryl); R4 is selected from -CF3, -CH2-O-CH3 and -R5-R6-R7, where:
R5 is selected from a binding; straight or branched C1-C3 alkyl wherein a methylene moiety in the alkyl of R5 is optionally substituted by -O-, -S- or -S(O); and C2C3 alkenyl or alkynyl;
R6 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-S(O)1-2-, -S(O)1-2-NH-, and tetrazolyl; R7 is carbocyclyl, aryl, heterocyclyl, or heteroaryl; R8 is selected from hydrogen and C1-C4 alkyl; or R8 and R1 are taken together with a nitrogen atom to form a 5-12 membered heterocyclyl; and
R9 is selected from hydrogen and C1-C4 alkyl; or R9 and R2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; or wherein any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents.
The compound of formula I inhibits mutant IDH1, particularly mutant IDH1 having novel alpha hydroxyl activity. Also described herein are pharmaceutical compositions comprising a compound of formula I. DETAILED DESCRIPTION OF THE INVENTION
This invention is not limited in its application to the details of construction and arrangement of components set out in the following description or illustrated in the drawings. The invention is capable of other modalities and of being practiced or being carried out in various ways. Furthermore, the phraseology and terminology used herein is for the purpose of description and should not be considered limiting. The use of "including", "comprising", or "having", "containing", "involving" and variations thereof herein is intended to cover the items listed below and equivalents thereof as well as additional items. Definitions:
The term "halo" or "halogen" refers to any fluorine, chlorine, bromine or iodine radical. The term "alkyl" refers to a hydrocarbon chain which may be a straight or branched chain, containing the indicated number of carbon atoms. For example, C1-C12 alkyl indicates that the group can 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 hydrogen atoms 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, for example, -CH2-, -CH2CH2-, and -CH2CH2CH2-.
The term "alkenyl" refers to a straight or branched hydrocarbon chain containing from 2-12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, among others, 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 from 2-12 carbon atoms and characterized by one or more triple bonds. Examples of alkynyl groups include, among others, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons can 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 alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).
The term "carbocyclyl" refers to a monocyclic and bicyclic, tricyclic hydrocarbon ring system that is not fully aromatic, where any ring atom capable of substitution may be substituted by one or more substituents. A carbocyclyl can be fully or partially saturated. A bicyclic or tricyclic carbocyclyl can contain one (in the case of a bicycle) or up to two (in the case of a tricycle) aromatic rings, provided that at least one ring in the carbocyclyl is non-aromatic. Unless otherwise noted, any ring atom capable of substitution in a carbocyclyl may be substituted by one or more substituents.
The term "aryl" refers to a fully aromatic monocyclic, bicyclic and tricyclic hydrocarbon ring system. Examples of aryl fractions are phenyl, naphthyl and anthracenyl. Unless otherwise noted, any ring atom in an aryl may be replaced by one or more substituents.
The term "cycloalkyl" as used herein refers to a saturated cyclic, bicyclic, tricyclic or polycyclic hydrocarbon group. Unless otherwise noted, any ring atom may be substituted by one or more substituents. Cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, among others, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl. Unless otherwise noted, any ring atom may be substituted by one or more substituents.
The term "heterocyclyl" refers to a monocyclic and bicyclic or tricyclic ring structure, which is not fully aromatic and includes from one to four heteroatoms independently selected from N, O or S in one or more of the rings. A heterocyclyl can be fully or partially saturated. A bicyclic or tricyclic heterocyclyl may contain one (in the case of a bicycle) or up to two (in the case of a tricycle) aromatic rings, provided that at least one ring in the heterocyclyl is non-aromatic. Unless otherwise noted, any ring atom capable of substitution may be replaced by one or more substituents. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, fenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoline, indazole, , quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, thiolazan, pyroxazine , piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinone, sultams, sultones, and the like.
The term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O , N or S, where each ring in a heteroaryl is fully aromatic. Unless otherwise noted, any ring atom capable of substitution in a heteroaryl may be substituted by one or more substituents. The terms "hetaroalkyl" and "heteroaralkyl", as used herein, refer to an alkyl group substituted by a heteroaryl group. The ring heteroatoms of the compounds provided herein include N-O, S(O) and S(O) 2 .
The term "substituted" refers to the replacement of one hydrogen atom by another moiety. Typical substituents include alkyl (eg straight or branched chain alkyl C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12), cycloalkyl, haloalkyl (eg perfluoroalkyl such as CF3), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (eg perfluoroalkoxy such as OCF3), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkylamino, SO3H, sulfate , phosphate, methylenedioxy (-O-CH2-O-: where oxygens are attached to the vicinal atoms), ethylenedioxy, oxo (not a substituent in heteroaryl), thioxo (eg, C=S) (not a substituent in heteroaryl) , imino (alkyl, aryl, aralkyl), S(O)n alkyl (where n is 0-2), S(O)n aryl (where n is 0-2), S(O)n heteroaryl (where n is 0-2), S(O)n heterocyclyl (where n is 0-2), amine (mono, di, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl) , aryl, heteroaryl), amide (m ono, di, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl and combinations thereof), sulfonamide (mono, di, alkyl, aralkyl, heteroaralkyl and combinations thereof). In one aspect, the substituents on a group are independently any single or any subset of the aforementioned substituents.
In another aspect, a substituent can be replaced by any of the above substituents. As used herein, the term "elevated 2HG levels" means 10%, 20%, 30%, 50%, 75%, 100%, 200%, 500% or more so 2HG is present in a subject that does not have an allele. mutant of IDH1. The term "elevated 2HG levels" can 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 "body fluid" includes one or more of amniotic fluid around a fetus, aqueous humor, blood (eg, blood plasma), serum, cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculation, interstitial fluid, lymph, breast milk, mucus (eg, nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal discharge, or vomiting.
As used herein, the terms "inhibit" or "prevent" include partial or total inhibition and prevention. An inhibitor can partially or totally inhibit.
The term "treat" means to reduce, suppress, attenuate, slow down, arrest, or stabilize the development or progression of a cancer (eg, a cancer outlined here), lessen the severity of the cancer, or ameliorate the symptoms associated with 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 that is effective, upon single or multiple dose administration to a subject, in treating a cell. , or in curing, mitigating, alleviating or ameliorating a subject with a disorder beyond what was expected in the absence of such treatment.
As used herein, the term "subject" is intended to include both human and non-human animals. Exemplary human subjects include a human patient having a disorder, for example, 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, domestic or agriculturally useful animals, e.g., sheep, dog, cat. , cow, pig, etc. Compounds
ou um sal farmaceuticamente aceitável do mesmo, em que: V e W são independentemente =O ou CF3;A compound with formula A is provided: or a pharmaceutically acceptable salt thereof, wherein: V and W are independently =O or CF3;
R1 is selected from C2-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), carbocyclyl, -C1-C2 alkylene)-(carbocyclyl), aryl, -(C1-C2 alkylene)-( aryl), -(C1-C2 alkylene)-heteroaryl), and -C1-C2 alkylene)-(heterocyclyl);
R2 is selected from C4-C8 alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(C1-C4 alkylene)-aryl), and -(C1-C4 alkylene)-(heteroaryl); R3 is selected from C2-C6 alkyl optionally substituted by =O or -OH; C2-C6 alkenyl; -C1-C3 alkylene)-O-(C1-C3 alkyl); carbocyclyl; aryl; heterocyclyl; heteroaryl; -(C1C2 alkylene)-carbocyclyl); -(C1-C2 alkylene)-(aryl); -(C1-C2 alkylene)-(heterocyclyl); and -C1-C2 alkylene)-(heteroaryl); R4 is selected from -CF3, -CH2-O-CH3, -CH2Cl, -C(R11)-N(R11)-C(O)-O-(C1-C4 alkyl) and -R5-R6-R7, in that: R5 is selected from a binding; straight or branched C1-C3 alkyl wherein a methylene moiety in the alkyl of R5 is optionally substituted by -O-, -S-, -S(O)- or -SO)2-; and C2-C3 alkenyl or alkynyl; R6 is selected from a bond, -N(R11)-C(O)-, -C(O)-N(R11)-, -N(R11)-S(O)1-2-, -S(O )1-2-N(R11)-, -NH-, -N(C1-C3 alkyl)-, and tetrazolyl; R7 is carbocyclyl, aryl, heterocyclyl, or heteroaryl; R8 is selected from hydrogen and C1-C4 alkyl; or R8 and R1 are taken together with a nitrogen atom to form a 5-12 membered heterocyclyl; R9 is selected from hydrogen and C1-C4 alkyl; or R9 and R2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; and each R11 is independently hydrogen or methyl, wherein any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents; and in which any hydrogen atom is replaced by deuterium.
(I R3 (I), ou um sal farmaceuticamente aceitável do mesmo, em que: V e W são independentemente =O ou CF3;In one embodiment, the compound has formula I: (I R3 (I), or a pharmaceutically acceptable salt thereof, wherein: V and W are independently =O or CF3;
R1 is selected from C2-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), carbocyclyl, -(C1-C2 alkylene)-(carbocyclyl), aryl, -(C1-C2 alkylene)- (aryl), -(C1-C2 alkylene)-(heteroaryl), and -(C1-C2 alkylene)-(heterocyclyl); R2 is selected from C4-C8 alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(C1-C4 alkylene)-(aryl), and -(C1-C4 alkylene)-(heteroaryl); R3 is selected from C2-C6 alkyl optionally substituted by =O or -OH; C2-C6 alkenyl; -(C1-C3 alkylene)-O-(C1-C3 alkyl); carbocyclyl; aryl, heterocyclyl, heteroaryl, -(C1C2 alkylene)-(carbocyclyl), -(C1-C2 alkylene)-(aryl), -(C1-C2 alkylene)-(heterocyclyl), and -(C1-C2 alkylene)-( heteroaryl); R4 is selected from -CF3, -CH2-O-CH3 and -R5-R6-R7, wherein: R5 is selected from a bond; straight or branched C1-C3 alkyl wherein a methylene moiety in the alkyl of R5 is optionally substituted by -O-, -S- or -S(O); and C2C3 alkenyl or alkynyl; R6 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-S(O)1-2-, -S(O)1-2-NH-, and tetrazolyl; R7 is carbocyclyl, aryl, heterocyclyl, or heteroaryl; R8 is selected from hydrogen and C1-C4 alkyl; or R8 and R1 are taken together with a nitrogen atom to form a 5-12 membered heterocyclyl; and R9 is selected from hydrogen and C1-C4 alkyl; or R9 and R2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; or wherein any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents. In a form of formula A or I, V is CF3 and W is =O. In another embodiment, W is CF3 and V is =O.
Também é fornecido um composto com fórmula I-b, ou um sal farmaceuticamente aceitável do mesmo, em que R1, R2, R3, R4, R8 e R9 é como definido na fórmula A. Em outra modalidade, qualquer carbociclil, aril, heterociclil ou heteroaril na fórmula A, I, I-a ou I-b é opcionalmente substituído por um ou mais substituintes independentemente selecionados de =O, -C(O)-(C1-C3 alquil), -C(O)-N(R10)2, -C(O)-O-(C1-C3 alquil), -C1-C4 alcoxi, -C1-C4 alquil, -C1-C4 haloalquil, -C2-C4 alquenil ou alquinil, -C3-C8 cicloalquil, halo, morfolinometil, morfolinosulfonil, morfolinil, -N(R10)2, -NH-C(O)-(C1-C3 alquil), -O-CH2-C(O)-N(R10)2, -OH, -O-fenil, fenil, -S(O)2-piperidin-1-il, e tetrazolil; em que cada R10 é independentemente selecionado de hidrogênio, C1-C3 alquil, e C3-C8 cicloalquil; e qualquer parte cicloalquil, fenil ou piperidinil de um substituinte é ainda opcionalmente substituída com um ou mais substituintes independentemente selecionados de halo, C1-C3 alquil, CF3, -NH2, e C1-C4 alcoxi.Also provided is a compound of formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 8 and R 9 is as defined in formula I. Also provided is a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 8 and R 9 is as defined in formula A. In another embodiment, any carbocyclyl, aryl, heterocyclyl or heteroaryl in formula A, I, Ia or Ib is optionally substituted by one or more substituents independently selected from =O, -C(O)-(C1-C3 alkyl), -C (O)-N(R10)2, -C(O)-O-(C1-C3 alkyl), -C1-C4 alkoxy, -C1-C4 alkyl, -C1-C4 haloalkyl, -C2-C4 alkenyl or alkynyl , -C3-C8 cycloalkyl, halo, morpholinomethyl, morpholinosulfonyl, morpholinyl, -N(R10)2, -NH-C(O)-(C1-C3 alkyl), -O-CH2-C(O)-N(R10 )2, -OH, -O-phenyl, phenyl, -S(O)2-piperidin-1-yl, and tetrazolyl; wherein each R10 is independently selected from hydrogen, C1-C3 alkyl, and C3-C8 cycloalkyl; and any cycloalkyl, phenyl or piperidinyl moiety of a substituent is further optionally substituted with one or more substituents independently selected from halo, C1-C3 alkyl, CF3, -NH2, and C1-C4 alkoxy.
In another embodiment of Formula A, I, I-a or I-b: any carbocyclyl, aryl, heterocyclyl or heteroaryl moiety of R 1 is optionally substituted by halo, or C 1 -C 4 alkoxy; carbocyclyl, aryl, heterocyclyl or heteroaryl in R2 is optionally substituted by one or more substituents independently selected from =O, -OH, halo, C1-C4 alkyl, C1-C4 alkoxy, morpholinyl, -N(R8)2 and -O -CH2-C(O)-N(R8)2; any carbocyclyl, aryl, heterocyclyl or heteroaryl in R3 is optionally substituted by one or more substituents independently selected from -OH, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH-C(O)-( C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -C(O)-O-(C1-C3 alkyl), tetrazolyl, C3-C8 cycloalkyl, phenyl, -O-phenyl, and - S(O)2-piperidin-1-yl; any cycloalkyl, phenyl or piperidinyl of an R3 substituent is further optionally substituted with one or more substituents independently selected from halo, C1-C3 alkyl, CF3, -NH2, and C1-C4 alkoxy; and
R7 is optionally substituted by one or more substituents independently selected from =O, -OH, halo, C1-C4 alkyl, C2-C4 alkenyl or alkynyl, C1-C4 haloalkyl, -C(O)-N(R8)2, - N(R8)2, C1-C4 alkoxy, morpholinomethyl, morpholinosulfonyl, and phenyl, wherein the phenyl substituent of R7 is further optionally substituted by one or more substituents independently selected from halo, C1-C3 alkyl, CF3, -NH2, and C1-C4 alkoxy.
In another embodiment of Formula A, I, I-a or I-b, R1 is piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, or tetrahydrofuranyl, wherein each member of R1 is optionally substituted.
In another embodiment of Formula A, I, I-a or I-b, R2 is selected from carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each member of R2 is optionally substituted.
In another embodiment of Formula A, I, I-a or I-b, R3 is carbocyclyl; aryl, heterocyclyl, heteroaryl, -(C1-C2 alkylene)-(carbocyclyl), -(C1-C2 alkylene)-(aryl), -(C1-C2 alkylene)-(heterocyclyl), and -(C1-C2 alkylene) -(heteroaryl), wherein each member of R3 is optionally substituted.
In another embodiment of Formula A, I, I-a or I-b, R3 is cyclopropyl, cyclopentyl, cyclohexyl or benzyl, wherein each member of R3 is optionally substituted.
In another embodiment of Formula A, I, I-a or I-b, -R5-R6-R7 is not phenyl or N-methyleneisoindoline-1,3-dione. In another embodiment of Formula A, I, I-a or I-b, R6 is not -NHC(O)-. In another embodiment of Formula A, I, I-a or I-b, R8 and R1 are taken together with a nitrogen atom to form a 5-12 membered heterocyclyl. In one aspect of this embodiment, R2 is selected from carbocyclyl, aryl, heterocyclyl, and heteroaryl. In another aspect of this embodiment, -R5-R6-R7 is not phenyl or N-methyleneisoindoline-1,3-dione. In another aspect of this embodiment, R6 is not -NHC(O).
In another embodiment of Formula A, I, Ia or Ib, R9 is H. In another embodiment, R9 is methyl or ethyl. In another embodiment of Formula A, I, Ia or Ib, R9 and R2 are taken together to form a 6-12 membered carbocyclyl or a 5-12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted. In another embodiment, a compound of Formula Ic, or a pharmaceutically acceptable salt thereof, is provided.
R1 is selected from a monocyclic or bicyclic C4-C7 cycloalkyl optionally substituted on a single carbon atom with 1 to 2 fluorine; tetrahydropyranyl, pyrrolidinyl, phenyl, and t-butyl, wherein the phenyl and pyrrolidinyl are optionally substituted; R2 is selected from phenyl, biphenyl, thien-2-yl, and furanyl, wherein R2 is optionally substituted; R3 is selected from phenyl, biphenyl, pyridinyl, thiazolylmethyl, thienylmethyl, cyclohexyl and pyrazolyl, wherein any phenyl, biphenyl, pyridinyl, thiazolyl, thienyl, cyclohexyl or pyrazolyl moiety of R3 is optionally substituted; and R4 is as defined in formula A.
In certain embodiments of Formula Ic, R 1 is selected from cyclohexyl, cyclopentyl, cycloheptyl, cyclobutyl, 3,3-difluorocyclobutyl, 4,4,-difluorocyclohexyl, bicyclo[2,2.1]heptanyl, tertahydropyran-3-yl, tertahydropyran- 4-yl, 1-t-butoxycarbonylpyrrolidin-3-yl, t-butyl, 2-bromophenyl, 2-methylphenyl, and bicyclo[3.1.0]hexan-3-yl.
In certain embodiments of Formula Ic, R2 is selected from phenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-bromo-5-fluorophenyl, 2,5-dichlorophenyl, 2-fluoro-5-methylphenyl , thien-2-yl, 4-fluorophenyl, 5-bromofuran-2-yl, 3-methylthien-2-yl, 2,4,5-trifluorophenyl, 3-fluoro-5-chlorophenyl, 2,5-difluoro-6 -chlorophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methylphenyl, 2,6-dimethylphenyl, 3-bromophenyl, 2-ethylphenyl, 2-nitrophenyl, 3'-methoxybiphenyl-3-yl, 2,5-dibromo-6- fluorophenyl, 2-trifluoromethylphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, and 2-fluoro-5-methoxyphenyl.
In certain embodiments of Formula Ic, R3 is selected from 3-fluorophenyl, 3-methylphenyl, 3-chlorophenyl, thien-2-ylmethyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 1-methyl- 1H-pyrazol-3-yl, 4-chlorophenyl, 3-acetylaminophenyl, 3'-trifluoromethoxy-biphenyl-3-yl, pyridin-3-yl, 4-fluorophenyl, thiazol-2-ylmethyl, cyclohexyl, 2-methylphenyl, 3 -fluoro-4-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, phenyl, 3-bromophenyl, 2-fluorophenyl, 3-chloro-4-methylphenyl, 3-(pyriminidin-5-yl)phenyl, biphenyl- 3-yl, 3-trifluoromethylphenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3-aminophenyl, 3-ethylcarbonylaminophenyl, 3-t-butoxycarbonylaminophenyl, 3-chloro-4-bromophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-(1-methyl-1H-pyrazol-5-yl)phenyl, 3-methoxycarbonylaminophenyl, 3-cetylphenyl, 3-(morpholin-4-yl)phenyl, 3,4-difluorophenyl, and 3-(4-t- butoxycarbonylpiperazin-1-yl)phenyl.
In some embodiments, R4 is selected from 1-(methylmethoxycarbonylamino)ethyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1-ethoxycarbonylpiperidin-2-yl, 1-ethoxycarbonylpyrrolidin-2-yl, 1H-benzimidazol-1 -ylmethyl, 1H-indazol-3-ylmethyl, indolin-1-ylmethyl, 1H-indol-3-ylmethyl, 1H-indol-5-ylmethyl, 1H-pyrrolo[2,3-b]pyridin-3-ylmethyl, 1H -pyrrolo[3,2-b]pyridin-3-ylmethyl, 1-methoxycarbonylpiperidin-2-yl, 1-methoxycarbonylpyrrolidin-2-yl, 2-fluoropyridin-3-ylaminomethyl, 2-imino-4-fluoropyridin-1-ylmethyl , 2-methoxyphenylaminomethyl, 2-methyl-1H-benzimidazol-1-ylmethyl, 2-methylimidazol-1-ylmethyl, 2-trifluoromethyl-1H-imidazol-1-yl, 3-cyanophenylaminomethyl, 3-fluoropyridin-2-ylaminomethyl, 3 -methoxyphenylaminomethyl, 4-(1,3,4-oxadiazol-2-yl)phenylaminomethyl, 4-(dimethylaminocarbonyloxy)phenylmethyl, 4,5-dichloroimidazol-1-ylmethyl, 4-cyanophenylaminomethyl, 4-fluorophenylaminomethyl, 4-fluoropyridin-2 -ylaminomethyl, 4-hydroxyphenylmethyl, 4-methoxycarbonylmorpholin-3-yl, 4-methoxycarbonylpiperazin-1-ylmethyl, 4-methoxyphenylaminomethyl, 4-methylca bonyloxyphenylmethyl, 5-fluoropyridin-2-aminomethyl, 5-fluoropyridin-2-oxymethyl, 6-fluoropyridin-3-ylaminomethyl, benzomorpholin-4-ylmethyl, methoxycarbonylaminomethyl, methylmethoxycarbonylaminomethyl, methylphenylaminomethyl, phenylaminomethyl, pyridin-2-oxymethyl, pyridin-2- ylaminomethyl, pyridin-2-yloxymethyl, pyridin-3-oxymethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, thiazol-4-ylmethyl, and thien-2-ylmethyl.



In another embodiment, exemplary compounds of formula I are shown below in Table 1.








(II), ou um sal farmaceuticamente aceitável do mesmo, em que:In another embodiment, the compound is selected from any one of Compound numbers 8, 15, 30, 31, 34, 44, 54, 80, 99 of Table 1. In yet another embodiment, the invention provides a compound of Formula II: (II), or a pharmaceutically acceptable salt thereof, wherein:
R1 is a monocyclic or bicyclic C4-C7 cycloalkyl optionally substituted on a single carbon atom with 1 to 2 fluorine; R3 is selected from 3-fluorophenyl, 3-methylphenyl, 3-chlorophenyl, and thien-2-ylmethyl; R4 is selected from heterocyclyl, -CH2-heterocyclyl, -CH2-heteroaryl, benzyl, 11 11 11 11 11 11 -CH(R )-N(R )-heteroaryl, -CH(R )-N(R )-phenyl, -CH(R )-N(R )-heterocyclyl, -CH(R11)-N(R11)-C(O)CH3, and -CH2-O-saturated heteroaryl, where each R11 is independently selected from hydrogen and methyl ; and each heterocyclyl, heterocyclyl, phenyl, benzyl and saturated heteroaryl is optionally substituted; and R10 is selected from methyl, hydrogen, fluorine, chlorine, and bromine.
In certain embodiments of a compound of Formula II, when R1 is cyclopentyl or cyclohexyl, and R3 is thien-2-ylmethyl, then R4 is other than thien-2-ylmethyl, 1H-benizimidazol-1-ylmethyl, 1H-indole- 3-ylmethyl, or 1H-benzotriazol-1-ylmethyl; when R1 is cyclopentyl, R10 is hydrogen, and R3 is 3-fluorophenyl, 3-methylphenyl, or 3-chlorophenyl, then R4 is other than thien-2-ylmethyl; when R1 is cyclopentyl, R10 is methyl and R3 is 3-fluorophenyl, then R4 is other than thien-2-ylmethyl or 1H-benzotriazol-1-ylmethyl; when R1 is cyclopentyl, R10 is fluorine and R3 is 3-methylphenyl, then R4 is other than thien-2-ylmethyl or 1H-benzotriazol-1-ylmethyl; when R1 is cyclopentyl, R10 is fluorine and R3 is 3-fluorophenyl, then R4 is other than thien-2-ylmethyl; when R1 is cyclohexyl, R10 is hydrogen, and R3 is 3-methylphenyl, or 3-chlorophenyl, then R4 is other than thien-3-ylmethyl; and when R1 is cyclohexyl, R10 is hydrogen, and R3 is 3-fluorophenyl, then R4 is other than 1H-benzotriazol-1-ylmethyl.
In certain aspects for Formula II, R3 is 3-fluorophenyl. In certain aspects of the above embodiments of Formula II: R1 is selected from cyclohexyl, cyclopentyl, cycloheptyl, 3,3-difluorocyclobutyl, 4,4,-difluorocyclohexyl, and bicyclo[2.2.1]heptanyl; and
R4 is selected from 1-(methylmethoxycarbonylamino)ethyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1-ethoxycarbonylpiperidin-2-yl, 1-ethoxycarbonylpyrrolidin-2-yl, 1H-benzimidazol-1-ylmethyl, 1H -indazol-3-ylmethyl, indolin-1-ylmethyl, 1H-indol-3-ylmethyl, 1H-indol-5-ylmethyl, 1H-pyrrolo[2,3-b]pyridin-3-ylmethyl, 1H-pyrrolo[3 ,2-b]pyridin-3-ylmethyl, 1-methoxycarbonylpiperidin-2-yl, 1-methoxycarbonylpyrrolidin-2-yl, 2-fluoropyridin-3-ylaminomethyl, 2-imino-4-fluoropyridin-1-ylmethyl, 2-methoxyphenylaminomethyl , 2-methyl-1H-benzimidazol-1-ylmethyl, 2-methylimidazol-1-ylmethyl, 2-trifluoromethyl-1H-imidazol-1-yl, 3-cyanophenylaminomethyl, 3-fluoropyridin-2-ylaminomethyl, 3-methoxyphenylaminomethyl, 4 -(1,3,4-oxadiazol-2-yl)phenylaminomethyl, 4-(dimethylaminocarbonyloxy)phenylmethyl, 4,5-dichloroimidazol-1-ylmethyl, 4-cyanophenylaminomethyl, 4-fluorophenylaminomethyl, 4-fluoropyridin-2-ylaminomethyl, 5 4-hydroxyphenylmethyl, 4-methoxycarbonylmorpholin-3-yl, 4-methoxycarbonylpiperazin-1-ylmethyl, 4-methoxyphenylaminomethyl, 4-methylcarbonyloxyphenylmethyl, 5-fluoropyridin-2-aminomethyl, 5-fluoropyridin-2-oxymethyl, 6-fluoropyridin-3-ylaminomethyl, benzomorpholin-4-ylmethyl, methoxycarbonylaminomethyl, methylmethoxycarbonylaminomethyl, methylphenylaminomethyl, phenylaminomethyl, pyridin-2-oxymethyl, pyridin-2-ylaminomethyl, pyridin-2-yloxymethyl, pyridin-3-oxymethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, thiazol-4-ylmethyl, and thien-2-ylmethyl.
In another embodiment, a compound is selected from any of the compounds shown in Table 2, below. Table 2. Compounds of Formula (A).




































In another embodiment, the compound is selected from any of the Compound numbers 104, 126, 135, 140, 150, 155, 160, 161, 165, 173, 185, 186, 197, 198, 201, 202, 203, 210 , 212, 213, 217, 218, 227, 228, 237, 240, 247, 253, 260, 265, 271, 272, 275, 276, 5 287, 288, 289, 290, 291, 293, 297, 301, 306, 307, 311, 313, 314, 316, 320, 321, 322, 331, 334, 341, 344, 348, 351, 356, 359, 361, 366, 378, 381, and 385 of Table 2.
The compounds of this invention can contain one or more asymmetric centers and occur as well as racemates, racemic mixtures, scalemic mixtures and diastereomeric mixtures, as well as single enantiomers or individual stereoisomers that are substantially free of 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 stereocenters selected 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 with 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 can be applied as far as possible to final compounds or starting materials or intermediates.
In one embodiment, when R2 and R9 are different, the compound of Formula I is enriched by a structure or structures having a selected stereochemistry at the carbon atom that is attached to R2 and R9. In one embodiment, the selected stereochemistry at the carbon atom is R. In another embodiment the selected stereochemistry at the carbon atom is S. For example, the compound is enriched in the specific stereoisomer by at least about 60%, 65%, 70% , 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.
Compounds of formula I can also comprise one or more isotopic substitutions. For example, H can be any isotopic form, including 1H, 2H (D or deuterium) and 3H (T or tritium); C can be any isotopic form, including 12C, 13C, and 14C; O can be any isotopic form, including 16O and 18O; and the like.
Unless otherwise stated when a disclosed compound is named or described by a structure without specifying stereochemistry and has one or more chiral centers, it is understood that this represents all possible stereoisomers of the compound.
The compounds of this invention may also be represented in various tautomeric forms, in which case the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., the alkylation of a ring system may result in alkylation at various locations, the invention expressly includes all products of this reaction). All such isomeric forms of these compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
Certain compounds of the invention are available from commercial and/or public compound libraries such as those sold by Evotec AG (Hamburg, Germany) and its affiliates, Asinex Ltd (Moscow, Russia) and its affiliates, and through the National Institute of Health. Other compounds of the invention can be synthesized by one of ordinary skill in the art using methods well known in the art, such as via Ugi chemistry.
Fórmula A Compostos de Fórmula A foram preparados reagindo o aldeído de R2 (a) com uma amina de R3 (b) em metanol. O ácido carboxílico de R4 (c) e o ciano de R1 (d) são então adicionados à mistura para produzir um composto da invenção (mais particularmente um composto de Fórmula I-b ou I-c). A forma de sal HCl do composto resultante foi preparada misturando o composto com HCl/Et2O. Esquema 2.For example, compounds of the invention can be prepared according to one or more of the following general schemes. Scheme 1. Preparation of Compounds of Formula A. Formula A Compounds of Formula A were prepared by reacting the aldehyde from R2 (a) with an amine from R3 (b) in methanol. The carboxylic acid from R4(c) and the cyano from R1(d) are then added to the mixture to produce a compound of the invention (more particularly a compound of Formula Ib or Ic). The HCl salt form of the resulting compound was prepared by mixing the compound with HCl/Et2O. Scheme 2.
Certain compounds of Formula A comprising an amine at R4 were also prepared from chloroacetyl and according to Scheme 2. Chloroacetyl and was synthesized according to Scheme 1, using 2-chloroacetic acid (c') in place of the carboxylic acid of A4. Chloroacetyl and was then used to produce compounds of the invention containing secondary and tertiary amines at R4. In Scheme 2, Ra represents hydrogen or C1-C3 alkyl; and Rb represents -R6-R7, as variables are defined for Formula A; or Ra and Rb are taken together to form an optionally substituted heterocyclyl or heteroaryl. The reaction between chloroacetyl and the amine can be achieved under some different conditions: a) in the presence of Et3N in DCM and TBAI; b) under reflux in the presence of Et3N in toluene under an atmosphere of N2; c) in the presence of NaI in acetone and moderate heating (eg, 70°C); or d) in the presence of Et3N in DMF. Scheme 3
Certain compounds of Formula A where R 1 is -CH 2 -O-R 7 have been prepared from the appropriate chloroacetyl and the appropriate hydroxyl R 7 . This reaction can be carried out in the presence of KOH and DMSO, or in the presence of K2CO3 in MeCN, heated to 40°C. Scheme 4
Certain compounds of the invention are produced according to Scheme 4. The aldehyde from R2 (a) is combined with the amine from R3 (b) in the presence of TMSCN to produce the cyanomethylamine f. The cyano fraction is converted to the corresponding carboxylic acid g by reaction with K2CO3 and H2O2, followed by reflux in NaOH and aqueous MeOH. The amine R1(h) is then reacted with g in the presence of HOBt/EDCI/Et3N in DCM to produce i, which is then reacted with a chlorocarbonyl derivative of R4 to produce a compound of the invention. Scheme 5
Certain compounds of the invention where R4 is -C(R11)-N(R11)-O-CH3 or 1-methyloxycarbonylpyrrolidin-2-yl are produced according to Scheme 5. In Scheme 5, each R12 is independently hydrogen or methyl, or two adjacent R12 are taken together with the carbon and nitrogen atoms to which they are respectively attached to form a pyrrolidine or piperidine ring. In Scheme 5, t-butyl derivative 1 is formed according to Scheme 1, using carboxylic acid k in place of carboxylic acid of R4(c). Treatment of l with acid produces amine m, which is converted to the compound of Formula A by treatment with methyl chloroformate.
Compounds produced by any of the general schemes defined above may be modified (e.g., by adding substituents to rings, etc.) to produce additional compounds of the invention. The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein describe variables which are defined proportionally herein with chemical group definitions (fractions, atoms, etc.) of the corresponding position in the compound formula here, identified with the same variable name (i.e., R1, R2, R3, etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is well known to one of skill in the art.
Additional methods of synthesizing compounds of Formula A and their synthetic precursors, including those within routes not explicitly shown in the schemes herein, are within the chemical capacity of those skilled in the art, as well as set forth in the specific examples. Synthetic chemical transformations and group protection (protection and deprotection) methodologies useful for synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive
Organic Transformations, VCH Publishers (1989); Greene, TW et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
It may be convenient or desirable to prepare, purify, and/or manipulate 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 that can be anionic (eg -COOH can be -COO-), then the salt can be formed by an appropriate cation. Examples of suitable inorganic cations include, among others, 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, among others, ammonium ions (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 can be cationic (eg -NH2 can be -NH3+), then a salt can be formed with an appropriate anion. Examples of suitable inorganic anions include, among others, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric and phosphorus.
Examples of suitable organic anions include, among others, those derived from the following organic acids: 2-acethioxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glycoheptonic, 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, sulphanilic, tartaric, toluenesulfonic and valeric. Examples of suitable polymeric organic anions include, among others, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise noted, a reference to a particular compound also includes salt forms thereof. Compositions and administration routes
Compounds used in the methods described herein can be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions before being administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective to achieve modulation of disease or disease symptoms, including those described herein.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a subject, together with a compound of this invention, and that does not destroy the pharmacological activity of the same and is non-toxic when administered in doses sufficient to release a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, among others, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as da-succinate. polyethylene glycol 1000 tocopherol, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric release matrices, whey proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures from 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, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, poly polyethylene-polyoxypropylene-block mers, polyethylene glycol and wool grease. Cyclodextrins such as α, β and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used advantageously to improve the release of compounds of formula described herein.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally or through an implanted reservoir, preferably by administration oral or injection administration. 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 can be adjusted with pharmaceutically acceptable acids, bases or buffers to improve the stability of the formulated compound or its release 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 oleaginous suspension. This suspension can be formulated according to known techniques using suitable wetting or dispersing 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 solvents and vehicles that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can 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. Such oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of solids, liquids or other pharmaceutically acceptable dosage forms or other dosage forms may also be used for formulation purposes. .
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 that are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase and 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 will therefore melt in the rectum to release the active components. Such materials include, among others, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of the present invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with an appropriate ointment containing the active components suspended or dissolved in a carrier. Carriers for the 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, wax emulsion and water. Alternatively, the pharmaceutical composition may be formulated with an appropriate lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, among others, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically to the lower intestinal tract by rectal suppository formulation or in an appropriate enema formulation. Topical transdermal patches are also included in the present invention.
The pharmaceutical compositions of this invention can be administered by nasal aerosol or inhalation. Such compositions are prepared in accordance with well known pharmaceutical formulation techniques and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and/or other dispersing or solubilizing agents known in the art. When the compositions of the present invention comprise a combination of a compound of the formula described herein and one or more additional therapeutic or prophylactic agents, 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. Additional agents may be administered separately as part of a multiple dose regimen of the compound of this invention. Alternatively, these agents may be part of a single dosage form, mixed with the compound 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, orally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of weight body, alternative dosage 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 administering an effective amount of the compound or compound composition to obtain 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. This administration can be used as an acute or chronic therapy. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the patient treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% of the active compound (w/w). Alternatively, these preparations contain about 20% to about 80% active compound.
Lower or higher doses than those mentioned above may be necessary. Specific treatment regimens and dosages for any particular subject will depend on a number of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, time of administration, excretion rate, 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.
As a subject's condition improves, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Thereafter, the dosage or frequency of administration, or both, may be reduced, as a function of symptoms, to a level at which the improved condition is maintained when symptoms are relieved to the desired level. Subjects may, however, require long-term intermittent treatment for any reoccurrence of disease symptoms.
The above-described pharmaceutical compositions comprising a compound of formula I or a compound described in any of the embodiments herein may further include another therapeutic agent useful in the treatment of cancer. Methods of Use
A method of inhibiting the activity of an IDH1 mutant comprising contacting a subject in need thereof with a compound of formula I, a compound described in any of the embodiments herein, or a pharmaceutically acceptable salt thereof, is provided. In one 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 R132 H.
Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising the step of administering to a subject in need thereof (a) a compound of formula I, a compound described in any of the embodiments, or a pharmaceutically salt acceptable thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
In one embodiment, the cancer being treated is characterized by a mutant allele of IDH1 having 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 R132 H. A cancer can be analyzed by sequencing cell samples to determine the presence of a mutation at amino acid 132 of IDH1.
In certain modalities, the cancer to be treated is still characterized by high levels of 2HG. In one aspect of this modality, the effectiveness of cancer treatment is monitored by measuring 2HG levels in the subject. Normal levels of 2HG are measured prior to treatment, where an elevated level is indicative of the use of the Formula I compound to treat cancer. Once elevated levels are established, the 2HG level is determined during the course and/or after the end of treatment to establish efficacy. In certain modalities, the 2HG level is only determined during the course and/or after the end of the treatment. A reduction in 2HG levels during the course of treatment and after treatment is indicative of efficacy. Likewise, a determination that 2HG levels are not elevated during the course or after treatment is also indicative of efficacy. Typically, these 2HG measurements will be used in conjunction with other well-known determinations of cancer treatment efficacy, such as reducing the number and size of tumors and/or other cancer-associated lesions, improving the subject's general health, and changes in others. biomarkers that are associated with the effectiveness of cancer treatment. 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 electrospray negative ionization (ESI, -3.0 kV) to triple-quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized in infused metabolite standard solutions .
Metabolites can be separated by reversed-phase chromatography using 10mM tributylamine as an ion-pairing agent in the mobile aqueous phase, according to a variant of the previously reported method (Luo et al. J Chromatogr A 1147, 153-64 , 2007). One method allows the 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 of 50%-95% B (buffers as defined above) for 5 minutes. A Synergi Hidro-RP, 100mm x 2mm, 2.1 μm particle size (Phenomonex) can be used as a column as described above. Metabolites can be quantified by comparing peak areas with pure standard metabolites in known concentration.
13 C-glutamine metabolite flux studies can be performed as described, for example, in Munger et al. Nat Biotechnol 26, 1179-86, 2008. In a 2HG modality it is directly evaluated.
In another embodiment, a 2HG derivative formed in the process of performing the analytical method is evaluated. By way of example, a derivative can be a derivative formed in MS analysis. Derivatives may include a salt adduct, for example, a Na adduct, a hydration variant, or a hydration variant that is also a salt adduct, for example, a Na adduct, for example, as formed in the analysis of MS.
In another modality, a metabolic derivative of 2HG is evaluated. Examples include species that accumulate or are elevated or reduced due to the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, eg, R-2HG.
Exemplary 2HG derivatives include dehydrated derivatives such as the compounds given below or an adduct salt thereof:
In one embodiment, cancer is a tumor in which at least 30, 40, 50, 60, 70, 80, or 90% of the tumor cells carry an IDH1 mutation at the time of diagnosis or treatment.
In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH1 in which the IDH1 mutation results in a novel ability of the enzyme to catalyze the NAPH-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 (eg, the presence of the changed amino acid in) a mutation at amino acid 132 of IDH1.
Without being bound by theory, applicants believe that mutant alleles of IDH1 in which the IDH1 mutation results in a novel ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate, and in In particular, R132H mutations of IDH1, characterize a subset of all types of cancers, regardless of their cellular nature or location in the body. Thus, the compound 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 transmitting that activity and in particular, an IDH1 R132H mutation.
The methods described herein can be used to treat cancer, for example, those described by the National Cancer Institute. A cancer can be evaluated to determine if it contains an HDI mutant using a method described here. Exemplary cancers described by the National Cancer Institute include: Acute Lymphoid Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Infant; AIDS-Related Lymphoma; AIDS Related Neoplasms; Anal Cancer; Astrocytoma, Infantile Cerebellar; Astrocytoma, Infant Brain; Cancer of the Biliary Duct, Extra-Hepatic; Bladder Cancer, Bladder Cancer, Infant; Bone Cancer, Osteosarcoma/Fibrous Malignant Histiocytoma; Children's Brainstem Glioma; Brain Tumor, Adult; Brain Tumor, Brainstem Glioma, Infantile; Cerebral Tumor, Cerebellar Astrocytoma, Infantile; Cerebral Tumor, Cerebral Astrocytoma/ Malignant Glioma, Infantile; Brain Tumor, Ependymoma, Infantile; Brain Tumor, Medulloblastoma, Infant; Brain Tumor, Neuroectodermal Primitive Supratentorial Tumors, Infantile; Cerebral Tumor, Hypothalamic Glioma and Via Visual, Infantile; Infant Brain Tumor, (Other); Breast cancer; Breast Cancer and Pregnancy; Breast Cancer, Infant; Male Breast Cancer; Adenomas/Bronchial Carcinoids, Infant; Carcinoid Tumor, Infant; Carcinoid Tumor, Gastrointestinal; Adrenocortical Carcinoma; Carcinoma, Islet Cells; Primary Unknown Carcinoma; Lymphoma Central Nervous System, Primary; Cerebellar Astrocytoma, Infant; Cerebral Astrocytoma / Malignant Glioma, Infantile; Cervical Cancer; Childhood Cancer; Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia; Chronic Myeloproliferative Disorders; Tendon Sheath Clear Cell Sarcoma; Colon Cancer, Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrium; Ependymoma, Infant; Epithelial Cancer, Ovary, Esophageal Cancer, Esophageal Cancer, Infantile, Ewing Family of Tumors; Infant, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor; Extra-Hepatic Biliary Duct Cancer, Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric Cancer (Stomach); Gastric Cancer (Stomach), Infant; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Infant; Germ Cell Tumor, Extragonadal; Cell Tumor
Germinatives, Ovary; Gestational Trophoblastic Tumor; Glioma, Infant Brainstem; Glioma, Infant and Hypothalamic Visual Pathway; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular Cancer (Liver), Adult (Primary); Hepatocellular Cancer (Liver), Infant (Primary); Hodgkin's Lymphoma, Adult, Hodgkin's Lymphoma, Child; Hodgkin's Lymphoma During Pregnancy, Hypopharyngeal Cancer; Hypothalamic Glioma and Via Visual, Infantile; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Laryngeal Cancer, Infantile; Adult, Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Chronic Lymphocytic Leukemia; Chronic myeloid leukemia; Leukemia, Hair Follicle; Cancer of the Oral Lip Cavity; Liver Cancer, Adult (Primary); Liver Cancer, Infant (Primary); Non-Small Cell Lung Cancer; Lung Cancer, Small Cells; Lymphoblastic Leukemia, Acute Adult; Lymphoblastic Leukemia, Acute Childhood, Lymphocytic Leukemia, Chronic; Lymphoma, Related to AIDS; Central Nervous System Lymphoma (Primary); Cutaneous T-Cell Lymphoma; Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Infant; Hodgkin's Lymphoma During Pregnancy; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Infant; Non-Hodgkin's Lymphoma During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Infantile; Thymoma Malignant; Medulloblastoma, Infant; Melanoma; Melanoma, Intraocular; Merkel, Cellular Carcinoma; Malignant Mesothelioma; Occult Primary Squamous Metastatic Neck Cancer; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Fungoid; Myelodysplastic Syndromes; Chronic myeloid leukemia; Acute Myeloid Leukemia, Childhood; Multiple Myeloma; Myeloproliferative, Chronic Disorders, Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Infant; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood, Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer, Oral Cancer, Childhood; Cancer of the Oral Cavity and Lip; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Cancer of the Ovary, Infant; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Low Potential Malignant Ovary Tumor; Pancreatic Cancer; Pancreatic Cancer, Infant; Pancreatic Cancer, Islet Cells; Cancer of the Nasal Cavity and Paranasal Sinus; cancer of
Parathyroid; Penis Cancer; Pheochromocytoma; Pineal and Supratentorial Neuroectodermal Primitive Tumors, Infant; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastomas; Breast Cancer and Pregnancy; Hodgkin's Lymphoma and Pregnancy; Non-Hodgkin's Lymphoma and Pregnancy, Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary, Infant Liver Cancer; Prostate Cancer, Rectal Cancer; Renal Cell Cancer (Kidney); Kidney Cell Cancer, Infant; Cancer of Renal Transition Cells of the Pelvis and Ureter; Retinoblastoma; Rhabdomyosarcoma, Infant; Salivary Gland Cancer; Salivar Gland Cancer, Infant; Sarcoma, Ewing Family of Tumors; Kaposi's sarcoma; Fibrous Histiocytoma of Bone Sarcoma (Osteosarcoma)/Malignant; Sarcoma, Rhabdomyosarcoma, Infantile; Soft Tissue Sarcoma, Adult; Children's Soft Tissue Sarcoma; Sezary's Syndrome; Skin Cancer, Skin Cancer, Children; Skin Cancer (Melanoma); Skin Carcinoma, Cell Merkel; Small Cell Lung Cancer; Small Intestine Cancer, Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Infant; Occult Primary Squamous Metastatic Neck Cancer, Metastatic; Stomach Cancer (Gastric); Stomach Cancer (Gastric), Infant; Primitive Neuroectodermal Supratentorial Tumors, Infant; Cutaneous T-Cell Lymphoma; Testicular Cancer; Thymoma, Infant; Thymoma Malignant; Thyroid Cancer, Thyroid Cancer, Childhood; Cancer of Transitional Cells of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Cancer of Unknown Primary Site, Childhood; Unusual Childhood Cancers; Cancer of Transitional Cells of the Renal Pelvis and Ureter; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Hypothalamic Glioma of the Visual Path, Infant; Vulvar Cancer; Waldenstrom's Macro Globulinemia, and Wilms' Tumor. Metastases from the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
The methods described herein are useful in the treatment of cancer of the nervous system, e.g., brain tumor, e.g., glioma, e.g., glioblastoma multiforme (GBM). Gliomas, a type of brain tumor, can be classified as grade I to grade IV, based on clinical and histopathological criteria established by the World Health Organization (WHO). WHO Grade I gliomas are often considered benign. WHO grade II or III gliomas are invasive, progressing to higher grade lesions. WHO grade IV tumors (glioblastomas) are the most invasive form. Exemplary brain tumors include, for example, astrocytic tumor (eg, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, adult primary gliogliblastoma, and glioblastoma primary); oligodendroglial tumor (for example, oligodendroglioma and anaplastic oligodendroglioma); oligoastrocytic tumor (e.g., oligoastrocytoma and anaplastic oligoastrocytoma); ependymoma (eg, myxopapillary ependymoma and anaplastic ependymoma); medulloblastoma; primitive neuroectodermal tumor, schwannoma, meningioma, metatypical meningioma, anaplastic meningioma; and pituitary adenoma. Exemplary cancers are described in Acta Neuropathol (2008) 116:597-602 and N Engl J Med. 2009 Feb 19; 360(8):765-73, the contents of which are incorporated herein by reference.
In one modality, the cancer is glioblastoma. In one modality, the cancer is paraganglioma. In one modality, the cancer is fibrosarcoma. In one modality, the cancer is prostate cancer, eg stage T1 (eg T1a, T1b and T1c), T2 (eg T2a, T2b and T2c), T3 (eg T3a and T3b) and T4, in the TNM phase determination system. In modalities, prostate cancer is grade G1, G2, G3 or G4 (where a higher number indicates a greater difference from normal tissue). Types of prostate cancer include, for example, adenocarcinoma of the prostate, small cell carcinoma, squamous cell carcinoma, sarcomas, and transitional cell carcinoma. In one aspect of this embodiment, the disorder is localized or metastatic prostate cancer, eg, adenocarcinoma of the prostate.
In one embodiment, the disorder is a hematologic cancer, eg, a leukemia, eg, AML, or acute lymphoblastic leukemia ("ALL"). In one aspect of this modality, the cancer is ALL (eg a pediatric or acute form). In one aspect of this modality cancer is all B-ALL or T-ALL
R132X IDH1 mutations are known to occur in certain types of cancers, as indicated in Table 3, below. Table 3. HDI mutations associated with certain types of cancer
Accordingly, in one modality, cancer is a cancer selected from any of the cancer types listed in Table 3, and the R132X IDH mutation is one or more of the R132X IDH1 mutations listed in Table 3 for that particular cancer type.
The methods of treatment described herein may additionally comprise several evaluation steps before and/or after treatment with a compound of formula I or a compound described in any of the embodiments described herein.
In one embodiment, before and/or after treatment with a compound of Formula A, I, Ia, Ib, Ic or II or a compound described in any of the embodiments described herein, the method further comprises the step of evaluating growth, size, weight, invasiveness, stage or other phenotype of cancer.
In one embodiment, before and/or after treatment with a compound of Formula A, I, Ia, Ib, Ic or II or a compound described in any of the embodiments described herein, the method further comprises the step of evaluating the IDH1 genotype of cancer.
This can be achieved by methods common in the art, such as DNA sequencing, immunological analysis and/or assessing the presence, distribution or level of 2HG.
In one embodiment, before and/or after treatment with a compound of Formula A, I, Ia, Ib, Ic or II or a compound described in any of the embodiments described herein, the method further comprises the step of determining the level of 2HG on the subject. This can be achieved by spectroscopic analysis, eg MRI-based analysis, eg MRI and/or MRS measurement, analysis of body fluid samples, such as serum or spinal cord fluid analysis, or by analysis of surgical material , for example, 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, for example, an additional cancer therapeutic agent or an additional cancer treatment. Additional exemplary 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-administer" as used herein with respect to 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 a second therapeutic agent as described above) or separately, multiple dosage forms. Alternatively, the additional cancer therapeutic agent can be administered before, consecutively with, or after 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. Administration of a composition of this invention, comprising a compound of the invention and a second therapeutic agent, to a subject does not preclude 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-administer" as used herein in connection with an additional cancer treatment means that the additional cancer treatment may occur before, consecutively with, concurrently with or after administration of a compound of this invention.
In some embodiments, the additional cancer therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (eg, folic acid, purine derivatives and pyrimidine) and alkylating agents (eg, nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others). Exemplary agents include Aclarrubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic Acid, Amrubicin, Amsacrine, Anagrelide, Arsenic Trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, Bleomycin, Bortezopcitamibine, Carbosulfantin, Carboquine Carmofur, Carmustine, Celecoxib Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Chrysantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Ephloram, Epharoxycin, Ethumoglycine, Ephloram, Ephrazine, Ethromycin , Floxuridine, Fludarabine (5FU), Fluoruracil, Fotemustine, Gemcitabine, Gliadel Implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal Doxorubicin, Loxycarbamide, Locusomalin, Losounorin , Melphalan, Merc Aptopurine, Mesna, Methotrexate, Methyl Aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxin, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pycomycin, Pentostatin Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagena Ceradenovec, Strataplatin, Streptozocine, Talaporphine, Tegafur-Uracil, Temoporphine, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitin, Tizofuran, Thiofurin , Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trophosphamide, Uramustine, Valrubicin, Verteporphine, 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. Typically, two or more chemotherapeutic agents are often used as combination chemotherapy.
In some embodiments, the additional cancer therapeutic agent is a targeted therapy agent. Targeted therapy is the use of specific agents for the dysregulated proteins of cancer cells. Small-molecule-targeted therapy drugs are often inhibitors of enzymatic domains on mutant, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are tyrosine kinase inhibitors like Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandecyclanib, and also inhibitors of selic kinase and allic kinase dependents and also allic kinase dependents. Monoclonal antibody therapy is another strategy where the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include the anti-HER2/neu trastuzumab antibody (HERCEPTIN®), commonly used in breast cancer, and the anti-CD20 antibody Rituximab and Tositumomab commonly used in a variety of malignant B-cell neoplasms. 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, for example, a biguanide such as metformin or phenformin, preferably phenformin.
Targeted therapy may also involve small peptides like "guided devices" that can bind to cell surface receptors or affected extracellular matrix around the tumor. Radionuclides that are attached to these peptides (eg, RGDs) eventually kill the cancer cell if the isotope decays in the cell's vicinity. 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 that aim 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 the use of interferon and other cytokines to induce an immune response in individuals with renal cell carcinoma and melanoma.
Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, as the donor's immune cells will often attack the tumor in a graft-versus-tumor effect. In some embodiments, immunotherapeutic agents can be used in combination with a compound or composition described herein.
In some embodiments, the additional cancer therapeutic agent is a hormone therapy agent. The growth of some cancers can be inhibited by supplying or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancer. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain types of cancer, the administration of hormonal agonists such as progestins may be therapeutically beneficial. In some embodiments, hormone therapy agents can be used in combination with a compound or composition described herein.
Other possible additional therapeutic modalities include imatinib, gene therapy, dendritic cell and peptide vaccines, synthetic chlorotoxins, and radiolabelled drugs and antibodies. EXAMPLES
List of abbreviations Genera 46 anhy. Anhydrous 20 conc. concentrate aq. aqueous min minute(s) ml milliliter mmol millimole(s) 25 mol mole(s) MS mass spectrometry NMR nuclear magnetic resonance TLC thin layer chromatography. HPLC high performance liquid chromatography 30 prep- HPLC preparative high performance liquid chromatography - Hz spectrum hertz δ chemical shift J coupling constant s singlet d doublet t triplet q quartet m multiplet br broad qd quartet of doublets dquin doublet of quintets dd doublet of doublets dt doublets of Solvents and Reagents triplets
CHCl3 chloroform DCM dichloromethane DMF Dimethylformamide DME 1,2-dimethoxyethane CCl4 carbon tetrachloride DMSO dimethylsulfoxide Et2O diethyl ether EtOH ethyl alcohol EtOAc ethyl acetate MeOH methyl alcohol MeCN acetonitrile PE petroleum ether THF tetrahydrofuran AcOH acetic acid HClO4 perchloric acid BuOH tert-butanol SOCl2 thionyl dichloride HCl hydrochloric acid H2SO4 sulfuric acid NH4Cl ammonium chloride KOH potassium hydroxide NaOH sodium hydroxide 1.iOHJbO lithium hydroxide monohydrate K2CO3 potassium carbonate Na2CO3 sodium carbonate TFA trifluoroacetic acid Na2SO4 sodium hydride NaBH sodium NaHCO3 sodium carbonate LiHMDS lithium hexamethyldisilylamide NaHMDS sodium hexamethyldisilylamide LAH lithium aluminum hydride NaBH4 sodium borohydride LDA lithium diisopropylamide PPh3 Triphenylphosphine ZnEt2 Diethyl zinc Et3N triethylamine DMAP 4-(dimethylamino)pyridine N,N-diisopropylamine ammonium E DCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt 1-hydroxybenzotriazole HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium BINAP 2.2'-bis (diphenylphosphanyl) -1,1'-binaphthyl Pd(dppf)Cl2 [1,1']-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) TBAI Tetrabutylammonium iodide TEBA Benzyltriethylammonium chloride
TMSCN Trimethylsilyl cyanide NMP 1-Methyl-pyrrolidin-2-one MsCl Methanesulfonyl chloride DPPA Diphenylphosphoryl azide Pd(OH)2 Palladium(II) hydroxide DAST Diethylaminosulfur trifluoride General experimental information
In the examples below, reagents (chemicals) were purchased from commercial sources (eg, Alpha, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. Flash chromatography was performed on an Ez III scrubber through the column with 200-300 mesh silica gel particles. Analytical and preparative thin layer chromatography (TLC) plates were HSGF 254 (0.15-0.2 mm thick, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-300 or an AMX-300 NMR (Brucker, Switzerland). Chemical shifts were reported in parts per million (ppm, δ) low field from tetramethylsilane. Mass spectra were performed with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA). HPLC chromatographs were recorded on an Agilent 1200 Liquid Chromatography (Agilent, USA, column: Ultimate 4.6mmx50mm, 5μM, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). The microwave reactions were performed on an Initiator 2.5 microwave synthesizer (Biotage, Sweden).
Example 1. Preparation of N-cyclohexyl-2-[(2-imidazol-1-yl-acetyl)-thiophen-2-ylmethyl-amino]-2-o-tolyl-acetamide (Compound 204) and its HCl Salt. Compound 204 was prepared according to Scheme 1, above, using the following protocol.
Step A: Compound 204. A mixture of 2-methyl-benzaldehyde (193 mg, 1.61 mmol) and thiophen-2-yl-methylamine (182 mg, 1.61 mmol) in MeOH (4 ml) was stirred at temperature environment for 30 minutes. Imidazol-1-yl-acetic acid (202 mg, 1.61 mmol) was added and the reaction mixture stirred for 10 minutes. Cyclohexyl isocyanide (176 mg, 1.61 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The precipitate was filtered and washed with MeOH to give the desired product (463 mg, 64% yield). 1 H NMR (300 MHz, DMSO-d6): δ 8.15-8.01 (m, 1H), 7.62-7.52 (m, 1H), 7.31-6.69 (m, 9H) , 6.24 (s, 1H), 5.65-4.66 (m, 4H), 2.60 (m, 1H), 2.20-2.05 (m, 3H), 1.76-1 1.51 (m, 5H), 1.29-0.83 (m, 5H); MS: 451.2 (M+1)+.
Step B: Compound 204 HCl salt. Compound 204 (460mg, 1.02mmol) in HCl/Et2O (5M, 20ml) was stirred at room temperature for 3 hours. The resulting mixture was concentrated and the solid was treated with Et2O to give the HCl salt (350 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 14.43 (s, 1H), 9.15-9.04 (m, 1H), 8.28-8.05 (m, 1H), 7.64 -6.23 (m, 10H), 5.95-4.41 (m, 4H), 3.60 (m, 1H), 2.23 (s, 3H), 1.74-1.51 (m , 5H), 1.30-0.71 (m, 5H); MS: 451.1 (M+1)+.
The following analogs were synthesized via the procedure described in Scheme 1, using the appropriate aldehyde from R2 (a), amine from R3 (b), carboxylic acid from R4 (c), and cyano from R1 (d) using the reagents and solvents described in step A, above, and purified by various methods including TLC, Chromatography, HPLC or chiral HPLC. The corresponding HCl salt was made as described in step B above. 1H NMR(400MHz, MeOD-d4): δ 7.66(d, 2H), 7.17-6.95 (m, 4H), 6.86-6.67 (m, 4H), 6.49 (m, 1H), 6.28 (S, 1H), 3.84 (d, 1H), 3.80 (m, 1H), 2.36 (s, 3H), 1.95-1.74 ( m, 6H), 1.52-1.34 (m, 2H); MS: 529.2 (M+1)+. Compound 361
1H NMR(400 MHz , MeOD-d4): δ 7,66(d, 2H), 7,17-6,95 (m, 4H), 6,86-6,67 (m, 4H), 6,49(m, 1H), 6,28 (S, 1H), 3,84 (d, 1H), 3,80 (m, 1H), 2,36 (s, 3H), 1,95-1,74 (m, 6H), 1,52-1,34 (m, 2H); MS: 529,2 (M+1)+. 5 Composto 379 1H NMR (400 MHz, CDCl3): δ 7.76 (br, 1H), 7.16-7.09 (m, 4H), 6.93-6.78 (m, 3H), 6.50(m , 1H), 6.37(d, 1H), 5.60(s, 1H), 4.29(d, 1H), 3.88(dq, 2H), 2.39(s, 3H); MS: 504.1 (M+1)+.Compound 342 1H NMR(400MHz, MeOD-d4): δ 7.66(d, 2H), 7.17-6.95 (m, 4H), 6.86-6.67 (m, 4H), 6.49 (m, 1H), 6.28 (S, 1H), 3.84 (d, 1H), 3.80 (m, 1H), 2.36 (s, 3H), 1.95-1.74 ( m, 6H), 1.52-1.34 (m, 2H); MS: 529.2 (M+1)+. 5 Compound 379
1H NMR (400 MHz, DMSO-d6): 8.60 (m, 1H), 7.80 (d, 1H, J = 4.8), 7.39-7.34 (m, 1H), 7. 19-7.05 (s, 4H), 6.90 (t, 1H, J = 4.0), 6.67-6.56 (m, 4H), 6.24 (s, 1H), 4, 11(br, 1H), 3.96 (dd, 1H, J = 15.2, 3.2), 3.62 (dd, 1H, J = 15.2, 3.2), 2.95 (br , 1H), 2.40(s, 3H), 1.31 10 1.18 (m, 4H); MS: 500.7 (M+1)+. Compound 17
1H NMR (300 MHz, CDCl3): δ 7.22-7.09 (m, 9H), 6.89-6.86 (m, 1H), 6.71-6.70 (m, 1H), 6 .03(s, 1H), 5.73-5.70(d, 1H), 4.23(m, 1H), 3.62(s, 2H), 2.36(s, 3H), 1, 96 (m, 15 1H), 1.58-1.54(m, 5H), 1.40-1.35 (m, 2H); 419.1 (M+1)+. Compound 333 (HCl Salt)
1H NMR (400 MHz, MeOD-d4): δ 8.12 (br, 1H), 7.82 (br, 1H), 7.46 (s, 2H), 7.16-6.82 (m, 7H) ), 6.35 (s, 1H), 5.04 (d, 1H), 4.78 (d, 1H), 4.33 (br, 2H), 2.59 (s, 3H), 2.48 (s, 3H), 2.30-2.27 (m, 2H), 1.75-1.68 (m,2H), 1.37-1.29 (m,2H), 0.46 (q , 1H), 0.01 (q, 1H); MS: 491.2 (M+1)+. 5 Compound 268
1H NMR (400 MHz, DMSO-d6): δ 8.22-7.99 (m, 2H), 7.37-7.35 (d, 1H,J=6.8), 7.29-6, 62 (m, 8H), 6.18 (s, 1H), 4.66-4.61 (m, 1H), 4.37-4.30 (m, 1H), 3.61 (s, 1H) , 2.36 (s, 3H), 2.09-2.01 (m, 3H), 1.73-1.52 (m, 5H), 1.25-0.95 (m, 5H); MS: 523.0 (M+1)+. 10 Compound 227
1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.85 (dr, 1H), 7.44-7.42 (d, 2H, J=8.8), 7 .12-6.99 (m, 4H), 6.89-6.73 (m, 4H), 6.56-6.54 (d, 2H, J=8.8), 6.22(s, 1H), 3.86-3.80 (m, 1H), 3.63-3.61 (m, 1H), 3.44-3.40 (m, 1H), 2.37 (s, 3H) , 1.76-1.52 (m, 5H), 1.29 15 0.96 (m, 5H); MS: 499.2 (M+1)+. Compound 228
1H NMR (400 MHz, DMSO-d6): δ 8.16-8.00 (m, 1H), 7.51-7.41 (m, 2H), 7.33-7.17 (m, 4H) , 7.08-6.93 (m, 1H), 6.81-6.78 (m, 1H), 6.67-6.54 (m, 3H), 6.29-5.66 (m, 1H), 5.04-4.85 (m, 1H), 4.72-4.42 (m, 1H), 4.27-4.06 (m, 1H), 3.90-3.77 ( m, 1H), 3.61 (s, 1H), 2.22-2.01 (m, 3H), 1.75-1.52 (m, 5H), 1.29-1.09 (m, 5H); MS: 501.2 (M+1)+. Compound 329
1H NMR (400 MHz, DMSO-d6): δ 8.05-8.01 (m, 2H), 7.89-7.71 (m, 2H), 7.28-7.03 (m, 4H) , 6.89-6.86 (m, 1H), 6.74-6.72 (d, 1H, J=7.2), 6.19 (s, 1H), 5.20-5.16 ( d, 1H, J=15.6), 4.92-4.89 (m, 1H), 3.63-3.61 (m, 1H), 2.39 (s, 3H), 1.70- 1.51 (m, 5H), 1.27-0.94 (m, 5H); MS: 450.2 (M+1)+. Compound 42
(300 MHz, DMSO-d6): δ 7.92 (d, 2H, J=7.8 Hz), 7.35-7.33 (m, 1H), 7.29-7.25 (m, 1H) ), 7.14-7.06 (m, 2H), 6.98 (t, 2H, J=7.5 Hz), 6.91-6.82 (m, 1H), 6.79 (t, 1H, J=7.5Hz), 6.69-6.66 (m,2H), 6.55-6.50 (m, 1H), 6.24 (s, 1H), 3.65-3 .45 (m, 3H), 2.30 (s, 3H), 1.77-1.51 (m, 5H), 1.25-0.93 (m, 5H); MS: 447.2 (M+1)+. Compound 113
1H NMR (300 MHz, DMSO-d6): δ 7.99-7.40 (m, 1H), 7.37 (d, 1H, J=6.6 Hz), 7.23 (br, 4H), 6.94-6.89 (m, 2H), 5.66 (s,1H), 4.00-3.90 (m,2H), 3.57 (s, 1H), 3.00 (s, 1H), 2.27-1.91 (m, 5H), 1.71-1.31 (m, 6H), 1.26-0.63 (m, 12H); MS: 451.64 (M-1)-. Compound 166
1H NMR (300 MHz, DMSO-d6): δ 8.09 (d, 2H, J=7.5 Hz), 7.43 (d, 1H, J=1.8 Hz), 7.36-7, 34 (m, 1H), 7.11-7.04 (m, 2H), 6.95-6.90 (m, 2H), 6.80-6.78 (m,2H), 6.11( s, 1H), 5.89 (d, 1H, J=2.1 Hz), 3.73-3.35 (m, 6H), 2.26 (s, 3H), 1.74-1.50 (m, 5H), 1.34-1.08 (m, 5H); MS: 451.2 (M+1)+. Compound 205
1H NMR (300 MHz, DMSO-d6): δ 8.11-8.08 (m, 2H), 7.76-7.74 (m, 2H), 7.62-7.59 (m, 1H) , 7.50-7.49 (m, 1H), 7.46-7.42 (m, 1H), 7.27 (d, 1H, J=5.7 Hz), 7.24-7.22 (m, 1H), 7.17-7.14 (m, 1H), 6.88 (d, 1H, J=5.7Hz), 6.26-6.24 (m, 2H), 6. 11(s, 1H), 5.28-4.90 (m, 2H), 3.63-3.60 (m, 1H), 1.99 (s, 3H), 1.76-1.49 ( m, 5H), 1.27-1.06 (m, 5H); MS: 503.2 (M+1)+. Compound 15
1H NMR (300 MHz, DMSO-d6): δ 7.15-6.72 (m, 10H), 6.40 (s, 1H), 5.38-5.36 (m, 1H), 3.85 -3.81 (m, 1H), 3.65 (s, 1H), 2.35 (s, 3H), 1.97-1.56 (m, 5H), 1.36-0.96 (m , 5H); MS: 465.2 (M+1)+. Compound 230
1H NMR (300 MHz, DMSO-d6): δ 8.02-7.99 (d, 2H), 7.09-6.69 (m, 7H), 6.20 (s, 1H), 3.83 -3.57 (m, 4H), 2.34 (s, 3H), 1.73-1.19 (m, 18H); MS: 467.3 (M+1)+. Compound 214
1H NMR (300 MHz, DMSO-d6): δ 8.05-8.03 (d, 2H), 7.33-6.72 (m, 11H), 6.25 (s, 1H), 4.40 (s, 2H), 3.99-3.95 (d, 1H), 3.73-3.69 (d, 1H), 3.67-3.62 (m, 1H), 2.35 (s , 3H), 1.79-1.53 (m, 5H), 1.30-0.97 (m, 5H); MS: 507.2 (M+1)+. Compound 176
1H NMR (300 MHz, DMSO-d6): δ 8.22-7.99 (m, 1H), 7.31-6.71 (m, 9H), 6.25 (s, 1H), 5.68 -4.71 (m, 4H), 3.61-3.57 (m, 1H), 2.22-2.01 (m, 6H), 1.76-1.51 (m, 5H), 1.300 .95 (m, 5H); MS: 465.2 (M+1)+. Compound 204
1H NMR (300 MHz, DMSO-d6): δ 8.15-8.01 (m, 1H), 7.62-7.52 (m, 1H), 7.31-6.69 (m, 9H) , 6.24 (s, 1H), 5.65-4.66 (m, 4H), 2.60 (m, 1H), 2.20-2.05 (m, 3H), 1.76-1 1.51 (m, 5H), 1.29-0.83 (m, 5H); MS: 451.2 (M+1)+. Compound 13
1H NMR (300 MHz, DMSO-d6): δ 7.49-6.80 (m, 9H), 6.65 (s, 1H), 6.11-5.95 (m, 1H), 5.94 -5.39 (m, 1H), 3.80-3.74 (m, 1H), 3.56 (s, 1H), 2.10 (s, 1.5H), 1.84 (s, 1 .5H), 5 1.93-1.52 (m, 5H), 1.39-1.01 (m, 5H); MS: 465.2 (M+1)+. Compound 243
1H NMR (400 MHz, DMSO-d6): δ7.97-7.80 (m, 2H), 7.37-6.26 (m, 13H), 3.71 (s, 3H), 3.62- 3.50 (m, 3H), 2.33 (s, 3H), 1.75-1.51 (m, 5H), 1.28-0.94 (m, 5H); MS: 512.2 10 (M+1)+.Compound 305
1H NMR (400 MHz, DMSO-d6): δ 8.42-8.41 (d, 1H, J=4.0 MHz), 8.01 (s, 1H), 7.67-7.66 (m , 2H), 7.23-6.25 (m, 10H), 3.67-3.54 (m, 2H), 3.17 (d, 1H, J=4.8MHz), 2.38 ( s, 3H), 1.77-1.52 (m, 5H), 1.29-0.87 (m, 5H); MS: 460.1 (M+1)+. Compound 311
1H NMR (400 MHz, DMSO-d6): δ 8.44-8.43 (m, 2H), 8.02 (s, 1H), 7.73 (s, 1H), 7.25-6.53 (m, 9H), 6.24 (s, 1H), 3.62-3.35 (m, 3H), 2.36 (s, 3H), 1.72-1.52 (m, 5H), 1,230.93 (m, 5H); MS: 460.1 (M+1)+. Compound 294
1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 8.05-7.87 (m, 3H), 7.36-6.58 (m, 7H), 6.19 (s, 1H), 4.96-4.70 (m, 2H), 3.61 (m, 1H), 2.39 (s, 3H), 1.74-1.52 (m, 5H), 1.28-0.93 (m, 5H); MS: 450.1 (M+1)+. Compound 320
1H NMR (400 MHz, DMSO-d6): δ 8.98 (d, 1H, J=1.6 MHz), 8.19-8.17 (d, 1H, J=7.2 MHz), 7, 62-6.69 (m, 9H), 6.31 (s, 1H), 3.67-3.52 (m, 3H), 1.74-1.55 (m, 5H), 1.290.99 ( m, 5H); MS: 470.0 (M+1)+. Compound 312
1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, 1H, J=4.8 MHz), 7.75 (s, 1H), 7.26-6.71 (m, 9H), 6.27 (s, 1H), 4.75-4.39 (m, 2H), 3.62 (m, 1H), 2.13 (s, 3H), 1.75-1.54 (m, 5H), 1.27-0.99 (m, 5H); MS: 467.1 (M+1)+. Compound 46
1H NMR (300 MHz, DMSO-d6): δ 8.12-8.07 (m, 1H), 8.02 (d, 1H, J=6.9 Hz), 7.366.66 (m, 10H), 6.31 (s, 1H), 4.09-4.02 (m, 1H), 3.54 (s, 2H), 2.36 (s, 3H), 1.86-1.14 (m, 8H); MS: 451.1 (M+1)+. Compound 47
1H NMR (300 MHz, DMSO-d6): δ 8.19 (d, 1H, J=7.2 Hz), 7.95-7.94 (m, 1H), 7.36-6.73 (m , 10H), 6.35(s, 1H), 4.08-4.02 (m, 1H), 3.55 (s, 2H), 1.85-1.15 (m, 8H); MS: 455.1 (M+1)+. Compound 2
1H NMR (300 MHz, DMSO-d6): δ 8.22 (d, 1H, J=7.2 Hz), 8.05-7.99 (m, 1H), 7.376.75 (m, 10H), 6.49 (s, 1H), 4.08-4.02 (m, 1H), 3.56 (s, 2H), 1.84-1.16 (m, 8H); MS: 471.1 (M+1)+. Compound 48
1H NMR (300 MHz, DMSO-d6): δ 8.09 (d, 1H, J=7.2 Hz), 7.90-7.89 (m, 1H), 7.36 6.72 (m, 11H), 5.99 (s, 1H), 4.05-4.02 (m, 1H), 3.52 (s, 2H), 1.77-1.21 (m, 8H); MS: 437.1 (M+1)+. Compound 49
1H NMR (300MHz, DMSO-d6): δ 8.00 (d, 1H, J=7.5Hz), 7.36-6.60 (m, 11H), 5 6.03 (s, 1H) , 3.60-3.56 (m, 6H), 1.71-1.56 (m, 5H), 1.24-0.93 (m, 5H); MS: 481.1 (M+1)+. Compound 50
1H NMR (300 MHz, DMSO-d6): δ 8.05 (d, 1H, J=7.5 Hz), 7.36-6.73 (m, 11H), 6.05 (s, 1H), 3.58-3.56 (m, 3H), 1.72-1.50 (m, 5H), 1.20-0.91 (m, 5H); MS: 469.1 (M+1)+. 10 Compound 51
1H NMR (300 MHz, DMSO-d6): δ 8.08 (d, 1H, J=7.5 Hz), 7.36-6.71 (m, 9H), 6.32 (s, 1H), 3.59-3.56 (m, 3H), 2.14 (s, 3H), 1.73-1.48 (m, 5H), 1.25-1.02 (m, 5H); MS: 471.1 (M+1)+. 15 Compound 115
1H NMR (300 MHz, DMSO-d6): δ 8.08 (d, 1H, J=7.5 Hz), 7.36-6.73 (m, 11H), 6.04 (s, 1H), 3.60-3.57 (m, 3H), 1.71-1.55 (m, 5H), 1.25-1.01 (m, 5H); MS: 529.1 (M+1)+. Compound 89
1H NMR (300 MHz, DMSO-d6): δ 7.98 (d, 1H, J=7.5 Hz), 7.36-6.73 (m, 11H), 6.03 (s, 1H), 3.58-3.56 (m, 3H), 2.14 (s, 3H), 1.71-1.46 (m, 5H), 1.25-0.94 (m, 5H); MS: 465.2 (M+1)+. Compound 91
1H NMR (300 MHz, DMSO-d6): δ 9.24 (s, 1H), 8.01-7.98 (m, 1H), 7.36-6.47 (m, 11H), 5.98 (s, 1H), 3.58-3.54 (m, 3H), 1.71-1.50 (m, 5H), 1.24-0.97 (m, 5H); MS: 467.1 (M+1)+. Compound 62
1H NMR (300 MHz, DMSO-d6): δ 8.15 (d, 1H, J=7.5 Hz), 7.98-7.95 (m, 1H), 7.46-6.76 (m , 10H), 6.47 (s, 1H), 3.65-3.51 (m, 3H), 1.66-1.52 (m, 5H), 1.23-0.91 (m, 5H) ); MS: 496.1 (M+1)+. Compound 92
1H NMR (300 MHz, DMSO-d6): δ 9.32 (s, 1H), 7.91 (d, 1H, J=7.5 Hz), 7.35-6.47 (m, 11H), 5.95 (s, 1H), 3.55-3.53 (m, 3H), 1.77-1.55 (m, 5H), 1.24-0.96 (m, 5H); MS: 467.1 (M+1)+. Compound 65
1H NMR (300 MHz, DMSO-d6): δ 7.98 (d, 1H, J=7.5 Hz), 7.36-6.27 (m, 11H), 5.75 (s, 1H), 3.62-3.57 (m, 3H), 2.74-2.64 (m, 2H), 1.74-1.48 (m, 5H), 1.28-0.95 (m, 8H) ); MS: 479.2 (M+1)+. Compound 116
1H NMR (300 MHz, DMSO-d6): δ 8.04 (d, 1H, J=7.5 Hz), 7.37-6.63 (m, 11H), 6.24 (s, 1H), 3.79(s, 1H), 3.64-3.54 (m, 3H), 1.74-1.50 (m, 5H), 1.26-0.97 (m, 5H); MS: 481.2 (M+1)+. Compound 94
1H NMR (300 MHz, DMSO-d6): δ 8.10 (d, 1H, J=7.8 Hz), 7.37-6.71 (m, 10H), 6.29 (s, 1H), 3.59-3.55 (m, 3H), 1.75-1.56 (m, 5H), 1.24-1.03 (m, 5H); MS: 457.1 (M+1)+. Compound 127
1H NMR (300 MHz, DMSO-d6): δ 8.13 (d, 1H, J=7.5 Hz), 7.36-6.64 (m, 10H), 5 6.26 (s, 1H) , 3.69-3.57 (m, 3H), 2.04 (s, 3H), 1.74-1.50 (m, 5H), 1.23-1.00 (m, 5H); MS: 483.1 (M+1)+. Compound 128
1H NMR (300 MHz, DMSO-d6): δ 8.19 (d, 1H, J=7.5 Hz), 7.36-6.34 (m, 10H), 10 6.25 (s, 1H) , 3.64-3.58 (m, 3H), 3.51 (s, 3H), 1.75-1.50 (m, 5H), 1.26-0.99 (m, 5H); MS: 499.1 (M+1) +.Compound 203
1H NMR (300 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.33-8.31 (m, 1H), 8.13-7.76 (m, 15 2H), 7. 31-6.61 (m, 10H), 6.26 (s, 1H), 3.66-3.37 (m, 3H), 2.34 (s, 3H), 1.73-1.50 ( m, 5H), 1.23-0.95 (m, 5H); MS: 499.2 (M+1)+. Compound 213
1H NMR (300 MHz, DMSO-d6): δ 12.03 (s, 1H), 8.33-7.96 (m, 3H), 7.50-5.66 (m, 10H), 5.00 -3.87 (m, 4H), 3.79 (m, 1H), 2.19 (s, 1.5H), 1.78-1.51 (m, 6.5H), 1.29-1 .04 (m, 5H); MS: 501.2 (M+1)+. Compound 261
1H NMR (400 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.84 (s, 1H), 8.27-6.63 (m, 12H), 6.26 (s, 1H) ), 3.73-3.51 (m, 3H), 2.36 (s, 3H), 1.74-1.52 (m, 5H), 1.27-0.93 (m, 5H); MS: 499.1 (M+1)+. Compound 269
1H NMR (400 MHz, DMSO-d6): δ 12.52 (s, 1H), 9.08 (s, 1H), 8.47-6.75 (m, 12H), 6.41 (s, 1H ), 3.78-3.76 (m, 1H), 2.38 (s, 3H), 1.91-1.56 (m, 5H), 1.35-0.85 (m, 5H); MS: 513.1 (M+1)+. Compound 223
1H NMR (400 MHz, DMSO-d6): δ 14.30-14.24 (m, 1H), 8.03-6.83 (m, 13H), 6.17 (s, 1H), 5.03 -4.66 (m, 2H), 3.89-3.52 (m, 4H), 2.49-2.37 (m, 6H), 1.75-1.71 (m, 5H), 1 .25-1.06 (m, 5H); MS: 525.3 (M+1)+. Compound 275
1H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H), 8.30 (s, 1H), 8.01-6.72 (m, 12H), 6.27 (s, 1H) ), 3.66-3.17 (m, 3H), 2.37 (s, 3H), 1.73-1.52 (m, 5H), 1.28-0.95 (m, 5H); MS: 499.1 (M+1)+. Compound 276
1H NMR (400 MHz, DMSO-d6): δ 14.92 (d, 1H, J=1.6 MHz), 12.74 (s, 1H), 9.09 (s, 1H), 8.25- 6.72 (m, 12H), 6.25 (s, 1H), 3.77-3.53 (m, 3H), 2.37 (s, 3H), 1.73-1.52 (m, 5H), 1.27-0.97 (m, 5H); MS: 499.1 (M+1)+. Compound 283
1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 7.95-6.23 (m, 15H), 3.75-3.50 (m, 2H), 2.41 (s, 1.43H), 2.13 (s, 1.59H), 1.77-1.54 (m, 5H), 1.39-1.09 (m, 8H); MS: 512.2 (M+1)+. Compound 304
1H NMR (400 MHz, DMSO-d6): δ 8.12 (d, 1H, J=7.6 MHz), 7.87 (s, 1H), 7.64 (d, 1H, J=3.2 MHz), 7.45 (d, 1H, J=3.2 MHz), 7.25-7.12 (m, 4H), 6.99 (s, 1H), 6.89 (d, 1H, J =7.6 MHz), 6.17 (s, 1H), 5.38 (d, 2H, J=4.0 MHz), 5.10 (d, 1H, J=18.4 MHz), 4. 83 (d, 1H, J=18.4 MHz), 3.61 (m, 1H), 1.99 (s, 3H), 1.76-1.51 (m, 5H), 1.29-0 .99 (m, 5H); MS: 452.1 (M+1)+. Compound 26
1H NMR (300 MHz, DMSO-d6): δ 8.12 (d, 1H, J = 8), 7.36-6.62 (m, 9H), 6.23 (s, 1H), 4.05 (m, 1H), 3.78 (s, 3H), 3.61-3.50 (m, 2H), 1.78 (m, 2H), 1.58-1.43 (m, 5H), 1.24 (m, 1H); MS: 467.1 (M+1)+. Compound 43
1H NMR (300 MHz, DMSO-d6): δ 8.25 (d, 1H, J = 8), 7.36-6.74 (m, 9H), 6.29 (s, 1H), 4.08 (m, 1H), 3.63 (m, 2H), 1.78 (m, 2H), 1.58-1.43 (m, 5H), 1.25 (m, 1H); MS: 455.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.29 (d, 1H, J = 8), 7.35-6.72 (m, 9H), 6.34 (s, 1H), 4.09 (m, 1H), 3.68-3.53 (m, 2H), 1.78 (m, 2H), 1.63-1.48 (m, 5H), 1.26 (m, 1H); MS: 471.1 (M+1)+. Compound 45
1H NMR (300 MHz, DMSO-d6): δ 8.12 (d, 1H, J = 8), 7.35-6.72 (m, 10H), 6.06 (s, 1H), 4.05 (m, 1H), 3.61-3.51 (m, 2H), 1.87-1.64 (m, 2H), 1.60-1.38 (m, 5H), 1.28(m) , 1H); MS: 437.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.35 (d, 1H, J = 7.5), 7.62-6.64 (m, 8H), 6.24 (s, 1H), 3 .69-3.04 (m, 3H), 1.75-1.50 (m, 5H), 1.36-0.96 (m, 5H); MS: 547.0, 549.0 (M+1)+. Compound 102
1H NMR (300 MHz, DMSO-d6): δ 8.14 (d, 1H, J = 7.5), 7.37-6.74 (m, 9H), 6.02 (s, 1H), 3 1.60 (m, 3H), 1.73-1.50 (m, 5H), 1.32-0.96 (m, 5H); MS: 503.1, 505.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.35 (d, 1H, J = 7.5), 7.41-6.74 (m, 8H), 6.30 (s, 1H), 3 1.66-3.52 (m, 3H), 1.73-1.50 (m, 5H), 1.32-1.02 (m, 5H); MS: 519.1, 521.1 (M+1)+. Compound 78
1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, 1H, J = 7.5), 7.34-6.74 (m, 10H), 6.02 (s, 1H), 3 .57 (m, 3H), 2.15 (s, 3H), 1.73-1.50 (m, 5H), 1.32-0.95 (m, 5H); MS: 465.2 (M+1)+. Compound 80
1H NMR (300 MHz, DMSO-d6): δ 8.05 (d, 1H, J = 7), 7.77-6.72 (m, 10H), 6.23 (s, 1H), 3.80 (m, 1H), 3.60 (m, 2H), 2.34 (s, 3H), 1.80-1.25 (m, 12H); MS: 479.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ9.70 (s, 1H), 8.02 (d, 1H, J = 7.5), 7.35-6.44 (m, 11H), 6. 20 (s, 1H), 3.60 (m, 3H), 1.70-1.50 (m, 5H), 1.24-1.00 (m, 5H); MS: 467.1 (M+1) + . Compound 106
1H NMR (300 MHz, DMSO-d6): δ 8.22 (d, 1H, J = 7.5), 7.52-6.75 (m, 8H), 6.23 (s, 1H), 3 1.62 (m, 3H), 1.70-1.50 (m, 5H), 1.35-1.00 (m, 5H); MS: 505.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 7.99 (d, 1H, J = 7.5), 7.73-6.78 (m, 8H), 6.39 (s, 5 1H), 3.64-3.50 (m, 3H), 1.70-1.50 (m, 5H), 1.35-1.00 (m, 5H); MS: 624.9 (M+1)+. Compound 87
1H NMR (300 MHz, DMSO-d6): δ 8.13 (d, 1H, J = 7.5), 7.35-6.73 (m, 5H), 6.30 (d, 1H, J = 3.3), 6.12 (s, 1H), 6.07 (d, 1H, J = 3.3), 3.60 (m, 3H), 1.72-1.50 (m, 5H) , 1.30 10 1.00 (m, 5H); MS: 519.0 (M+1)+. Compound 108
1H NMR (300 MHz, DMSO-d6): δ 8.02 (d, 1H, J = 7.5), 7.65-6.73 (m, 8H), 6.40 (s, 1H), 3 1.59(m, 3H), 1.72-1.50 (m, 5H), 1.39-1.00 (m, 5H); MS: 519.1 (M+1)+. 15 Compound 130
1H NMR (300 MHz, DMSO-d6): δ 7.79 (m, 2H), 7.45-6.67 (m, 7H), 6.40 (s, 1H), 5.85-5.64 (m, 1H), 3.56 (m, 3H), 2.15-1.50 (m, 11H), 1.25-1.07 (m, 5H); MS: 479.2 (M+1)+. Compound 394
1H NMR (300 MHz, DMSO-d6): δ 8.66 (m, 1H), 7.36-6.74 (m, 14H), 6.34 (s, 1H), 4.35 (m, 2H) ), 3.64 (m, 2H), 2.35 (s, 3H); MS: 473.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 7.76 (br, 2H), 7.34-6.74 (m, 9H), 6.22 (s, 1H), 3.60 (m, 2H) ), 2.33 (s, 3H), 1.25 (s, 9H); MS: 439.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ9.63 (s, 1H), 7.36-6.76 (m, 13H), 6.50 (s, 1H), 3.64 (m, 2H) , 2.42(s, 3H), 2.10(s, 3H); MS: 471.1 (M -1) -. Compound 125
1H NMR (300 MHz, DMSO-d6): δ 8.10 (d, 1H, J = 7.5), 7.09-6.65 (m, 12H), 6.45 (s, 1H), 4 1.15 (m, 3H), 3.64 (m, 1H), 2.34 (s, 3H), 1.75-1.50 (m, 5H), 1.38-1.03 (m, 5H) ); MS: 503.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 10.80 (s, 1H), 7.96-6.70 (m, 13H), 6.28 (s, 1H), 3.64-3.42 (m, 3H), 2.32 (s, 3H), 1.75-1.50 (m, 5H), 1.34-1.03 (m, 5H); MS: 498.2 (M+1)+. Compound 150
1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, 1H, J = 7.5), 7.74-6.74 (m, 10H), 6.26 (s, 1H), 3 1.64 (m, 1H), 3.38 (m, 2H), 2.33 (s, 3H), 1.78-1.52 (m, 5H), 1.34-0.95 (m, 5H) ); MS: 465.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.09 (d, 1H, J = 7.5), 7.15-6.73 (m, 11H), 6.45 (s, 1H), 5 1.96 (s, 2H), 3.64 (m, 1H), 2.35 (s, 3H), 1.70-1.52 (m, 5H), 1.34-1.03 (m, 5H) ); MS: 489.2 (M+1)+. Compound 137
1H NMR (300 MHz, DMSO-d6): δ 8.07 (d, 1H, J = 7.5), 7.30-6.73 (m, 11H), 6.06 5 (s, 1H), 3.58 (m, 3H), 1.78-1.52 (m, 5H), 1.34-1.03 (m, 5H); MS: 469.1 (M+1)+. Compound 138
1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, 1H, J = 7.5), 7.65 (d, 1H, J = 3.2), 7.15-10 6.55 (m, 8H), 6.41 (s, 1H), 3.63 (m, 1H), 2.39 (s, 3H), 1.78-1.52 (m, 5H), 1.34- 1.03 (m, 5H); MS: 451.1 (M+1) +.Compound 139
1H NMR (300 MHz, DMSO-d6): δ 8.19 (d, 1H, J = 7.5), 7.29-6.83 (m, 8H), 6.51(s, 15 1H), 3.69 (m, 1H), 2.32 (s, 3H), 2.14 (s, 6H), 1.80-1.52 (m, 5H), 1.34-1.03 (m, 5H); MS: 464.2 (M+1)+. Compound 107
1H NMR (300 MHz, DMSO-d6): δ 8.10 (d, 1H, J = 7.5), 7.30-6.87 (m, 10H), 6.74 (s, 1H), 6 .05 (s, 1H), 3.60 (m, 3H), 1.70-1.52 (m, 5H), 1.34-0.95 (m, 5H); MS: 485.1, 487.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.07 (d, 1H, J = 7.5), 7.21-6.76 (m, 8H), 619 (s, 1H), 4.24 (s, 1H), 3.63 (m, 1H), 2.33 (s, 3H), 1.78-1.52 (m, 5H), 1.32-0.98 (m, 5H); MS: 393.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.96 (s, 1H), 7.99-6.54 (m, 10H), 6.25 (s, 1H), 3.65 (m, 3H) ), 2.36 (s, 3H), 1.70-1.50 (m, 5H), 1.32-0.96 (m, 5H); MS: 466.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.25 (d, 1H, J = 7.5), 7.70-6.74 (m, 9H), 6.28 (s, 1H), 3 1.63 (m, 3H), 1.70-1.50 (m, 5H), 1.30-0.95 (m, 5H); MS: 529.1, 531.1 (M+1)+. Compound 105
1H NMR (300 MHz, DMSO-d6): δ 7.98 (d, 1H, J = 7.5), 7.76-6.77 (m, 8H), 6.46 (m, 2H), 3 1.62 (m, 3H), 1.74-1.50 (m, 5H), 1.32-0.96 (m, 5H); MS: 521.1 (M+1)+. 5 Compound 5
1H NMR (300 MHz, DMSO-d6): δ 8.28-6.74 (m, 13H), 6.26 (s, 1H), 5.28 (m, 2H), 4.05 (m, 1H) ), 2.40 (s, 3H), 1.78 (m, 2H), 1.57-1.23 (m, 6H); MS: 486.2 (M+1)+. Compound 151
1H NMR (300 MHz, DMSO-d6): δ 8.05-6.78 (m, 12H), 6.19 (s, 1H), 5.58-5.15 (m, 2H), 3.59 (m, 1H), 2.41 (s, 3H), 1.69-1.53 (m, 5H), 1.32-0.96 (m, 5H); MS: 500.2 (M+1)+. Compound 157
1H NMR (300 MHz, DMSO-d6): δ 8.26-6.64 (m, 12H), 6.21 (s, 1H), 6.06-4.47 (m, 4H), 3.59 (m, 1H), 2.22 (s, 3H), 1.69-1.47 (m, 5H), 1.32-0.96 (m, 5H); MS: 502.2 (M+1)+. Compound 262
1H NMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 8.35 (m, 2H), 7.90 (d, 1H, J = 5.7), 7.46-6 1.74 (m, 11H), 6.40 (s, 1H), 3.78 (m, 1H), 2.37 (s, 3H), 1.87-1.60 (m, 5H), 1. 34-1.07 (m, 5H); MS: 512.1 (M+1)+. 5 Compound 270
1H NMR (400 MHz, DMSO-d6): δ 9.50 (m, 1H), 8.68 (d, 2H, J = 4.5), 8.15 (d, 1H, J = 5.7) , 7.38-6.74 (m, 9H), 6.22 (s, 1H), 4.35 (m, 2H), 3.64 (m, 1H), 2.40 (s, 3H), 1.72-1.50 (m, 5H), 1.34-1.07 (m, 5H); MS: 503.1 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8.28 (d, 1H, J = 5.7), 7.55 (s, 1H), 7.29-6.79 (m, 9H), 6 .37 (s, 1H), 3.69 (m, 4H), 2.48 (s, 3H), 1.79-1.50 (m, 5H), 1.34-1.07 (m, 5H) ); MS: 477.1 (M+1)+. 15
1H NMR (400 MHz, DMSO-d6): δ 8.01-7.78 (m, 3H), 7.38-6.55 (m, 10H), 6.22(s, 1H), 3.94 (m, 1H), 3.61 (m, 2H), 2.38 (s, 3H), 1.70-1.50 (m, 5H), 1.34-1.00 (m, 5H); MS: 493.1 (M+1)+. Compound 316
1H NMR (400 MHz, DMSO-d6): δ 8.01-7.88 (m, 3H), 7.35-6.46 (m, 11H), 6.22 (s, 1H), 3.81 (m, 1H), 3.61 (m, 2H), 2.38 (s, 3H), 1.70-1.50 (m, 5H), 1.34-1.07 (m, 5H); MS: 475.1 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8.04-7.68 (m, 4H), 7.23-6.46 (m, 8H), 6.22 (s, 1H), 3.84 -3.35 (m, 3H), 2.38 (s, 3H), 1.70-1.50 (m, 5H), 1.34-1.07 (m, 5H); MS: 493.1 (M+1)+. Compound 30
1H NMR (300 MHz, DMSO-d6): δ 8.04-8.02 (d, 1H, J=5.7), 7.35-6.72 (m, 11H), 6.07 (s, 1H), 3.61-3.58 (m, 3H), 1.72-1.63 (m, 5H), 1.24-1.14 (m, 5H); MS: 451.1 (M+1)+. Compound 31
1H NMR (300 MHz, DMSO-d6): δ 8.25-8.23 (d, 1H, J=6), 7.74-6.73 (m, 10H), 6.35 (s, 1H) , 3.69-3.52 (m, 3H), 1.75-1.51 (m, 5H), 1.30-0.97 (m, 5H); MS: 485.1 (M+1)+. Compound 56
1H NMR (300 MHz, DMSO-d6): δ 8.38-8.32 (m, 2H), 7.73-6.68 (t, 1H), 7.39-6.73 (m, 10H) , 5.75 (s, 1H), 3.70-3.66 (m, 1H), 1.75-1.52 (m, 5H), 1.30-1.02 (m, 5H); MS: 466.1 (M+1)+. Compound 32
1H NMR (300 MHz, DMSO-d6): δ 8.32 (s, 1H), 8.18(br, 1H), 7.73-7.67 (t, 1H), 7.36-6.73 (m, 10H), 6.45 (s, 1H), 3.69-3.66 (m, 1H), 2.41 (s, 3H), 1.76-1.57 (m, 5H), 1 .28-1.03 (m, 5H); MS: 446.2 (M+1)+. Compound 33
1H NMR (300 MHz, DMSO-d6): δ 8.32-8.28 (m, 2H), 7.71-7.69 (t, 1H), 7.39-7.36 (d, 1H, J = 7.8), 7.26-6.77 (m, 9H), 6.53 (s, 1H), 3.69-3.65 (m, 1H), 1.77-1.60 ( m, 5H), 1.29-1.07 (m, 5H); MS: 450.1 (M+1)+. 5 Compound 34
1H NMR (300 MHz, DMSO-d6): δ 8.18-8.15 (d, 1H,J=6.9), 7.36-7.34 (d, 1H,J=8.1), 7.24-6.84 (m, 7H), 6.74-6.73 (d,1H,J=2.7), 6.30 (s, 1H), 3.69-3.52 (m , 3H), 1.74-1.51 (m, 5H), 1.29-0.97 (m, 5H); MS: 469.1 (M+1)+. 10 Compound 98
1H NMR (300 MHz, DMSO-d6): δ 8.38-8.35 (d, 1H,J=8.1), 7.79-7.77 (d, 1H,J=7.5), 7.42-6.63 (m, 10H), 6.35 (s, 1H), 3.58-3.49 (m, 3H), 2.54 (s,3H), 1.77-1, 51 (m, 5H), 1.27-0.88 (m, 5H); MS: 525.1 (M+1)+. 15 Compound 117
1H NMR (300 MHz, DMSO-d6): δ 7.99-7.95 (br, 1H), 7.36-6.47 (m, 9H), 6.23 (s, 1H), 3.66 -3.48 (m, 3H), 2.32 (s,3H), 2.18 (s,3H), 1.77-1.51 (m, 5H), 1.29-0.98 (m , 5H); MS: 495.1 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 7.92-7.89 (d, 1H, J=7.5), 7.71 (br, 1H), 7.35-7.33 (b, 1H, J=6.3), 7.09-6.31 (m, 8H), 6.22 (s, 1H), 3.61-3.45 (m, 3H), 2.33 (s, 3H), 2.22-1.96 (m, 3H), 1.77-1.51 (m, 5H), 1.29-0.92 (m, 5H); MS: 461.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.05-8.02 (d, 1H, J=8.1), 7.90-7.61 (br, 1H), 7.11-6, 97 (m, 4H), 6.87-6.82 (t, 1H), 6.72-6.70 (d, 1H, J=7.5), 6.21 (s, 1H), 4. 17-3.88 (q, 2H), 3.65-3.61 (m, 1H), 2.36 (s, 3H), 1.79-1.52 (m, 5H), 1.30- 0.96 (m, 5H); MS: 417.1 (M+1)+. Compound 101
1H NMR (300 MHz, DMSO-d6): δ 7.97-5.98 (m, 11H), 5.89 (s, 1H), 3.69-3.53 (m, 3H), 2.36 -2.33 (m, 3H), 1.77-1.53 (m, 5H), 1.29-0.95 (m, 5H); MS: 491.2 (M+1)+. Compound 100
1H NMR (300 MHz, DMSO-d6): δ 7.96-7.94 (d, 1H, J=7.5), 7.35-7.33 (m, 1H), 7.14-7, 01 (m, 8H), 6.91-6.88 (m, 1H), 6.71 (s, 1H), 3.59-3.50 (m, 3H), 1.76-1.51 ( m, 5H), 1.28-0.95 (m, 5H); MS: 433.2 (M+1)+. Compound 251
1H NMR (300 MHz, DMSO-d6): δ 8.03-8.02 (d, 1H, J=4.2), 7.10-6.70 (m, 6H), 6.21 (s, 1H), 4.04 (s, 1H), 3.94-3.89 (m, 1H), 3.70-3.54 (m, 6H), 2.35 (s, 3H), 1.82 -1.53 (m, 7H), 1.29-0.96 (m, 5H); MS: 469.2 (M+1)+. Compound 222
1H NMR (300 MHz, DMSO-d6): δ 8.04-8.01 (d, 1H, J=7.5H), 7.40-6.70 (m, 10H), 6.24 (s, 1H), 4.50-4.49 (m, 2H), 4.01-4.62 (m, 3H), 2.36 (s, 3H), 1.80-1.52 (m, 5H) , 1.31-0.96 (m, 5H); MS: 507.2 (M+1)+. 5 Compound 229
1H NMR (300 MHz, DMSO-d6): δ 8.51-8.48 (m, 2H), 8.04-8.02 (d, 1H, J=7.2H), 7.27-7, 25 (d, 2H, J = 6), 7.10-6.70 (m, 6H), 6.24 (s, 1H), 4.50 (s, 2H), 4.08-3.77 ( m, 2H), 3.63-3.62 (m, 1H), 2.35 (s, 3H), 1.80-1.52 (m, 5H), 1.30-0.96 (m, 5H); MS: 490.2 (M+1)+. 10 Compound 233
1H NMR (300 MHz, DMSO-d6): δ 8.49-8.48 (m, 2H), 8.06-8.04 (m, 1H), 7.70-7.68 (d, 1H, J=5.7), 7.37-6.72 (m, 6H), 6.25 (s, 1H), 4.47 (s, 2H), 4.04-3.74 (m, 2H) , 3.65-3.63 (m, 1H), 2.36 (s, 3H), 1.80-1.52 (m, 5H), 1.30-0.96 (m, 5H); MS: 490.2 (M+1)+. 15 Compound 234
1H NMR (300 MHz, DMSO-d6): δ 8.05-8.03 (d, 1H, J=7.2), 7.37-6.71 (m, 10H), 6.24 (s, 1H), 4.45 (s, 2H), 4.03-3.72 (m, 2H), 3.63-3.62 (m, 1H), 2.35 (s, 3H), 1.80 -1.52 (m, 5H), 1.31-0.96 (m, 5H); MS: 507.2 (M+1)+. 5 Compound 235
1H NMR (300 MHz, DMSO-d6): δ 8.03-8.00 (d, 1H, J=7.8), 7.10-6.69 (m, 7H), 6.20 (s, 1H), 4.42 (s, 1H), 4.24(s, 1H), 4.06-3.76 (m, 2H), 3.63-3.60 (m, 1H), 2.35 (s, 3H), 1.89-1.49 (m, 9H), 1.30-0.95 (m, 9H); MS: 499.2 (M+1)+. 10 Compound 259
1H NMR (300 MHz, DMSO-d6): δ 8.02-8.01 (d, 1H, J=4.8), 7.10-6.70 (m, 7H), 6.21 (s, 1H), 3.96-3.61 (m, 5H), 3.42-3.38 (m, 1H), 3.27-3.22 (m, 2H), 2.35 (s, 3H) , 1.79-1.53 (m, 7H), 1.30-0.96 (m, 7H); MS: 483.1 (M+1)+. 15 Compound 273
1H NMR (300 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.90-7.86 (m, 2H), 7.44-7.41 (m, 1H), 7.13 -6.48 (m, 8H), 6.21 (s, 1H), 4.67-4.35 (m, 2H), 3.62-3.60 (m, 1H), 2.39 (s , 3H), 1.72-1.52 (m, 5H), 1.28-0.96 (m, 5H); MS: 477.1 (M+1)+. Compound 274
1H NMR (300 MHz, DMSO-d6): δ 8.35 (s, 1H), 8.05-8.03 (br, 1H), 7.83-7.81 (d, 1H, J=6. 6), 7.45-6.75 (m, 8H), 6.20(s, 1H), 4.91-4.46 (m, 2H), 3.63-3.61 (m, 1H) , 2.37 (s, 3H), 2.28 (s, 4H), 1.74-1.52 (m, 5H), 1.29-0.95 (m, 5H); MS: 539.3 (M+1)+. Compound 281
1H NMR (300 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.05 (s, 1H), 7.79-7.75 (m, 1H), 7.37-6.71 (m, 9H), 6.24 (s, 1H), 4.52 (s, 2H), 4.09-3.80 (m, 2H), 3.64-3.63 (m, 1H), 2.35 (s, 3H), 1.79-1.52 (m, 5H), 1.29-0.96 (m, 5H); MS: 490.1 (M+1)+. Compound 282
1H NMR (300 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.57 (s, 2H), 8.05-8.03 (m, 1H), 7.79 (br, 1H) ), 7.10-6.71 (m, 6H), 6.24 (s, 1H), 4.61 (s, 2H), 4.14-3.85 (m, 2H), 3.64- 3.63 (m, 1H), 2.33 (s, 3H), 1.79-1.52 (m, 5H), 1.29-0.96 (m, 5H); MS: 491.1 (M+1)+. 5 Compound 303
1H NMR (300 MHz, DMSO-d6): δ 8.38 (s, 1H), 8.01-8.00 (m, 1H), 7.88 (br, 1H), 7.35-6.70 (m, 8H), 6.20 (s, 1H), 4.82-4.56 (m, 2H), 3.61-3.59 (m, 1H), 2.39(s, 3H), 2.28 (s, 4H), 1.70-1.51 (m, 5H), 1.27-0.95 (m, 5H); MS: 544.1 (M+1)+. .
1H NMR (300 MHz, DMSO-d6): δ 8.15-8.13 (d, 1H, J = 8.4), 8.02-7.99 (d, 1H, J = 1.2), 7.99-6.74 (m, 10H), 6.49 (s, 1H), 3.61-3.56 (m, 3H), 1.75-1.51 (m, 5H), 1. 32-1.0.85 (m, 5H); MS: 485.1 (M+1)+. Compound 36
1H NMR (300 MHz, DMSO-d6): δ 8.02-7.99 (d, 1H, J = 7.5), 7.92-7.89 (t, 1H), 7.35-6, 88 (m, 9H), 6.72 (s, 1H), 6.01 (s, 1H), 3.61-3.52 (m, 3H), 1.77-1.50 (m, 5H) , 1,280.88 (m, 5H); MS: 451.1 (M+1)+. Compound 73
1H NMR (300 MHz, DMSO-d6): δ 8.05-7.35 (m, 2H), 7.11-6.88 (m, 9H), 6.24 (s, 2H), 3.67 -3.58 (m, 3H), 2.33(s, 3H), 1.78-1.51 (m, 5H), 1.29-0.85 (m, 5H); MS: 561.0 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.25-6.60 (m, 13H), 6.53 (s, 1H), 3.75-3.35 (s, 1H), 2.49 -1.52 (m, 5H), 1.31-0.89 (m, 5H); MS: 450.1 (M+1)+. Compound 39
1 H NMR (300 MHz, DMSO-d6): δ 8.10-8.09 (d, 1H, J = 2.1), 7.96-7.93 (d, 1H, J = 7.5), 7.36-7.35 (d, 1H, J = 1.2), 7.33-6.67 (m, 8H), 6.32 (s, 1H), 3.75-3.54 (m , 3H), 2.37 (m, 3H), 1.89-1.56 (m, 5H), 1.24-1.19 (m, 5H); MS: 465.2 (M+1)+. Compound 111
1H NMR (300 MHz, DMSO-d6): δ 8.28-8.26 (d, 1H, J = 10.2), 8.04-8.02 (d, 1H J = 7.5), 7 .36-6.63 (m, 9H), 6.29 (s, 1H), 3.67-3.5 (m, 3H), 2.36 (s, 3H), 1.714-1.56 ( m, 5H), 1.25-1.15 (m, 5H); MS: 448.2 (M+1)+. Compound 112
1H NMR (300 MHz, DMSO-d6): δ 10.1-9.65 (m, 1H), 7.05-6.74 (m, 11H), 6.20 (s, 1H), 3.59 -3.52 (m, 3H), 2.50-2.26 (m, 5H), 1.25 (m, 12H); MS: 518.2 (M+1)+. Compound 122
1H NMR (300 MHz, DMSO-d6): δ 8.05-8.03 (m, 2H), 7.48-6.67 (m, 10H), 6.28 (s, 1H), 3.69 -3.52 (m, 3H), 2.35 (s, 3H), 1.79-1.52 (m, 5H), 1.30-0.95 (m, 5H); MS: 515.2 (M+1)+. Compound 123
1H NMR (300 MHz, DMSO-d6): δ7.91-7.82 (m, 1H), 7.66-7.33 (m, 2H), 7.07-6.68 (m, 10H), 6.22 (s, 1H), 6.15-5.85 (m, 1H), 3.72-3.50 (m, 7H), 3.00-2.68 (m, 4H), 2. 33 (s, 3H), 1.78-1.52 (m, 5H), 1.29-0.94 (m, 5H); MS: 532.2 (M+1)+. Compound 131
1H NMR (300 MHz, DMSO-d6): δ 8.00-7.98 (m, 2H), 7.69-7.67 (d, 1H, J = 7.5), 7.35-6, 77 (m, 9H), 6.29 (s, 1H), 3.66-3.31 (m, 3H), 2.50-2.24 (m, 6H), 1.79-1.52 ( m, 5H), 1.30-0.97 (m, 5H); MS: 489.2 (M+1)+. Compound 140
1H NMR (300 MHz, DMSO-d6): δ 8.01-7.85 (m, 2H), 7.36-6.68 (m, 10H), 6.25 (s, 1H), 3.66 -3.32 (m, 3H), 2.35(s, 3H), 1.78-1.52 (m, 5H), 1.30-0.97 (m, 5H); MS: 481.1 (M+1)+. Compound 124
1H NMR (300 MHz, DMSO-d6): δ 7.91 (s, 1H), 7.35-7.33 (m, 2H), 7.07-6.67 (m,8H), 6.23 -6.01 (m, 2H), 3.67-3.42 (m, 6H), 2.35 (s, 3H), 1.78-1.52 (m, 5H), 1.29-0 .94 (m, 5H); MS: 477.2 (M+1)+. Compound 149
1H NMR (300 MHz, DMSO-d6): δ 7.86 (s, 1H), 7.35-7.3 (m, 2H), 7.08-6.70 (m, 7H), 6.19 (s, 1H), 6.05-5.95 (m, 1H), 4.15-4.06 (m, 4H), 3.65-3.48 (m, 3H), 2.32 (s , 3H), 1.71-1.51 (m, 5H), 1.29-0.93 (m, 5H); MS: 505.2 (M+1)+. Compound 144
1H NMR (300 MHz, DMSO-d6): δ 7.91-7.88 (d, 1H, J = 7.8), 7.34-7.33 (s, 1H), 7.09-6, 68 (m, 10H), 6.24 (s, 1H), 3.60-3.31 (m, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.77 -1.51 (m, 5H), 1.29-0.93 (m, 5H); MS: 462.2 (M+1)+. Compound 145
1H NMR (300 MHz, DMSO-d6): δ 7.96-7.93 (d, 2H, J = 6.9), 7.35-7.33 (m, 1H), 7.11-6, 65 (m, 8H), 6.24 (s, 1H), 3.65-3.47 (m, 3H), 2.34 (s, 3H), 1.78-1.51 (m, 5H) , 1.29-0.98 (m, 5H); MS: 465.2 (M+1)+. Compound 146
1H NMR (300 MHz, DMSO-d6): δ 8.21-7.99 (m, 2H), 7.36-7.31 (m, 2H), 7.09-6.71 (m, 8H) , 6.25 (s, 1H), 3.68-3.62 (m, 3H), 2.33 (s, 3H), 1.78-1.52 (m, 5H), 1.30-0 .94 (m, 5H); MS: 527.1 (M+1)+. Compound 147
1H NMR (300 MHz, DMSO-d6): δ 8.34-8.31 (m, 1H), 7.84-7.82 (d, 1H, J = 7.5), 7.36-6, 64 (m, 10H), 6.37 (s, 1H), 3.33-3.49 (m, 1H), 3.31 (s, 2H), 3.31 (s, 3H), 1.75 -1.49 (m, 5H), 1.35-0.78 (m, 5H); MS: 481.1 (M+1)+. Compound 148
1H NMR (300 MHz, DMSO-d6): δ 7.98-7.96 (d, 2H, J = 7.5), 7.36-7.34 (m, 2H), 7.11-6, 67 (m, 8H), 6.24 (s, 1H), 3.66-3.31 (m, 3H), 2.33 (s, 3H), 1.78-1.51 (m, 5H) , 1.29-0.97 (m, 5H); MS: 481.1 (M+1)+. Compound 238
5 H NMR (400 MHz, DMSO-d6): δ 8,11-8,09 (d, 1H, J = 7,6), 7,44 (s, 1H), 7,37 7,34 (m, 2H), 7,11-6,75 (m, 7H), 6,12 (s, 1H), 5,89 (s, 1H), 3,72 (s, 3H), 3,62-3,51 (m, 6H), 2,28 (s, 3H), 1,63-1,50 (m, 5H), 1,47-1,09 (m, 5H); MS:498,3 (M+1) +. Composto 3071H NMR (300 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.10-8.07 (d, 1H, J = 7.8), 7.52-6.58 (m, 10H), 6.14 (s, 1H), 5.87-5.86 (d, 1H, J = 2.1), 3.61-3.37 (m, 6H), 2.28 (s, 3H), 1.70-1.64 (m, 5H), 1.29-1.06 (m, 5H); MS:484.3 (M+1)+. Compound 244 5 H NMR (400 MHz, DMSO-d6): δ 8.11-8.09 (d, 1H, J = 7.6), 7.44 (s, 1H), 7.37 7.34 (m, 2H), 7.11-6.75 (m, 7H), 6.12 (s, 1H), 5.89 (s, 1H), 3.72 (s, 3H), 3.62-3.51 (m, 6H), 2.28 (s, 3H), 1.63-1.50 (m, 5H), 1.47-1.09 (m, 5H); MS:498.3 (M+1)+. Compound 307
1H NMR (300 MHz, DMSO-d6): δ 8.98-8.97 (d, 1H, J = 1.6), 8.27-8.25 (d, 1H, J = 6.0), 7.69 (s, 1H), 7.39-6.76 (m, 8H), 6.35(s, 1H), 3.67-3.53 (m, 3H), 1.76-1, 52 (m, 5H), 1.29-0.98 (m, 5H); MS:486.0 (M+1)+. Compound 8
1H NMR (300 MHz, CDCl3): δ 8,41-8,35 (m, 1H), 7,56-6,92 (m, 13H), 6,65 (s, 1H), 3,94 (m, 1H), 2,15-1,85 (m, 2H), 1,68-1,58 (m, 2H), 1,42-1,11 (m, 6H); MS: 448,1 (M+1) +. 5 Composto 101H NMR (300 MHz, CDCl3): δ 7.26-6.72 (m, 10H), 6.39 (s, 1H), 5.45 (m, 1H), 4.28-4.25 (m , 1H), 3.65 (s, 2H), 2.35 (s, 3H), 1.97-1.93 (m, 2H), 1.58-1.51 (m, 4H), 1. 27-1.25 (m, 2H); MS: 451.1 (M+1)+. Compound 4 1H NMR (300 MHz, CDCl3): δ 8.41-8.35 (m, 1H), 7.56-6.92 (m, 13H), 6.65 (s, 1H), 3.94 (m , 1H), 2.15-1.85 (m, 2H), 1.68-1.58 (m, 2H), 1.42-1.11 (m, 6H); MS: 448.1 (M+1)+. 5 Compound 10
1H NMR (300 MHz, CDCl3): δ 7.84-7.75 (m, 3H), 7.62-7.48 (m, 3H), 7.23-6.73 (m, 6H), 6 .25 (s, 1H), 5.53-5.50 (m, 1H), 5.43-5.39 (m, 1H), 3.77-3.74 (m, 1H), 3.50 -3.49 (m, 2H), 1.92-1.59 (m, 4H), 1.54-0.95 (m, 6H); MS: 542.2 (M+1)+. 10 Compound 28
1H NMR (300 MHz, CDCl3): δ 7.81-7.78 (m, 2H), 7.69-7.49 (m, 4H), 7.11-7.09 (m, 2H), 6 .91-6.83 (m, 2H), 6.66-6.63 (m, 1H), 6.23 (s, 1H), 5.74-5.72 (m, 1H), 5.35 (d, 1H, J=8.1MHz), 4.20-4.18 (m, 1H), 3.51-3.46 (m, 2H), 2.24 (s, 3H), 1.94 -1.89 (m, 2H), 15 1.55-1.50 (m, 4H), 1.27-1.22 (m, 2H); MS: 524.1 (M+1)+. Compound 29
1H NMR (300 MHz, CDCl3): δ 7.81-7.78 (m, 2H), 7.59-7.48 (m, 4H), 7.11-6.81 (m, 5H), 6 .66-6.63 (m, 1H), 6.23 (s, 1H), 5.73-5.69 (m, 1H), 5.26 (d, 1H, J=8.1), 3 1.75 (m, 1H), 3.50-3.45 (m, 2H), 2.24 (s, 3H), 1.85-1.84 (m, 2H), 1.65-1.55 (m, 4H), 1.34-1.25 (m, 2H), 1.08-0.98 (m, 2H); MS: 538.2 (M+1)+. Compound 54
1H NMR (CDCl3, 300MHz), δ 8,34 (d, 1H, J=12,3 MHz), 7,65 (s, 1H), 7,47-7,43 (m, 1H), 7,40-7,35 (m, 1H), 7,18-7,16 (m, 4H), 6,94-6,70 (m, 7H), 6,65 (s, 1H), 3,72 (s, 2H), 2,41 (s, 3H); MS: 366,1 (M+1) +. Composto 231The single isomer was isolated by chiral HPLC, 1H NMR (300 MHz, DMSO-d6): δ 7.15-6.72 (m, 10H), 6.40 (s, 1H), 5.38-5, 36 (m, 1H), 3.85-3.81 (m, 1H), 3.65 (s, 1H), 2.35 (s, 3H), 1.97-1.56 (m, 5H) , 1.36-0.96 (m, 5H); MS: 465.2 (M+1)+. Compound 164 1H NMR (CDCl3, 300MHz), δ 8.34 (d, 1H, J=12.3 MHz), 7.65 (s, 1H), 7.47-7.43 (m, 1H), 7.40 -7.35 (m, 1H), 7.18-7.16 (m, 4H), 6.94-6.70 (m, 7H), 6.65 (s, 1H), 3.72 (s , 2H), 2.41 (s, 3H); MS: 366.1 (M+1)+. Compound 231
1H NMR (CDCl3, 300MHz), δ 7.54 (s, 1H), 7.27 (s, 1H), 7.12 (m, 2H), 6.90-6.83 (m, 5H), 6 3.34 (s, 1H), 5.83 (m, 1H), 5.33 (m, 1H), 4.42 (m, 2H), 3.86-3.74 (m, 5H), 3. 14 (m, 2H), 2.76 (m, 2H), 2.38 (s, 3H), 2.29 (s, 3H), 1.66-1.26 (m, 4H), 1.10 -0.95 (m, 6H); MS: 530.3 (M+1)+. Compound 271
1H NMR (CDCl3, 300MHz), δ 7.56 (d, 1H, J=6.0 MHz), 7.15-7.07 (m, 6H), 6.92-6.87 (m, 4H) , 6.76 (m, 1H), 6.45 (d, 1H, J=1.8 MHz), 6.36 (s, 1H), 5.24 (m, 1H), 4.66 (s, 2H), 3.80 (m, 1H), 2.34 (s, 3H), 1.89-1.56 (m, 4H), 1.30-1.04 (m, 6H); MS: 498.1 (M+1)+. Compound 297
1H NMR (CDCl3, 400MHz), δ 8.11 (s, 1H), 7.27-6.79 (m, 11H), 6.44 (s, 1H), 6.41 (s, 1H), 5 .35 (d, 1H, J = 7.2), 3.84 (m, 1H), 3.64-3.52 (m, 2H), 2.32 (s, 3H), 1.65-1 .57 (m, 4H), 1.34-0.89 (m, 6H); MS: 498.1 (M+1)+. Compound 288 and its HCL salt
1H NMR (CDCl3, 400MHz), δ 8.45 (d, 1H, J=3.6), 8.19 (s, 1H), 7.60 (d, 1H, J=7.6), 7, 24-6.75 (m, 8H), 6.38 (s, 1H), 5.33 (m, 1H), 3.83 (m, 1H), 3.49-3.46 (m, 2H) , 2.35 (s, 3H), 1.98-1.61 (m, 4H), 1.33-1.07 (m, 6H); MS: 460.1 (M+1)+. HCl salt: 1H NMR (DMSO-d6, 400MHz), δ ppm: 8.74-8.73 (m, 1H), 8.62 (s, 1H), 8.23-8.21 (m, 1H) , 8.01-7.87 (m, 3H), 7.12-6.71 (m, 6H), 6.23 (s, 1H), 3.79-3.56 (m, 3H), 2 .33 (s, 3H), 1.73-1.52 (m, 5H), 1.28-0.98 (m, 5H); MS: 460.1 (M+1)+. Compound 289
1H NMR (CDCl3, 400MHz), δ 9.91 (s, 1H), 7.68-6.79 (m, 12H), 6.47 (s, 1H), 5.66 (m, 1H), 3 1.86 (m, 3H), 2.35 (s, 3H), 1.93-1.89 (m, 2H), 1.67-1.62 (m, 3H), 1.33-1.10 (m, 5H); MS: 499.1 (M+1)+.
1H NMR (CDCl3, 400MHz), δ 7.23-6.77 (m, 9H), 6.05 (s, 1H), 5.38 (m, 1H), 4.35-4.33 (m, 2H), 3.82 (m, 1H), 2.24 (s, 3H), 1.93-1.52 (m, 5H), 1.33-1.10 (m, 5H); MS: 449.1 (M+1)+.
1H-NMR (CDCl3, 300MHz), δ 7,55 (s, 1H), 7,31 (s, 1H), 7,13-7,01 (m, 2H), 6,90- 9,65 (m, 5H), 6,33 (s, 1H), 6,21-5,80 (m, 1H), 5,40-5,21 (m, 1H), 4,45-4,23 (m, 2H), 3,80 (m, 1H), 3,58-3,46 (m, 4H), 3,13 (m, 2H), 2,77 (m, 2H), 2,38 (s, 3H), 2,27 (s, 3H), 1,881,61 ( m, 5H), 1,49 (s, 9H), 1,33-0,91 (m, 5H); MS: 629,4 (M+1) +. Composto 2871H NMR (CDCl3, 400MHz), δ 7.52-6.94 (m, 10H), 6.05 (s, 1H), 5.42 (, 1H), 4.47 (s, 2H), 3. 81 (m, 1H), 1.93-1.07 (m, 10H); MS: 435.1 (M+1)+. Compound 232 1H-NMR (CDCl3, 300MHz), δ 7.55 (s, 1H), 7.31 (s, 1H), 7.13-7.01 (m, 2H), 6.90-9.65 (m , 5H), 6.33 (s, 1H), 6.21-5.80 (m, 1H), 5.40-5.21 (m, 1H), 4.45-4.23 (m, 2H) ), 3.80 (m, 1H), 3.58-3.46 (m, 4H), 3.13 (m, 2H), 2.77 (m, 2H), 2.38 (s, 3H) , 2.27 (s, 3H), 1.881.61 (m, 5H), 1.49 (s, 9H), 1.33-0.91 (m, 5H); MS: 629.4 (M+1)+. Compound 287
A uma mistura do Composto 118 (300 mg, 0,72 mmol), 1,2,3,4-Tetrahidro- quinolina (200 mg, 1,5 mmol) e Et3N (300 mg, 3 mmol) em DCM (10 ml) foi adicionado TBAI (266 mg, 0,72 mmol) em temperatura ambiente. A mistura de reação foi agitada durante 24 horas na mesma temperatura. A mistura resultante foi lavada com água, solução saturada de NaHCO3, salmoura, seca com Na2SO4 e filtrada. O solvente foi evaporado sob vácuo e a mistura bruta foi purificada por TLC para gerar o produto desejado (120 mg, 32% de rendimento). 1H NMR (300 MHz, DMSO-d6): δ 7,94-7,93(m, 2H), 7,14-6,19 (m, 10H), 3,86-3,57 (m, 3H), 3,25 (s, 2H), 2,63-2,66 (t, 2H), 2,37 (s, 3H), 1,81-1,51 (m, 5H), 1,27-0,92 (m, 5H); MS: 514,3 (M+1) +. Sal HCl:1H NMR (400 MHz, DMSO-d6): δ 8.02-6.71 (m, 11H), 6.44-6.38 (m, 2H), 6.23 (s, 1H), 3.92 -3.90 (m, 1H), 3.61-3.57 (m, 2H), 2.33 (s, 3H), 1.77-1.52 (m, 5H), 1.29-0 .96 (m, 5H); MS: 493.1 (M+1)+. Example 2: Preparation of Compound 160 and its HCl Salt. Compound 160 was synthesized following Scheme 2, above using the following protocol. To a mixture of Compound 118 (300mg, 0.72mmol), 1,2,3,4-Tetrahydroquinoline (200mg, 1.5mmol) and Et3N (300mg, 3mmol) in DCM (10ml) ) was added TBAI (266 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred for 24 hours at the same temperature. The resulting mixture was washed with water, saturated NaHCO3 solution, brine, dried over Na2SO4 and filtered. The solvent was evaporated under vacuum and the crude mixture was purified by TLC to give the desired product (120 mg, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.94-7.93(m, 2H), 7.14-6.19 (m, 10H), 3.86-3.57 (m, 3H) , 3.25 (s, 2H), 2.63-2.66 (t, 2H), 2.37 (s, 3H), 1.81-1.51 (m, 5H), 1.27-0 .92 (m, 5H); MS: 514.3 (M+1)+. HCl salt:
1H NMR (300 MHz , DMSO-d6), δ 8,08 (d, 1H, J=6,3), 7,86 (br, 0,5H), 7,15-7,00 (m, 7H), 6,70 (d, 2H, J=7,5), 6,47 (t, 1H, ), 6,21 (s, 1H, J=7,2), 6,24 (s, 1H), 6,21 (d, 1H, J=5,4), 3,87-3,72 (m, 4H), 3,63 (br, 0,5H), 3,57 (br, 0,4H), 3,38-3,23 (m, 3H), 2,64 (t, 2H, J=5,7), 2,37 (s, 3H), 1,81-1,78 (m, 2H), 1,71-1,66 (br, 2H), 1,40-1,35 (m, 1H), 1,23-1,15 (m, 1H); MS: 516,2 (M+1) +. Composto 3301H NMR (300 MHz, DMSO-d6): δ7.93(br, 2H), 7.13-6.18(m, 11H), 4.09(m, 1H), 3.86-3.55( m, 3H), 3.22(m, 2H), 2.63(m, 2H), 2.36(s, 3H), 1.72-1.50(m, 7H), 1.32-0 .89(m, 5H); MS: 514.3 (M+1)+. The following compounds of the invention were also synthesized via Scheme 2 following the general procedure set out above for Compound 118. The corresponding HCl salt was synthesized following the general procedure set out in Example 1, step B. Compound 179 1H NMR (300 MHz, DMSO-d6), δ 8.08 (d, 1H, J=6.3), 7.86 (br, 0.5H), 7.15-7.00 (m, 7H) , 6.70 (d, 2H, J=7.5), 6.47 (t, 1H, ), 6.21 (s, 1H, J=7.2), 6.24 (s, 1H), 6.21 (d, 1H, J=5.4), 3.87-3.72 (m, 4H), 3.63 (br, 0.5H), 3.57 (br, 0.4H), 3.38-3.23 (m, 3H), 2.64 (t, 2H, J=5.7), 2.37 (s, 3H), 1.81-1.78 (m, 2H), 1.71-1.66 (br, 2H), 1.40-1.35 (m, 1H), 1.23-1.15 (m, 1H); MS: 516.2 (M+1)+. Compound 330
1H NMR (400 MHz, MeOD-d4), δ 7.69 (br, 1H), 7.27 (br, 0.4H), 7.03-6.70 (br, 8H), 6.57-6 .47 (br, 1H), 6.24 (ds, 1H), 4.58 (d, 1H, J=17), 4.39 (d, 1H, J=17), 3.81 (br, 1H ), 2.35 (s, 1H), 2.14 (s, 1H), 1.96-1.75 (m, 6H), 1.50-1.34 (m, 2H); MS: 499.2 (M+1)+. Compound 187
1H NMR (300 MHz, DMSO-d6): δ 8,03-8,00 (d, 1H,J=8,1), 7,10-7,08 (m, 2H), 7,03-6,97 (m, 2H), 6,87-6,82 (m, 1H), 6,72-6,70 (d, 1H, J=7,5), 6,23 (s, 1H), 3,70-3,54 (m, 5 4H),3,21-3,12 (m, 2H), 2,91-2,85 (d, 1H, J=16,5), 2,35 (s, 3H), 1,84-1,50 (m, 7H), 1,30 0,95 (m, 6H); MS: 468,2 (M+1) +. Composto 188 1H NMR (300 MHz, DMSO-d6): δ 8,01-7,99 (d, 1H,J=7,8), 7,76 (dr, 1H), 7,24- 10 6,94 (m, 8H), 6,88-6,83 (m, 1H), 6,73-6,70 (d, 1H, J=7,5), 6,26 (s, 1H), 3,99 (s, 4H),3,64- 3,62 (d, 1H, J=7,5), 3,46 (s, 1H), 3,32 (s, 1H), 2,37 (s, 3H), 1,78-1,51 (m, 5H), 1,30-0,95 (m, 5H); MS: 500,2 (M+1)+. Composto 1921H NMR (300 MHz, DMSO-d6): δ 7.98-7.82 (m, 1H), 7.24-6.28 (m, 10H), 5.845.64 (m, 1H), 5.10 -4.62 (m, 1H), 4.27-4.22 (m, 1H), 4.05-3.99 (m, 4H), 3.68-3.51 (m, 2H), 3 .32 (s, 1H), 2.20-1.93 (m, 3H), 1.73-1.44 (m, 4H), 1.25-0.95 (m, 6H); MS: 502.2 (M+1)+. Compound 191 1H NMR (300 MHz, DMSO-d6): δ 8.03-8.00 (d, 1H,J=8.1), 7.10-7.08 (m, 2H), 7.03-6, 97 (m, 2H), 6.87-6.82 (m, 1H), 6.72-6.70 (d, 1H, J=7.5), 6.23 (s, 1H), 3. 70-3.54 (m, 5 4H), 3.21-3.12 (m, 2H), 2.91-2.85 (d, 1H, J=16.5), 2.35 (s, 3H), 1.84-1.50 (m, 7H), 1.30-0.95 (m, 6H); MS: 468.2 (M+1)+. Compound 188 1H NMR (300 MHz, DMSO-d6): δ 8.01-7.99 (d, 1H,J=7.8), 7.76 (dr, 1H), 7.24-10 6.94 (m , 8H), 6.88-6.83 (m, 1H), 6.73-6.70 (d, 1H, J=7.5), 6.26 (s, 1H), 3.99 (s , 4H), 3.64-3.62 (d, 1H, J=7.5), 3.46 (s, 1H), 3.32 (s, 1H), 2.37 (s, 3H), 1.78-1.51 (m, 5H), 1.30-0.95 (m, 5H); MS: 500.2 (M+1)+. Compound 192
1H NMR (300 MHz, DMSO-d6): δ 8.49-8.47 (d, 1H,J=4.2), 8.10-8.09 (m, 1H), 7.84-7, 79 (m, 2H), 7.37-7.32 (m, 2H), 7.11-6.98 (m, 4H), 6.87-6.82 (m, 1H), 6.72- 6.70 (d, 1H, J=7.8), 6.26 (s, 1H), 3.63-3.60 (m, 1H), 3.42 (s, 1H), 3.08- 2.82 (m, 5H), 2.39 (s, 3H), 1.78-1.51 (m, 5H), 1.29-0.95 (m, 5H); MS: 503.3 (M+1)+. Compound 184 and its HCl Salt
1H NMR (300 MHz, DMSO-d6): δ 8.42-8.41 (d, 2H,J=4.2), 8.01-7.99 (d, 1H,J=5.1), 7.73 (dr, 1H), 7.21-6.94 (m, 6H), 6.86-6.83 (m, 1H), 6.72-6.70 (d, 1H, J=6 ), 6.52 (dr, 1H), 6.23 (s, 1H), 3.63-3.61 (m, 1H), 3.13-3.08 (d, 1H, J=12.3 ), 2.88-2.84 (d, 1H, J=12.3), 2.69-2.64 (m, 4H), 2.33 (s, 3H), 1.78-1.52 (m, 5H), 1.29-0.96 (m, 5H); MS: 503.3 (M+1)+. HCl salt: 1H NMR (400 MHz, DMSO-d6): δ9.25(m, 2H), 8.77(d, 2H, J = 4.5), 8.18(m, 1H), 7.80 (m, 3H), 7.38-6.59(m, 8H), 6.24(s, 1H), 3.82-3.63(m, 5H), 3.24-3.16(m) , 4H), 2.38(s, 3H), 1.72-1.50(m, 7H), 1.32-1.07(m, 5H); MS: 503.3 (M+1)+. Compound 201 and its HCl salt
1H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H), 7.86 (dr, 1H), 7.12-7.00 (m, 4H), 6.90-6.85 (m, 3H), 6.74-6.72 (d, 1H, J=7.2), 6.44-6.41 (m, 2H), 6.23 (s, 1H), 5.67 -5.64 (m, 1H), 3.70-3.61 (m, 2H), 2.36 (s, 3H), 1.76-1.52 (m, 5H), 1.29-0 .96 (m, 5H); MS: 492.2 (M+1)+. HCl salt: 1H NMR (400MHz, DMSO-d6): δ8.05(s, 1H), 7.85(dr, 1H), 7.12-6.86(m, 7H), 6.74-6, 53(m, 3H), 6.23(s, 1H), 5.67-5.64(m, 1H), 3.70-3.61(m, 2H), 3.38-3.33( d, 1H, J=20), 2.37(s, 3H), 1.73-1.51(m, 5H), 1.28-0.98(m, 5H); MS: 492.2 (M+1)+. Compound 193
1H NMR (300 MHz, DMSO-d6): δ 8.39-8.37 (m, 2H), 8.01-7.99 (d, 1H,J=7.5), 7.60-7, 58 (d, 1H, J=8.1), 7.29-7.25 (m, 1H), 7.10-6.96 (m, 4H), 6.86-6.82 (m, 1H) ), 6.726.70 (d, 1H, J=7.2), 6.23 (s, 1H), 3.63-3.60 (d, 1H, J=8.1), 3.17-3 1.12 (d, 1H, J=16.2), 2.93 5 2.87 (m, 1H), 2.71-2.62 (m, 4H), 2.33 (s, 3H), 1 .78-1.51 (m, 5H), 1.29-0.95 (m, 5H); MS: 503.3 (M+1)+. Compound 206
1H NMR (400 MHz, DMSO-d6): δ 8.35-8.33 (m, 1H), 7.96-7.65 (m, 2H), 7.26-7.11 10 (m, 5H) ), 6.98-6.72 (m, 1H), 6.54-6.26 (m, 1H), 5.80-5.62 (m, 1H), 5.05-4.63 (m) , 1H), 4.26-4.22 (d, 1H, J=15.2), 4.05-3.94 (m, 4H), 3.78-3.74 (m, 1H), 3 .53-3.48 (m, 1H), 3.26-3.23 (m, 1H), 2.20-1.94 (m, 3H), 1.72-1.43 (m, 4H) , 1.23-0.76 (m, 6H); MS: 503.2 (M+1)+. Compound 209 and its HCl salt
1H NMR (400 MHz, DMSO-d6): δ 8,04 (s, 1H), 7,84 (dr, 1H), 7,12-7,01 (m, 3H), 6,88-6,68 (m, 4H), 6,57-6,54 (m, 1H), 6,24 (s, 1H), 6,12-6,10 (d, 1H, J=7,6), 5,16-5,13 (m, 10 1H), 3,79 (s, 3H), 3,73-3,61 (m, 2H), 3,37 (s, 1H), 2,37 (s, 3H), 1,78-1,52 (m, 5H), 1,29 0,96 (m, 5H); MS: 504,2 (M+1) +. Composto 2101H NMR (400 MHz, DMSO-d6): δ 8.33-8.32 (d, 1H, J=4.4), 8.01-7.99 (d, 1H, J=7.2), 7.63-7.61 (d, 2H, J=7.6), 7.19-6.95 (m, 5H), 6.87-6.84 (m, 1H), 6.73-6 .61 (d, 1H, J=7.6), 6.25 (s, 1H), 3.99-3.94 (m, 4H), 3.63-3.62 (m, 1H), 3 .44-3.40 (d, 1H, J=15.6), 3.233.19 (d, 1H, J=16), 2.36 (s, 3H), 1.74-1.52 (m, 5H), 1.29-0.95 (m, 5H); MS: 501.3 (M+1)+. HCl salt: 1H NMR (400MHz, DMSO-d6): δ8.33-8.32(d, 1H, J=4.8), 8.01-7.95(m, 1H), 7.63-7 .61(d, 1H, J=7.6), 7.19-6.95(m, 5H), 6.87-6.84(m, 1H), 6.73-6.71(d, 1H, J=7.6), 6.25(s, 1H), 3.99-3.90(m, 4H), 3.62(s, 1H), 3.45-3.41(d, 1H, J=16), 3.23-3.18(d, 1H, J=18), 5 2.37(s, 3H), 1.74-1.52(m, 5H), 1.29 -0.85(m, 5H); MS: 501.3 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.04 (s, 1H), 7.84 (dr, 1H), 7.12-7.01 (m, 3H), 6.88-6.68 (m, 4H), 6.57-6.54 (m, 1H), 6.24 (s, 1H), 6.12-6.10 (d, 1H, J=7.6), 5.16 -5.13 (m, 10 1H), 3.79 (s, 3H), 3.73-3.61 (m, 2H), 3.37 (s, 1H), 2.37 (s, 3H) , 1.78-1.52 (m, 5H), 1.29-0.96 (m, 5H); MS: 504.2 (M+1)+. Compound 210
1H NMR (400 MHz, DMSO-d6): δ 8,08 (s, 1H), 7,75 (dr, 1H), 7,21-7,19 (d, 2H, J=8,4), 7,12-6,96 (m, 4H), 6,87-6,84 (m, 3H), 6,73-6,71 (m, 1H), 6,24 (s, 1H), 3,72-3,61 (m, 6H), 3,28-3,24 (d, 1H, J=16,8), 2,99-2,95 (d, 1H, J=16,4), 2,35 (s, 3H), 1,76-1,52 (m, 5H), 1,30-0,96 (m, 5H); MS: 518,3 (M+1) +. 1H NMR (400 MHz, DMSO-d6): δ 8,07-8,06 (d, 1H, J=5,2), 7,77 (dr, 1H), 7,27-7,21 (m, 2H), 7,11-6,83 (m, 7H), 6,72-6,70 (d, 1H, J=7,6), 6,48 (dr, 1H), 6,23 (s, 1H), 3,75-3,62 (m, 6H), 3,30-3,26 (m, 2H), 3,01-2,97 (d, 1H, J=16), 2,35 (s, 3H), 1,78-1,52 (m, 5H), 1,29-0,95 (m, 5H); MS: 518,3 (M+1) +. Composto 221 (Sal HCl)1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.84 (dr, 1H), 7.10-7.01 (m, 3H), 15 6.88-6, 84 (m, 1H), 6.74-6.66 (m, 4H), 6.40-6.38 (d, 2H, J=8.8), 6.24 (s, 1H), 6. 27 (s, 1H), 3.61 (s, 5H), 3.26 (s, 1H), 2.36 (s, 3H), 1.77-1.52 (m, 5H), 1.28 -0.99 (m, 5H); MS: 504.3 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.75 (dr, 1H), 7.21-7.19 (d, 2H, J=8.4), 7 .12-6.96 (m, 4H), 6.87-6.84 (m, 3H), 6.73-6.71 (m, 1H), 6.24 (s, 1H), 3.72 -3.61 (m, 6H), 3.28-3.24 (d, 1H, J=16.8), 2.99-2.95 (d, 1H, J=16.4), 2, 35 (s, 3H), 1.76-1.52 (m, 5H), 1.30-0.96 (m, 5H); MS: 518.3 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.07-8.06 (d, 1H, J=5.2), 7.77 (dr, 1H), 7.27-7.21 (m, 2H), 7.11-6.83 (m, 7H), 6.72-6.70 (d, 1H, J=7.6), 6.48 (dr, 1H), 6.23 (s, 1H), 3.75-3.62 (m, 6H), 3.30-3.26 (m, 2H), 3.01-2.97 (d, 1H, J=16), 2.35 ( s, 3H), 1.78-1.52 (m, 5H), 1.29-0.95 (m, 5H); MS: 518.3 (M+1)+. Compound 221 (HCl Salt)
1H NMR (400MHz, DMSO-d6): δ9.29(s, 1H), 8.16(s, 1H), 7.76(s, 1H), 7.30-7.26(m, 1H), 7.11-6.87(m, 8H), 6.73-6.71(d, 1H, J=6.4), 6.52(s, 1H), 6.23(s, 1H), 4.06-3.94(m, 2H), 3.74-3.65(m, 6H), 2.36(s, 3H), 1.78-1.52(m, 5H), 1, 30-0.98(m, 5H); MS: 518.3 (M+1)+. Compound 247
1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.86 (dr, 1H), 7.12-6.72 (m, 6H), 6.23 (s, 1H) ), 6.13-6.11 (m, 1H), 6.03-5.99 (m, 2H), 5.74-5.71 (m, 1H), 3.70-3.61 (m) , 5H), 3.33 (s, 1H), 2.33 (s, 3H), 1.77-1.52 (m, 5H), 1.28-0.85 (m, 5H); MS: 504.2 (M+1)+. Compound 256
1H NMR (400 MHz, DMSO-d6): δ 9,01-9,00 (d, 1H, J=1,6), 8,04-8,02 (d, 1H, J=5,2), 7,73 (dr, 1H), 7,38 (s, 1H), 7,10-6,93 (m, 4H), 6,86-6,83 (m, 1H), 6,72-6,70 (d, 1H, J=7,2), 6,49 (dr, 1H), 6,25 (s, 1H), 3,75 (s, 2H), 3,64-3,62 (m, 1H), 3,18-3,14 (d, 1H, J=16,4), 2,91-2,87 (d, 1H, J=16,4), 2,44 (s, 1H), 2,35 (s, 3H), 1,78-1,52 (m, 5H), 1,29-0,95 15 (m, 5H); MS: 495,1 (M+1) +. 1H NMR (400 MHz, DMSO-d6): δ 8.03-8.01 (d, 1H, J=6.8), 7.75 (dr, 1H), 7.51 (s, 5 1H), 7.11-6.93 (m, 3H), 6.86-6.82 (m, 1H), 6.71-6.69 (d, 1H, J=7.2), 6.46 (dr , 1H), 6.25 (s, 1H), 6.01 (s, 1H), 3.73 (s, 3H), 3.64-3.61 (m, 1H), 3.51 (s, 1H), 3.10-3.06 (d, 1H, J=16.8), 2.87-2.83 (d, 1H, J=16), 2.36 (s, 3H), 2. 15 (s, 1H), 1.79-1.52 (m, 5H), 1.29-0.95 (m, 5H); MS: 492.3 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 9.01-9.00 (d, 1H, J=1.6), 8.04-8.02 (d, 1H, J=5.2), 7.73 (dr, 1H), 7.38 (s, 1H), 7.10-6.93 (m, 4H), 6.86-6.83 (m, 1H), 6.72-6, 70 (d, 1H, J=7.2), 6.49 (dr, 1H), 6.25 (s, 1H), 3.75 (s, 2H), 3.64-3.62 (m, 1H), 3.18-3.14 (d, 1H, J=16.4), 2.91-2.87 (d, 1H, J=16.4), 2.44 (s, 1H), 2.35 (s, 3H), 1.78-1.52 (m, 5H), 1.29-0.95 (m, 5H); MS: 495.1 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8.04-8.02 (d, 1H, J=6.4), 7.67-7.66 (d, 1H, J=3.2), 7.55-7.54 (d, 1H, J=3.2), 7.11-6.82 (m, 5H), 6.71-6.69 (d, 1H, J=7.6) , 6.25 (s, 1H), 3.95 (s, 2H), 3.64-3.62 (m, 1H), 3.22-3.18 (d, 1H, J=16.8) , 2.98-2.94 (d, 2H, J=16.4), 2.37 (s, 3H), 1.76-1.52 (m, 5H), 1.30-0.95 ( m, 5H); MS: 495.1 (M+1)+. Compound 318
1H NMR (300 MHz, DMSO-d6): δ 8,01-7,99 (d, 1H, J=6,9), 7,88-7,61 (br, 1H), 7,11-6,98 (m, 4H), 6,84-6,82 (t, 1H), 6,72-6,70 (d, 1H, J=7,5), 6,26 (s, 1H), 3,64-3,62 (m, 1H), 3,16-2,86 (q, 2H), 2,35 (s, 3H), 2,06-2,04 (m, 1H), 1,79-1,51 (m, 5H), 1,30-1,16 (m, 5H), 0,26-0,09 (m, 4H); MS: 438,2(M+1) +. DRAWCODE1H NMR (400 MHz, DMSO-d6): δ 8.25-8.24 (d, 1H, J=4.4), 8.05 (s, 1H), 7.79 (dr, 1H), 7 .54-7.52 (d, 1H, J=7.2), 7.26-6.99 (m, 5H), 6.88-6.84 (m, 1H), 6.73-6, 59 (m, 2H), 6.24 (s, 1H), 3.63-3.52 (m, 2H), 3.33-3.15 (m, 1H), 3.04-2.95 ( m, 2H), 2.70-2.63 (m, 2H), 2.36-2.31 (m, 3H), 1.78-1.52 (m, 5H), 1.29-0, 84 (m, 5H); MS: 515.1 (M+1)+. Compound 119 1H NMR (300 MHz, DMSO-d6): δ 8.01-7.99 (d, 1H, J=6.9), 7.88-7.61 (br, 1H), 7.11-6, 98 (m, 4H), 6.84-6.82 (t, 1H), 6.72-6.70 (d, 1H, J=7.5), 6.26 (s, 1H), 3. 64-3.62 (m, 1H), 3.16-2.86 (q, 2H), 2.35 (s, 3H), 2.06-2.04 (m, 1H), 1.79- 1.51 (m, 5H), 1.30-1.16 (m, 5H), 0.26-0.09 (m, 4H); MS: 438.2(M+1)+. DRAWCODE
1H NMR (300 MHz, DMSO-d6): δ 8.00-7.97 (d, 1H, J=7.2), 7.88-7.61 (br, 1H), 7.10-6, 94 (m, 4H), 6.87-6.82 (t, 1H), 6.72-6.69 (d, 1H, J=7.5), 6.24 (s, 1H), 3. 64-3.61 (m, 5 1H), 3.09-2.85 (m, 3H), 2.35 (s, 3H), 1.80-1.00 (m, 18H); MS: 466.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8,01-7,99 (d, 1H, J=6,9), 7,30-6,99 (m, 5H), 6,89-6,84 (t, 1H), 6,75-6,72 (d, 1H, J=7,8), 6,31-6,21 (m, 4H), 6,08-6,05 (m, 1H), 3,69- 10 3,61 (m, 2H), 3,39-3,34 (m, 1H), 2,37 (s, 3H), 1,77-1,52 (m, 5H), 1,29-0,96 (m, 5H); MS: 492,2(M+1) +. Composto 1411H NMR (300 MHz, DMSO-d6): δ 8.01-7.99 (d, 1H, J=6.9), 7.30-6.99 (m, 5H), 6.89-6, 84 (t, 1H), 6.75-6.72 (d, 1H, J=7.8), 6.31-6.21 (m, 4H), 6.08-6.05 (m, 1H ), 3.69-10 3.61 (m, 2H), 3.39-3.34 (m, 1H), 2.37 (s, 3H), 1.77-1.52 (m, 5H) , 1.29-0.96 (m, 5H); MS: 492.2(M+1)+. 1H NMR (300 MHz, DMSO-d6): δ 8.01-7.99 (d, 1H, J=6.9), 7.30-6.99 (m, 5H), 6.89-6, 84 (t, 1H), 6.75-6.72 (d, 1H, J=7.8), 6.31-6.21 (m, 4H), 6.08-6.05 (m, 1H ), 3.69-10 3.61 (m, 2H), 3.39-3.34 (m, 1H), 2.37 (s, 3H), 1.77-1.52 (m, 5H) , 1.29-0.96 (m, 5H); MS: 492.2(M+1)+. Compound 141
1H NMR (300 MHz, DMSO-d6): δ 7.96-7.94 (d, 1H, J=6.6), 7.10-6.82 (m, 5H), 15 6.72-6 .69 (d, 1H, J=7.8), 6.23 (s, 1H), 3.64-3.61 (m, 1H), 2.88-2.78 (m, 2H), 2 1.34 (s, 3H), 2.21 (s, 4H), 1.78-1.52 (m, 5H), 1.36-0.96 (m, 5H); MS: 466.2 (M+1)+. Compound 152
1H NMR (300 MHz, DMSO-d6): δ 8.02-8.00 (d, 1H, J=7.8), 7.29-6.84 (m, 11H), 6.73-6, 70 (d, 1H, J=7.2), 6.26 (s, 1H), 3.63-3.60 (m, 1H), 3.59 (s, 2H), 3.10-2, 81 (m, 2H), 2.35 (s, 3H), 1.74-1.52 (m, 5H), 1.27-0.99 (m, 5H); MS: 488.3 (M+1)+. 5 Compound 154
1H NMR (300 MHz, DMSO-d6): δ 8.00-7.97 (d, 1H, J=7.5), 7.28-6.96 (m, 9H), 6.86-6, 82 (t, 1H), 6.72-6.69 (d, 1H, J=7.8), 6.23 (s, 1H), 3.61-3.59 (m, 1H), 3. 13-2.84 (m, 2H), 2.63 (s, 4H), 2.34 (s, 3H), 1.79-1.52 (m, 5H), 1.30-1.00 ( m, 5H); MS: 502.3 (M+1)+. 10 Compound 135 and its HCl Salt
1H NMR (300 MHz, DMSO-d6): δ 8.05 (s, 1H), 8.00-7.98 (d, 1H, J=8.1), 7.65-7.61 (d, 1H, J=9.3), 7.39-7.36 (d, 1H, J=8.7), 7.27-6.87 (m, 7H), 6.78-6.75 (d , 1H, J=7.5), 6.20 (s, 1H), 5.04-4.69 (m, 2H), 3.61-3.59 (m, 1H), 2.40 (s , 3H), 1.77-1.50 (m, 5H), 1.26-0.94 (m, 5H); MS: 499.2 (M+1)+. HCl salt: 1H NMR (300 MHz, DMSO-d6): δ9.51(s, 1H), 8.05(s, 1H), 8.00-7.98(d, 1H, J=8.1) , 7.89-7.76(m, 12H), 6.19(s, 1H), 5.38-5.05(m, 2H), 3.57-3.54(m, 1H), 2 .43(s, 3H), 1.77-1.50 (m, 5H), 1.26-0.95 (m, 5H); MS: 499.2(M+1)+. Compound 153
1H NMR (300 MHz, DMSO-d6): δ 7.98-7.96 (d, 1H, J=7.2), 7.12-6.83 (m, 7H), 6.74-6, 72 (d, 1H, J=7.5), 6.54-6.49 (t, 1H), 6.24-6.22 (m, 2H), 3.79-3.49 (m, 3H) ), 3.38 5 3.35 (m, 2H), 2.87-2.81 (t, 2H), 2.37 (s, 3H), 1.74-1.51 (m, 5H), 1.29-0.95 (m, 5H); MS: 500.2 (M+1)+. Compound 143
1H NMR (300 MHz, DMSO-d6): δ 8.00-7.97 (d, 1H, J=7.8), 7.10-6.85 (m, 9H), 10 6.73-6 .71 (d, 1H, J=7.5), 6.27 (s, 1H), 3.56-3.54 (m, 1H), 3.53 (s, 2H), 3.14-2 .92 (m, 2H), 2.71-2.61 (m, 4H), 2.35 (s, 3H), 1.75-1.57 (m, 5H), 1.26-0.95 (m, 5H); MS: 514.3 (M+1)+. Compound 156
1H NMR (300 MHz, DMSO-d6): δ 8.02-8.00 (d, 1H, J=7.2), 7.59 (s, 1H), 7.39 (s, 15 1H), 7.14-7.01 (m, 4H), 6.89-6.84 (t, 1H), 6.73-6.71 (d, 1H, J=7.2), 6.22-6 .20 (m, 2H), 4.87-4.56 (m, 2H), 3.62-3.60 (m, 1H), 2.38 (s, 3H), 1.76-1.51 (m, 5H), 1.29-0.94 (m, 5H); MS: 449.2(M+1)+. Compound 155
1H NMR (300 MHz, DMSO-d6): δ 7,98 (s, 1H), 7,76 (br, 1H), 7,09-6,83 (m, 5H), 6,72-6,71 (d, 1H, J=5,7), 6,23 (s, 1H), 3,63-3,62 (m, 1H), 3,46 (s, 4H), 2,85-2,93 (m, 2H), 2,34 (s, 3H), 2,28 (s, 4H), 1,78-1,52 (m, 5H), 1,29-0,95 (m, 5H); MS: 468,2 (M+1)+. 10 Sal HCl: 1H NMR (300 MHz, DMSO-d6): δ10,65 (br, 1H), 8,18(s, 1H), 7,77(s, 1H), 7,356,66 (m, 6H), 6,23(s, 1H), 4,03(br, 1H), 3,82(s, 4H), 3,64-3,62(m, 1H), 3,36-3,17(m, 5H), 2,38(s, 3H), 1,77-1,52 (m, 5H), 1,29-0,95 (m, 5H); MS: 468,3(M+1) +. Composto 165 e seu Sal HCl F 1H NMR (300 MHz, DMSO-d6): δ 8,00-7,98 (d, 1H, J=7,5), 7,13-6,73 (m, 6H), 6,65 (s, 1H), 4,66-4,31 (m, 2H), 3,64-3,60 (m, 1H), 2,37 (s, 3H), 2,09 (s, 3H),1,74-1,51 (m, 5H), 1,30-0,95 (m, 5H); MS: 463,2 (M+1) +. Sal HCl: 1H NMR (300 MHz, DMSO-d6): δ14,82(br, 1H), 8,09-8,07(d, 1H, J=6,3), 7,85(br,1H), 7,52(s, 2H), 7,13-6,74(m, 6H), 6,18 (s, 1H), 5,08-4,67(m, 2H), 3,64-3,61 (m, 1H), 2,48(s, 3H), 2,38(s, 3H), 1,74-1,51(m, 5H), 1,30-0,95(m, 5H); MS: 463,2 (M+1) +. 1H NMR (300 MHz, DMSO-d6): δ 8.02-8.00 (d, 2H, J=7.5), 7.86 (br, 1H), 7.126.42 (m, 11H), 5 .66 (br, 1H), 3.71-3.37 (m, 3H), 2.37 (s, 3H), 1.77-1.51 (m, 5H), 1.29-1.00 (m, 5H); MS: 474.2 (M+1)+. 5 Compound 134 and its HCl salt 1H NMR (300 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.76 (br, 1H), 7.09-6.83 (m, 5H), 6.72-6.71 (d, 1H, J=5.7), 6.23 (s, 1H), 3.63-3.62 (m, 1H), 3.46 (s, 4H), 2.85-2.93 (m, 2H), 2.34 (s, 3H), 2.28 (s, 4H), 1.78-1.52 (m, 5H), 1.29-0.95 (m, 5H); MS: 468.2 (M+1)+. 10 HCl salt: 1H NMR (300 MHz, DMSO-d6): δ 10.65 (br, 1H), 8.18(s, 1H), 7.77(s, 1H), 7.356.66 (m, 6H) , 6.23(s, 1H), 4.03(br, 1H), 3.82(s, 4H), 3.64-3.62(m, 1H), 3.36-3.17(m , 5H), 2.38(s, 3H), 1.77-1.52 (m, 5H), 1.29-0.95 (m, 5H); MS: 468.3(M+1)+. Compound 165 and its HCl salt F 1H NMR (300 MHz, DMSO-d6): δ 8.00-7.98 (d, 1H, J=7.5), 7.13-6.73 (m, 6H), 6.65 (s , 1H), 4.66-4.31 (m, 2H), 3.64-3.60 (m, 1H), 2.37 (s, 3H), 2.09 (s, 3H),1. 74-1.51 (m, 5H), 1.30-0.95 (m, 5H); MS: 463.2 (M+1)+. HCl salt: 1H NMR (300 MHz, DMSO-d6): δ14.82(br, 1H), 8.09-8.07(d, 1H, J=6.3), 7.85(br,1H) , 7.52(s, 2H), 7.13-6.74(m, 6H), 6.18(s, 1H), 5.08-4.67(m, 2H), 3.64-3 1.61(m, 1H), 2.48(s, 3H), 2.38(s, 3H), 1.74-1.51(m, 5H), 1.30-0.95(m, 5H) ); MS: 463.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8,01-7,99 (d, 1H, J=7,5), 7,10-6,70 (m, 6H), 6,23 (s, 1H), 4,52-4,47 (m, 2H), 4,28-4,22 (m, 2H), 3,76-3,71 (m, 1H), 3,63-3,61 (m, 1H), 3,12-2,81 (m, 2H), 2,59 (s, 1H), 2,34 (s, 3H), 1,79-1,52 (m, 5H), 1,30-0,96 (m, 5H); MS: 454,3 (M+1) +. 15 Composto 173 e seu Sal HCl 1H NMR (300 MHz, DMSO-d6): δ 8,00-7,97 (m, 2H), 7,51-6,76 (m, 11H), 6,18 (s, 1H), 4,99-4,51 (m, 2H), 3,60-3,59 (m, 1H), 2,39-2,38 (m, 6H), 1,74-1,50 (m, 5H), 1,280,93 (m, 5H); MS: 513,3 (M+1) +. Sal HCl: 1H NMR (400 MHz, DMSO-d6): δ8,10-6,80(m, 13H), 6,17(s, 1H), 5,40(m, 1H), 4,77(m, 1H), 3,59(m, 1H), 2,74(s, 3H), 2,39(s, 3H), 1,78-1,50(m, 5H), 1,23-0,96(m, 5H); MS: 513,2 (M+1) +. Composto 1801H NMR (400 MHz, CDCl3): δ 7.54 (br, 1H), 7.07 (m, 2H), 6.89 (m, 3H), 6.65 (s, 1H), 6.40 ( s, 1H), 6.30 (m, 3H), 4.31 (s, 2H), 4.17 (m, 1), 2.85 (m, 2H), 2.30-2.17 (m , 7H), 1.92(m, 2H); MS: 470.9 (M+1)+. 1H NMR (300 MHz, DMSO-d6): δ 8.01-7.99 (d, 1H, J=7.5), 7.10-6.70 (m, 6H), 6.23 (s, 1H), 4.52-4.47 (m, 2H), 4.28-4.22 (m, 2H), 3.76-3.71 (m, 1H), 3.63-3.61 ( m, 1H), 3.12-2.81 (m, 2H), 2.59 (s, 1H), 2.34 (s, 3H), 1.79-1.52 (m, 5H), 1 .30-0.96 (m, 5H); MS: 454.3 (M+1)+. 15 Compound 173 and its HCl Salt 1H NMR (300 MHz, DMSO-d6): δ 8.00-7.97 (m, 2H), 7.51-6.76 (m, 11H), 6.18 (s, 1H), 4.99 -4.51 (m, 2H), 3.60-3.59 (m, 1H), 2.39-2.38 (m, 6H), 1.74-1.50 (m, 5H), 1.280 .93 (m, 5H); MS: 513.3 (M+1)+. HCl salt: 1H NMR (400 MHz, DMSO-d6): δ 8.10-6.80(m, 13H), 6.17(s, 1H), 5.40(m, 1H), 4.77(m , 1H), 3.59(m, 1H), 2.74(s, 3H), 2.39(s, 3H), 1.78-1.50(m, 5H), 1.23-0, 96(m, 5H); MS: 513.2 (M+1)+. Compound 180
1H NMR (300 MHz, DMSO-d6): δ 8.01-7.99 (m, 1H), 7.11-6.70 (m, 6H), 6.24 (s, 1H), 4.27 (s, 1H), 3.61-3.51 (m, 2H), 3.12-2.81 (m, 2H), 2.35 (s, 3H), 2.03 (s, 1H), 1.801.42 (m, 7H), 1.30-0.96 (m, 9H); MS: 496.0 (M+1)+. 10 Compound 181
1H NMR (300 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.79 (br, 1H), 7.12-6.59 (m, 7H), 6.24 (s, 1H) ), 3.79-3.77 (d, 2H, J=8.1), 3.64-3.62 (m, 1H), 3.40-3.36 (m,1H), 3.22 -3.17 (m, 2H), 3.11-3.07 (m, 1H), 2.74 (s, 1H), 2.36 (s,3H), 1.78-1.52 (m , 7H), 1.32-0.97 (m, 8H); 15 MS: 482.3(M+1)+. Compound 171 and its HCl salt
1H NMR (300 MHz, DMSO-d6): δ9,89(br, 1H), 8,79(s, 2H), 8,14(s, 1H), 7,78(s, 3H), 7,14-6,59(m, 7H), 6,22(s, 1H), 4,25(s, 2H), 3,87(m, 1H), 3,63(m, 2H), 2,37(s, 3H), 1,72-1,54(m, 5H), 1,32-0,96(m, 5H); MS: 489,2 (M+1) +. 1H NMR (300 MHz, DMSO-d6): δ 8,44-8,40 (m, 2H), 8,04-8,02 (d, 1H, J=7,5), 7,68-6,70 (m, 8H), 6,25 (s, 1H), 3,67-3,61 (m, 3H), 3,16-2,90 (m, 2H), 2,35 (s, 3H), 1,801,52 (m, 5H), 1,31-0,96 (m, 5H); MS: 489,0 (M+1) +. Composto 172 e seu Sal HCl1H NMR (300 MHz, DMSO-d6): δ 8.44-8.42 (d, 1H, J=5.4), 8.02-8.00 (d, 1H, J=7.2), 7.25-6.70 (m, 8H), 6.25 (s, 1H), 3.65-3.60 (m, 3H), 3.13-2.82 (m, 2H), 2, 35 (s, 3H), 1.80-1.52 (m, 5H), 1.31-0.96 (m, 5H); MS: 489.3 (M+1)+. HCl salt: 1H NMR (300 MHz, DMSO-d6): δ9.89(br, 1H), 8.79(s, 2H), 8.14(s, 1H), 7.78(s, 3H), 7.14 -6.59(m, 7H), 6.22(s, 1H), 4.25(s, 2H), 3.87(m, 1H), 3.63(m, 2H), 2.37( s, 3H), 1.72-1.54(m, 5H), 1.32-0.96(m, 5H); MS: 489.2 (M+1)+. 1H NMR (300 MHz, DMSO-d6): δ 8.44-8.40 (m, 2H), 8.04-8.02 (d, 1H, J=7.5), 7.68-6, 70 (m, 8H), 6.25 (s, 1H), 3.67-3.61 (m, 3H), 3.16-2.90 (m, 2H), 2.35 (s, 3H) , 1.801.52 (m, 5H), 1.31-0.96 (m, 5H); MS: 489.0 (M+1)+. Compound 172 and its HCl Salt
1H NMR (300 MHz, DMSO-d6): δ 8.48-8.46 (m, 2H), 8.07-8.05 (d, 1H, J=7.2), 7.87-6, 70 (m, 10H), 6.26 (s, 1H), 3.95-3.83 (m, 2H), 3.62-3.60 (m, 1H), 3.27-3.05 ( s, 2H), 2.37 (s, 3H), 1.72-1.51 (m, 5H), 1.31-0.96 (m, 5H); MS: 489.0 (M+1)+. HCl salt: 1H NMR (300 MHz, DMSO-d6): δ9.46(s, 2H), 8.60(d, 1H, J = 3.3), 8.16(s, 1H), 7.87 (m, 2H), 7.46-7.07(m, 6H), 6.87(m, 1H), 6.72(s, 1H), 6.54(s, 1H), 6.25( s, 1H), 5.92(br, 2H), 4.27(s, 2H), 3.84(m, 1H), 3.63(m, 2H), 2.39(s, 3H), 1.70-1.50(m, 5H), 1.34-1.00(m, 5H); MS: 489.2 (M+1)+. Compound 177 and its HCl Salt
1H NMR (300 MHz, DMSO-d6): δ14,39(s, 1H), 8,09-8,07(d, 1H, J=7,2), 7,53- 7,07(m, 10H), 6,02(s, 1H), 4,94-4,74 (m, 2H), 3,61-3,58(m, 1H), 2,47(s, 3H), 1,72-1,49(m, 5H), 1,23-1,07(m, 5H); MS: 448,2(M+1) +. Composto 327 (Sal HCl) F 1H NMR(400 MHz, MeOD-d4): δ 8,12 (br, 1H), 7,82 (br, 1H), 7,46 s, 2H), 7,166,82 (m, 7H), 5,04 (d, 1H), 4,78 (d, 1H), 4,33 (m, 1H), 2,58 (s, 3H), 2,48 (s, 3H), 2,29 (m, 2,5H), 1,71 (t, 2H), 1,30 (t, 2H), 0,46 (q, 1H), 0 (q, 1H); MS: 461,2 (M+1) +. Composto 1691H NMR (300 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.72 (br, 1H), 7.09-6.56 (m, 7H), 6.23 (s, 1H ), 3.64-3.62 (m, 1H), 3.05-2.92 (m, 2H), 2.45 (s, 4H), 2.34 (s, 3H), 1.83- 1.52 (m, 9H), 1.29-0.96 (m, 5H); MS: 502.3 (M+1)+. HCl salt: 1H NMR (300 MHz, DMSO-d6): δ 10.29 (br, 1H), 8.13-6.61 (m, 9H), 6.21 (s, 1H), 4.09- 3.19(m, 7H), 2.37-2.29(m, 6H), 1.70-1.50(m, 5H), 1.34-1.00(m, 5H); MS: 502.2 (M+1)+. Compound 239 (HCl Salt) 1H NMR (300 MHz, DMSO-d6): δ14.39(s, 1H), 8.09-8.07(d, 1H, J=7.2), 7.53-7.07(m, 10H ), 6.02(s, 1H), 4.94-4.74(m, 2H), 3.61-3.58(m, 1H), 2.47(s, 3H), 1.72- 1.49(m, 5H), 1.23-1.07(m, 5H); MS: 448.2(M+1)+. Compound 327 (HCl Salt) F 1H NMR (400 MHz, MeOD-d4): δ 8.12 (br, 1H), 7.82 (br, 1H), 7.46 s, 2H), 7.166.82 (m, 7H), 5.5 04 (d, 1H), 4.78 (d, 1H), 4.33 (m, 1H), 2.58 (s, 3H), 2.48 (s, 3H), 2.29 (m, 2 .5H), 1.71 (t, 2H), 1.30 (t, 2H), 0.46 (q, 1H), 0 (q, 1H); MS: 461.2 (M+1)+. Compound 169
1H NMR (300 MHz, DMSO-d6): δ 8.49-8.44 (m, 2H), 7.98-7.97 (m, 1H), 7.33-6.30 (m, 9H) , 5.73-5.48 (m, 1H), 4.91-4.25 (m, 2H), 3.77-3.23 (m, 5H), 2.19-1.88 (m, 3H), 1.69-1.49 (m, 5H), 1.29-0.98 (m, 6H); MS: 491.2 (M+1)+.
1H NMR (300 MHz, DMSO-d6): δ 8.11-8.08 (d, 1H, J = 6.9), 7.52-6.88 (m, 9H), 6.17-6, 17 (d, 1H, J = 2.1), 6.07 (s, 1H), 5.00-4.94 (d, 1H, J = 17.4), 4.65-4.59 (d , 1H, J = 18.0), 3.65-3.51 (m, 4H), 2.41 (s, 3H), 2.31 (s, 3H), 1.75-1.68 (m , 5H), 1.27-1.16 (m, 5H); 10 MS:499.3 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8.15-8.13 (d, 1H, J = 8.0), 7.47-7.46 (d, 1H, J = 2), 7. 13-6.80 (m, 6H), 6.49-6.29 (t, 1H), 6.29-6.27 (d, 1H, J = 8.4), 5.99 (s, 1H ), 5.98 (s, 15 1H), 3.98-3.93 (d, 1H, J = 18), 3.67-3.64 (m, 4H), 3.34-3.30 ( m, 2H), 2.66-2.65 (m, 1H), 2.30 (s, 3H), 1.84-1.52 (m, 7H), 1.34-1.14 (m, 7H); MS: 500.3 (M+1)+. DRAWCODE 1H NMR (400 MHz, DMSO-d6): δ 8.10-8.08 (d, 1H, J = 7.6), 7.47 (s, 1H), 7.116.85 (m, 5H), 6.66 (s, 1H), 6.09 (s, 2H), 4.73-4.69 (d, 1H, J = 17.6), 4.40-4.36 (d, 1H, J = 16.8), 3.66-3.61 (m, 4H), 2.30 (s, 3H), 2.11 (s, 3H), 1.76-1.52 (m, 5H), 1.52-1.06 (m, 5H); MS:449.2 (M+1)+. Compound 255
1H NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1H), 8.10-8.06 (d, 1H, J = 7.6), 7.667.60 (d, 1H, J = 7.6), 7.52-7.51 (d, 1H, J = 2.0), 7.33-6.88 (m, 7H), 6.18-6.17 (d, 1H, J =1.6), 6.09 (s, 1H), 5.12-5.08 (d, 1H, J = 16.8), 4.76-4.72 (d, 1H, J = 17, 2), 3.65-3.55 (m, 4H), 2.32 (s, 3H), 1.74-1.63 (m, 5H), 1.30-1.09 (m, 5H) ; MS:485.2 (M+1)+. Compound 314
1H NMR (400 MHz, DMSO-d6): δ 8.30-8.28 (d, 1H, J = 5.2), 7.80-7.79 (d, 1H, J = 6.0), 7.40-6.79 (m, 9H), 6.30 (s, 1H), 4.78 (s, 1H), 4.51-4.47 (d, 1H, J = 16.4), 3.63-3.59 (m, 1H), 2.21 (s, 3H), 1.74-1.51 (m, 5H), 1.28-0.89 (m, 5H); MS:483.1 (M+1)+. Compound 322
1H NMR (400 MHz, DMSO-d6): δ 8.28-8.27 (d, 1H J = 6.4), 7.79-6.82 (m, 10H), 6.56-6.53 (d, 2H, J = 8.4), 6.33 (s, 1H), 3.81-3.42 (m, 3H), 1.74-1.52 (m, 5H), 1.28 -0.99 (m, 5H); MS: 519.0 (M+1)+. Compound 285
1H NMR (400 MHz, DMSO-d6): δ 9,14 (s, 1H), 8,05 (s, 1H), 7,90 (s, 1H), 7,717,69 (d, 2H J = 8,4), 7,12-6,60 (m, 10H), 6,24 (s, 1H), 3,85-3,82 (d, 1H, J = 14,0), 3,633,42 (m, 2H), 2,38 (s, 3H), 1,73-1,51 (m, 5H), 1,28-0,86 (m, 5H); MS: 542,1 (M+1) +. Composto 291 1H NMR (400 MHz, DMSO-d6): δ 9,52 (s, 1H), 8,05 (s, 1H), 7,89 (s, 1H), 7,73- 7,71 (d, 2H, J = 8,8), 7,12-6,47 (m, 9H), 6,24 (s, 1H), 3,80-3,60 (m, 3H), 2,38 (s, 3H), 1,76-1,52 (m, 5H), 1,28-1,05 (m, 5H); MS: 542,1 (M+1) +. Composto 1951H NMR (300 MHz, DMSO-d6): δ 8.21-7.69 (m, 4H), 7.14-6.65 (m, 9H), 6.18-6.16 (d, 1H, J = 7.2), 5.63-5.68 (t, 1H), 5.17-5.12 (t, 1H), 3.64-3.58 (m, 1H), 2.32 ( s, 3H), 1.731.51 (m, 5H), 1.27-0.87 (m, 5H); MS:542.2 (M+1)+. Compound 290 1H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.717.69 (d, 2H J = 8. 4), 7.12-6.60 (m, 10H), 6.24 (s, 1H), 3.85-3.82 (d, 1H, J = 14.0), 3.633.42 (m, 2H), 2.38 (s, 3H), 1.73-1.51 (m, 5H), 1.28-0.86 (m, 5H); MS: 542.1 (M+1)+. Compound 291 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.73-7.71 (d, 2H , J = 8.8), 7.12-6.47 (m, 9H), 6.24 (s, 1H), 3.80-3.60 (m, 3H), 2.38 (s, 3H) ), 1.76-1.52 (m, 5H), 1.28-1.05 (m, 5H); MS: 542.1 (M+1)+. Compound 195
1H NMR (300 MHz, DMSO-d6): δ 8.12-8.10 (m, 1H), 7.18-6.22 (m, 13H), 3.86-3.74 (m, 3H) , 3.54-3.49 (m, 2H), 2.87-2.81 (m, 2H), 2.36 (s, 3H), 2.01-1.67 (m, 2H), 1 .29-1.17 (m, 6H); MS: 502.2 (M+1)+.
1H NMR (400 MHz, CDCl3): δ 7.37-6.38 (m, 11H), 5.61-5.55 (m, 1H), 4.87-4.65 (m, 3H), 4.07-3.84 (m, 3H), 2.27 (s, 3H), 2.18-1.92 (m, 2H), 1.67-1.55 (m, 2H), 1. 32-1.07 (m, 6H); MS: 494.2 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8,47 (d, 2H, J=5,6 MHz), 8,24 (d, 1H, J=7,2 15 MHz), 7,28-6,87 (m, 10H), 6,32 (s, 1H), 3,74-3,65 (m, 3H), 3,21-3,17 (m, 2H), 3,01-2,95 (m, 1H), 1,74-1,53 (m, 5H), 1,21-0,86 (m, 5H); MS: 493,2 (M+1) +. Exemplo 3. Preparação do Composto 302. O Composto 302 também foi sintetizado através do Esquema 2 usando o seguinte protocolo. A uma solução do Composto 118 (400mg, 0,96 mmol) em acetona (10 ml) foi adicionada 6-Fluor-piridin-2-ilamina (269 mg, 2,4mmol) e NaI (288 mg, 1,92mmol). A mistura de reação foi agitada a 70°C durante a noite. A mistura resultante foi concentrada sob vácuo e DCM (20 ml) foi adicionado. A solução orgânica foi lavada com água, salmoura, seca com Na2SO4 e filtrada. O solvente foi evaporado sob vácuo. O resíduo foi purificado por prep-TLC para gerar o produto desejado como um sólido branco (196 mg, 41,52% de rendimento). H NMR (400 MHz, DMSO-d6): δ 8,02 (s, 1H), 7,83 (br, 1H), 7,52-7,46 (m, 1H), 7,33-7,02 (m, 5H), 6,86 (s, 1H), 6,72-6,65 (m, 2H), 6,48-6,47 (d, 1H, J=7,2), 6,23 (s, 1H), 6,12-6,10 (d, 1H, J=6,8), 3,86-3,83 (d, 1H, J=13,6), 3,62-3,61 (d, 1H, J=6), 3,49-3,41 (m, 1H), 2,38 (s, 3H), 1,70-1,52 (m, 5H), 1,25-0,96 (m, 5H); MS: 493,1 (M+1) +. Os seguintes compostos da invenção também foram sintetizados através do Esquema 2 seguindo o procedimento geral previsto acima para o Composto 302. O sal HCl correspondente foi sintetizado seguindo o procedimento geral previsto em Exemplo 1, etapa B. 1H NMR (400MHz, MeOD-d4), δ 8,27-8,017 (br, 2H), 7,04 (s, 1H), 7,11-6,99 (m, 20 4H), 6,87-6,84 (m, 2H), 6,74-6,72 (m, 2H), 6,21 (s, 1H), 6,01 (t, 1H, J=6), 3,78-3,73 (m, 1H), 3,61 (br, 1H), 3,37-3,33 (m, 1H), 2,36 (s, 3H), 1,72-1,52 (m, 5H), 1,28-0,96 (m, 5H); MS: 493,2 (M+1) +. Composto 3251H NMR (400 MHz, DMSO-d6): δ 8.60-8.48 (m, 3H), 8.03-7.74 (m, 2H), 7.11-6.24 10 (m, 8H) ), 3.79 (s, 2H), 3.62 (m, 1H), 3.21-2.89 (m, 2H), 2.33 (s, 3H), 2.01 (m, 1H) , 1.72-1.52 (m, 5H), 1.29-0.81 (m, 5H); MS: 490.2 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, 2H, J=5.6 MHz), 8.24 (d, 1H, J=7.2 15 MHz), 7.28-6 .87 (m, 10H), 6.32 (s, 1H), 3.74-3.65 (m, 3H), 3.21-3.17 (m, 2H), 3.01-2.95 (m, 1H), 1.74-1.53 (m, 5H), 1.21-0.86 (m, 5H); MS: 493.2 (M+1)+. Example 3. Preparation of Compound 302. Compound 302 was also synthesized via Scheme 2 using the following protocol. To a solution of Compound 118 (400mg, 0.96mmol) in acetone (10ml) was added 6-Fluor-pyridin-2-ylamine (269mg, 2.4mmol) and NaI (288mg, 1.92mmol). The reaction mixture was stirred at 70°C overnight. The resulting mixture was concentrated in vacuo and DCM (20 ml) was added. The organic solution was washed with water, brine, dried over Na2SO4 and filtered. The solvent was evaporated under vacuum. The residue was purified by prep-TLC to give the desired product as a white solid (196 mg, 41.52% yield). 1 H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H), 7.83 (br, 1H), 7.52-7.46 (m, 1H), 7.33-7.02 (m, 5H), 6.86 (s, 1H), 6.72-6.65 (m, 2H), 6.48-6.47 (d, 1H, J=7.2), 6.23 (s, 1H), 6.12-6.10 (d, 1H, J=6.8), 3.86-3.83 (d, 1H, J=13.6), 3.62-3, 61 (d, 1H, J=6), 3.49-3.41 (m, 1H), 2.38 (s, 3H), 1.70-1.52 (m, 5H), 1.25- 0.96 (m, 5H); MS: 493.1 (M+1)+. The following compounds of the invention were also synthesized via Scheme 2 following the general procedure set out above for Compound 302. The corresponding HCl salt was synthesized following the general procedure set out in Example 1, step B. 1H NMR (400MHz, MeOD-d4), δ 8.27-8.017 (br, 2H), 7.04 (s, 1H), 7.11-6.99 (m, 20 4H), 6.87-6 6.84 (m, 2H), 6.74-6.72 (m, 2H), 6.21 (s, 1H), 6.01 (t, 1H, J=6), 3.78-3.73 (m, 1H), 3.61 (br, 1H), 3.37-3.33 (m, 1H), 2.36 (s, 3H), 1.72-1.52 (m, 5H), 1.28-0.96 (m, 5H); MS: 493.2 (M+1)+. Compound 325
1H NMR (400MHz, MeOD-d4), δ 8.65 (d, 1H, J=8), 8.62 (d, 1H, J=6), 8.26 (d, 1H, J=4), 8.02 (br, 1H), 7.75 (dd, 1H, J=6), 7.24-7.12 (m, 4H), 7.01-6.90 (m, 4H), 6. 41(s, 1H), 5.64 (d, 0.59H, J=16), 3. 5.41 (d, 1H, J=16), 4.35 (t, 1H, J=8), 2.55 (s, 3H), 2.33-2.28 (m, 5 2H), 1.75-1.69 (m, 2H), 1.38-1.26 (m, 3H), 0 .46 (m, 1H), 0 (m, 1H); MS: 497.2 (M+1)+. Compound 272
1H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H), 7.85 (dr, 1H), 7.35-7.34 (d, 1H, J=4.8), 7 .12-7.03 (m, 4H), 6.87-6.85 (d, 2H, J=6.8), 6.74-6.66 (m, 2H), 6.21 (s, 1H), 5.82 10 (s, 1H), 3.81-3.79 (m, 1H), 3.62-3.60 (m, 1H), 3.47-3.42 (m, 1H) ), 3.31-3.26 (m, 1H), 2.43 2.34 (s, 3H), 1.72-1.52 (m, 5H), 1.28-0.95 (m, 5H); MS: 493.1 (M+1)+. Compound 258
1H NMR (400 MHz, DMSO-d6): δ 8.04-8.01 (m, 1H), 7.87 (dr, 1H), 7.55-7.53 (d, 15 2H, J=8 .4), 7.12-6.97 (m, 4H), 6.89-6.73 (m, 3H), 6.60-6.58 (d, 2H, J=8.8), 6 .22 (s, 1H), 3.85-3.81 (m, 1H), 3.62-3.61 (d, 1H, J=6.4), 3.45-3.41 (m, 1H), 3.03 (s, 3H), 2.38 (s, 3H), 1.76-1.52 (m, 5H), 1.28-0.96 (m, 5H); MS: 552.1 (M+1)+. Compound 280
1H NMR (400 MHz, DMSO-d6): δ 8.59-8.54 (d, 2H, J=19.2), 8.07-7.88 (m, 3H), 7.42-7, 05 (m, 4H), 6.90-6.87 (m, 1H), 6.78-6.63 (m, 4H), 6.17 (s, 1H), 4.95-4.74 ( m, 2H), 3.62-3.60 (d, 1H, J=6), 2.38 (s, 3H), 1.70-1.52 (m, 5H), 1.28-0, 93 (m, 5H); MS: 493.1 5 (M+1)+. Compound 308
1H NMR (400 MHz, DMSO-d6): δ 8.04-8.03 (d, 1H, J=4.4), 7.79 (dr, 1H), 7.30 (dr, 1H), 7 .12-6.99 (m, 3H), 6.89-6.85 (m, 1H), 6.74-6.72 (d, 2H, J=7.2), 6.43 (s, 1H), 6.31 (s, 10 1H), 6.19 (s, 1H), 5.07 (s, 2H), 4.40-4.35 (d, 1H, J=16.8), 4.13-4.08 (d, 1H, J=17.6), 3.63-3.61 (m, 1H), 2.38 (s, 3H), 1.76-1.52 (m , 5H), 1.28-0.83 (m, 5H); MS: 464.1 (M+1)+. Compound 317
1H NMR (400 MHz, DMSO-d6): δ 8,03 (s, 1H), 7,84 (dr, 1H), 7,32-7,00 (m, 6H), 6,88-6,84 (m, 1H), 6,72-6,51 (m, 2H), 6,18 (s, 1H), 4,77-4,73 (m, 1H), 4,51-4,47 (m, 1H), 3,62-3,59 (m, 1H), 2,37-2,34 (m, 3H), 1,98-1,96 (m, 3H), 1,76-1,52 (m, 5H), 1,28-0,94 (m, 5 5H); MS: 463,1 (M+1) +. 1H NMR (400 MHz, DMSO-d6): δ 8,03 (s, 2H), 7,86 (dr, 1H), 7,51-7,49 (d, 1H, J=9,2), 7,12-7,01 (m, 3H), 6,87-6,74 (m, 4H), 6,22 (s, 1H), 3,90-3,85 (d, 1H, J=20,4), 3,61 10 (s, 1H), 3,48-3,44 (d, 1H, J=16), 2,37 (s, 3H), 1,75-1,52 (m, 4H), 1,28-0,99 (m, 6H); MS: 543,1 (M+1) +.1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.84-7.83 (m, 1H), 7.59 (s, 1H), 15 7.40-7, 00 (m, 5H), 6.88-6.85 (m, 1H), 6.73-6.54 (m, 2H), 6.22-6.20 (m, 2H), 4.87- 4.83 (d, 1H, J=15.6), 4.60-4.57 (d, 1H, J=15.2), 3.63-3.61 (m, 1H), 2.38 -2.34 (s, 3H), 1.72-1.52 (m, 5H), 1.28-0.94 (m, 5H); MS: 449.1 (M+1)+. Compound 309 1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.84 (dr, 1H), 7.32-7.00 (m, 6H), 6.88-6.84 (m, 1H), 6.72-6.51 (m, 2H), 6.18 (s, 1H), 4.77-4.73 (m, 1H), 4.51-4.47 (m) , 1H), 3.62-3.59 (m, 1H), 2.37-2.34 (m, 3H), 1.98-1.96 (m, 3H), 1.76-1.52 (m, 5H), 1.28-0.94 (m, 5 5H); MS: 463.1 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 2H), 7.86 (dr, 1H), 7.51-7.49 (d, 1H, J=9.2), 7 .12-7.01 (m, 3H), 6.87-6.74 (m, 4H), 6.22 (s, 1H), 3.90-3.85 (d, 1H, J=20, 4), 3.61 10 (s, 1H), 3.48-3.44 (d, 1H, J=16), 2.37 (s, 3H), 1.75-1.52 (m, 4H ), 1.28-0.99 (m, 6H); MS: 543.1 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.84 (s, 1H), 7.45-7.00 (m, 5H), 15 6.86-6, 54 (m, 3H), 6.18 (s, 1H), 5.98 (s, 1H), 4.77-4.73 (m, 1H), 4.47-4.43 (d, 1H, J=16), 3.62-3.61 (m, 1H), 2.38-2.34 (m, 3H), 2.11 (s, 3H), 1.72-1.51 (m, 5H), 1.28-0.94 (m, 5H); MS: 463.1 (M+1)+. Compound 167

1H NMR (300 MHz, MeOD-d4): δ 7,55-6,67 (m, 11H), 6,39 (s, 1H), 5,44-4,87 (m, 4H), 3,73 (s, 1H), 2,45 (s, 3H), 2,14 (s, 3H), 1,83-1,59 (m, 5H), 1,39-1,15 (m, 5H); MS: 515,0 (M+1) +. 1H NMR (400 MHz, DMSO-d6): δ 13,07 (s, 1H), 8,66-6,78 (m, 13H), 6,18 (s, 1H), 5,61-5,24 (m, 2H), 3,59 (s, 1H), 2,41 (s, 3H), 1,71-1,49 (m, 5H), 1,22-1,04 (m, 5H); MS: 499,2 (M+1) +. 1H NMR (400 MHz, DMSO-d6): δ 8,19-8,12 (m, 2H), 7,68-6,95 (m, 12H), 6,26 (s, 1H), 5,06 (d, 1H, J=16,8 MHz), 4,74 (d, 1H, J=20,0 MHz), 3,59 (m, 1H), 1,74-1,52 (m, 5H), 1,25-0,92 (m, 5H); MS: 503,1 (M+1) +. 1H NMR (400 MHz, DMSO-d6): δ 8,38-8,19 (m, 4H), 7,38-6,93 (m, 9H), 6,52 (s, 1H), 6,27 (s, 1H), 5,45-5,03 (m, 2H), 3,59 (m, 1H), 1,75-1,51 (m, 5H), 1,23-0,93 (m, 5H); 5 MS: 503,2 (M+1) +. Composto 240 1H NMR (300 MHz, CDCl3): δ 7.86-6.44 (m, 14H), 5.34-4.82 (m, 4H), 3.82 (m, 1H), 2.29 (s , 3H), 1.91-0.87 (m, 10H); MS: 501.2 (M+1)+. 1H NMR (300 MHz, MeOD-d4): δ 7.55-6.67 (m, 11H), 6.39 (s, 1H), 5.44-4.87 (m, 4H), 3.73 (s, 1H), 2.45 (s, 3H), 2.14 (s, 3H), 1.83-1.59 (m, 5H), 1.39-1.15 (m, 5H); MS: 515.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 8.66-6.78 (m, 13H), 6.18 (s, 1H), 5.61-5.24 (m, 2H), 3.59 (s, 1H), 2.41 (s, 3H), 1.71-1.49 (m, 5H), 1.22-1.04 (m, 5H); MS: 499.2 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.19-8.12 (m, 2H), 7.68-6.95 (m, 12H), 6.26 (s, 1H), 5.06 (d, 1H, J=16.8 MHz), 4.74 (d, 1H, J=20.0 MHz), 3.59 (m, 1H), 1.74-1.52 (m, 5H) , 1.25-0.92 (m, 5H); MS: 503.1 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.38-8.19 (m, 4H), 7.38-6.93 (m, 9H), 6.52 (s, 1H), 6.27 (s, 1H), 5.45-5.03 (m, 2H), 3.59 (m, 1H), 1.75-1.51 (m, 5H), 1.23-0.93 (m , 5H); 5 MS: 503.2 (M+1)+. Compound 240
1H NMR (400 MHz, DMSO-d6): δ 8.84 (br, 2H), 8.15-8.06 (m, 2H), 7.25-6.72 (m, 10H), 6.13 (s, 1H), 4.88-4.78 (m, 2H), 3.59 (m, 1H), 2.40 (s, 3H), 1.72-1.50 (m, 5H), 1.34 10 0.87 (m, 5H); MS: 493.2 (M+1)+. Compound 253
1H NMR (400 MHz, DMSO-d6): δ9,46(s, 1H), 8,13-6,77(m, 13H), 6,19(s, 1H), 5,41-5,12(m, 2H), 4,03(m, 1H), 2,42(s, 3H), 1,79(m, 2H), 1,56-1,26(m, 6H); MS: 485,6 (M+1) +. Composto 266 1H-NMR (300 MHz, CDCl3), δ 8,64-8,51 (m, 2H), 7,82-7,68 (m, 3H), 7,12-6,77 (m, 6H), 6,39 (s, 1H), 5,89 (s, 1H), 4,81-5,19 (m, 2H), 3,75 (s, 1H), 2,32 (s, 3H), 1,85-1,44 (m, 4H), 1,33-0,96 (m, 6H); MS: 499,2 (M+1) +. 1H NMR (400 MHz, DMSO-d6): δ 8.04 (br, 1H), 7.85 (m, 2H), 7.37-6.65 (m, 10H), 6.22 (s, 1H) ), 3.85 (m, 1H), 3.55 (m, 2H), 2.37 (s, 3H), 1.72-1.50 (m, 5H), 1.34-1.07 15 (m, 5H); MS: 493.2 (M+1)+. Compound 162 1H NMR (400 MHz, DMSO-d6): δ9.46(s, 1H), 8.13-6.77(m, 13H), 6.19(s, 1H), 5.41-5.12( m, 2H), 4.03(m, 1H), 2.42(s, 3H), 1.79(m, 2H), 1.56-1.26(m, 6H); MS: 485.6 (M+1)+. Compound 266 1H-NMR (300MHz, CDCl3), δ 8.64-8.51 (m, 2H), 7.82-7.68 (m, 3H), 7.12-6.77 (m, 6H), 6.39 (s, 1H), 5.89 (s, 1H), 4.81-5.19 (m, 2H), 3.75 (s, 1H), 2.32 (s, 3H), 1 .85-1.44 (m, 4H), 1.33-0.96 (m, 6H); MS: 499.2 (M+1)+.
1H NMR (400 MHz, DMSO-d6): 8,16 (br, 1H), 7,84 (br, 1H), 7,36 (d, 1H, J = 4,8), 7,14-7,02 (m, 5H), 6,90-6,84 (m, 2H), 6,75 (d, 1H, J = 8,4), 6,22 (s, 1H), 5,84 (t, 1H, J = 5,2), 3,84-3,79 (m, 2H), 3,49 (d, 1H, J = 12,4), 2,39 (s, 3H), 1,92-1,80 (m, 6H), 151-1,49 (m, 1H), 1,36-1,31 (m, 1H); MS: 528,7 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8,65 (s, 1H), 7,77-7,35 (m, 2H), 7,15-7,03 (m, 5H), 6,90-6,67 (m, 4H), 6,21(s, 1H), 5,81 (m, 1H), 4,08(m, 1H), 3,82-3,76 (m, 1H), 3,46 (m, 1H), 2,92 (m, 2H), 2,38 (m, 5H); MS: 500,9 (M+1)+. Exemplo 4. Preparação do Composto 202 e seu Sal HCl. O Composto 202 também foi preparado pelo Esquema 2, usando o seguinte protocolo. O sal HCl correspondente foi preparado a partir do Composto 202 seguindo o protocolo previsto no Exemplo 1, etapa B.1H NMR (400 MHz, DMSO-d6): 7.92-7.81 (2H, br), 7.36 (d, 1H, J = 4.4), 7.13-7.01 (m, 5H ), 6.90-6.83 (m, 2H), 6.73-6.67 (m, 2H), 6.20 (s, 1H), 5.84 (s, 1H), 4.19 ( s, 1H), 4.18 (d, 1H, J = 4.4), 3.83 (dd, 1H, J = 16.8, 4.8), 3.46 (d, 1H, J = 16 .0), 3.33 (s, 1H), 2.37 (s, 3H), 2.19-2.13 (m, 2H), 2.10 (s, 1H), 1.63 (q, 2H, J = 13.6), 1.24-1.20 (m, 3H); MS: 490.7 (M+1)+. 1H NMR (400 MHz, DMSO-d6): 8.16 (br, 1H), 7.84 (br, 1H), 7.36 (d, 1H, J = 4.8), 7.14-7, 02 (m, 5H), 6.90-6.84 (m, 2H), 6.75 (d, 1H, J = 8.4), 6.22 (s, 1H), 5.84 (t, 1H, J = 5.2), 3.84-3.79 (m, 2H), 3.49 (d, 1H, J = 12.4), 2.39 (s, 3H), 1.92- 1.80 (m, 6H), 151-1.49 (m, 1H), 1.36-1.31 (m, 1H); MS: 528.7 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 7.77-7.35 (m, 2H), 7.15-7.03 (m, 5H), 6.90 -6.67(m, 4H), 6.21(s, 1H), 5.81(m, 1H), 4.08(m, 1H), 3.82-3.76(m, 1H), 3.46 (m, 1H), 2.92 (m, 2H), 2.38 (m, 5H); MS: 500.9 (M+1)+. Example 4. Preparation of Compound 202 and its HCl Salt. Compound 202 was also prepared by Scheme 2, using the following protocol. The corresponding HCl salt was prepared from Compound 202 following the protocol provided in Example 1, step B.
To a solution of Compound 118 (1.3 g, 3.1 mmol) in toluene (50 ml) was added Et3N (1.9 g, 18.7 mmol) and 3,4-Dihydro-2H-benzo[1, 4]oxazine (422mg, 3.1mmol). The mixture was refluxed overnight under N2 atmosphere. The resulting mixture was concentrated and DCM (20 ml) was added. The organic liquid was washed with water, brine, dried over Na2SO4, filtered and the solvent was concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a white solid (70mg, 4.37% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.87 (dr, 1H), 7.14-7.12 (d, 1H, J=6.8), 7 .06-6.99 (m, 2H), 6.88-6.85 (m, 1H), 6.72-6.63 (m, 4H), 6.52-6.48 (m, 1H) , 6.38-6.36 (d, 1H, J=8), 6.19 (s, 1H), 4.12-4.09 (m, 2H), 3.923.87 (d, 1H, J= 17.2), 3.67-3.59 (m, 2H), 3.36-3.34 (m, 2H), 2.36 (s, 3H), 1.73-1.51 (m, 5H), 1.27-0.93 (m, 5H); LC-MS: purity >95%, MS: 516.3 (M++1). HCl salt: 1H NMR (300 MHz, DMSO-d6): δ7.93(br, 2H), 7.13-6.18(m, 11H), 4.09(m, 1H), 3.86-3 1.55(m, 3H), 3.22(m, 2H), 2.63(m, 2H), 2.36(s, 3H), 1.72-1.50(m, 7H), 1. 32-0.89(m, 5H); MS: 514.3 (M+1)+. The following compounds of the invention were also synthesized via Scheme 2 following the general procedure set out above for Compound 202. The corresponding HCl salt was synthesized following the general procedure set out in Example 1, step B. Compound 242
1H NMR (400 MHz, DMSO-d6): δ 8.01-7.99 (m, 1H), 7.12-6.84 (m, 7H), 6.74-6.71 (m, 1H) , 6.57-6.55 (m, 1H), 6.45-6.35 (m, 1H), 6.23 (s, 1H), 5.39-5.37 (m, 1H), 3 .77-3.70 (m, 1H), 3.64-3.60 (m, 1H), 3.46-3.34 (m, 1H), 2.37 (s, 3H), 1.75 -1.50 (m, 5H), 1.29-0.85 (m, 5H); MS: 492.2 (M+1)+. Compound 265
1H NMR (300MHz, CDCl3): δ 7.19-7.13 (m, 4H), 7.00-6.91 (m, 3H), 6.76 (d, 1H, J=5.7 MHz) , 6.69-6.66 (m, 1H), 6.55 (s, 1H), 6.39 (s, 1H), 5.25 (d, 1H, J=5.7 MHz), 5. 03 (m, 1H), 3.86 (m, 1H), 3.56 (d, 2H, J=3.3 MHz), 2.40 (s, 3H), 1.97-1.87 (m , 2H), 1.68-1.55 (m, 3H), 1.36-1.10 (m, 5H); MS: 499.1 (M+1)+. Compound 278
A uma solução do Composto 118 (200 mg, 0,48 mmol) em DMF (4 ml) foi adicionada Et3N (0,4 ml, 2,87 mmol) e Metil-fenil-amina (103 mg, 0,96 mmol). A mistura foi agitada durante a noite em temperatura ambiente. Água (20 ml) foi adicionada e foi então extraída com DCM (3x10 ml). A camada orgânica combinada foi lavada com água, salmoura, seca com Na2SO4, filtrada e concentrada sob vácuo. O resíduo foi purificado por prep-HPLC para gerar o produto desejado como um sólido branco (10,7 mg, 4,58% de rendimento). H NMR (300 MHz, DMSO-d6): δ 7,94-7,92 (d, 1H, J = 6,6), 7,15-6,51 (m, 12H), 6,18 (s, 1H), 3,97-3,91 (d, 1H, J = 17,1), 3,71-3,58 (m, 2H), 2,89 (s, 3H), 2,36 (s, 3H), 1,73-1,50 (m, 5H), 1,26-0,99 (m, 5H); MS: 488,2 (M+1) +. Os seguintes compostos da invenção também foram sintetizados através do Esquema 2 seguindo o procedimento geral previsto acima para o Composto 161. O sal HCl correspondente foi sintetizado seguindo o procedimento geral previsto em Exemplo 1, etapa B. Composto 1821H NMR (400MHz, CDCl3): δ 7.19-7.13 (m, 4H), 7.00-6.89 (m, 3H), 6.76 (d, 1H, J=6.8 MHz) , 6.69-6.66 (m, 1H), 6.55 (s, 1H), 6.39 (s, 1H), 5.25 (d, 1H, J=7.6 MHz), 5. 03-5.02 (m, 1H), 3.87 (m, 1H), 3.58-3.57 (d, 2H, J=4.4 MHz), 2.40 (s, 3H), 1 1.99-1.80 (m, 2H), 1.69-1.55 (m, 2H), 1.36-1.02 (m, 6H); MS: 499.1 (M+1)+. Example 5. Preparation of Compound 161. Compound 161 was prepared according to Scheme 2 using the following protocol. To a solution of Compound 118 (200mg, 0.48mmol) in DMF (4ml) was added Et3N (0.4ml, 2.87mmol) and Methyl-phenyl-amine (103mg, 0.96mmol) . The mixture was stirred overnight at room temperature. Water (20 ml) was added and was then extracted with DCM (3x10 ml). The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a white solid (10.7 mg, 4.58% yield). 1 H NMR (300 MHz, DMSO-d6): δ 7.94-7.92 (d, 1H, J = 6.6), 7.15-6.51 (m, 12H), 6.18 (s, 1H), 3.97-3.91 (d, 1H, J = 17.1), 3.71-3.58 (m, 2H), 2.89 (s, 3H), 2.36 (s, 3H), 1.73-1.50 (m, 5H), 1.26-0.99 (m, 5H); MS: 488.2 (M+1)+. The following compounds of the invention were also synthesized via Scheme 2 following the general procedure set out above for Compound 161. The corresponding HCl salt was synthesized following the general procedure set out in Example 1, step B. Compound 182
A uma suspensão de KOH (105 mg, 1,87 mmol) em DMSO seco (5 ml) foi adicionada 3-Fluor-fenol (106 mg, 0,94 mmol) e o Composto 118 (260 mg, 0,62 mmol). A mistura de reação foi agitada em temperatura ambiente durante 3 horas. A mistura resultante foi interrompida por H2O (15 ml) e então extraída com EtOAc (2x10 ml). A camada orgânica combinada foi lavada com solução de NaHCO3, salmoura, seca com Na2SO4, filtrada e o solvente foi evaporado sob vácuo. O resíduo foi purificado através de cromatografia com sílica gel para gerar o produto desejado como um sólido branco (122,5 mg, 40% de rendimento). 1H NMR (300 MHz, DMSO-d6): δ 8,03-8,00 (d, 1H, J=6,9), 7,31-6,62 (m, 11H), 6,21 (s, 1H), 4,69-4,23 (m, 2H), 3,62-3,61 (m, 1H), 2,36 (s, 3H), 1,761,56 (m, 5H), 1,29-1,00 (m, 5H); MS: 493,2 (M+1) +. Os seguintes compostos da invenção também foram sintetizados através do Esquema 2 seguindo o procedimento geral previsto acima para o Composto 189. O sal HCl correspondente foi sintetizado seguindo o procedimento geral previsto em Exemplo 1, etapa B. Composto 136 1H NMR (300 MHz, DMSO-d6): δ 8.09-8.07 (d, 1H, J=8), 7.82 (br, 1H), 7.15-6.98 (m, 6H) , 6.89-6.84 (m, 1H), 6.72-6.51 (m, 5H), 6.19 (s, 1H), 3.98-3.92 (d, 1H, J= 22.8), 3.81-3.66 (m, 4H), 2.89 (s, 3H), 2.36 (s, 3H), 1.70-1.66 (d, 2H, J= 14.8), 1.38-1.12 (m, 4H); MS: 490.2 (M+1)+. Example 6. Preparation of Compound 189. Compound 189 was synthesized according to Scheme 3 using the following protocol To a suspension of KOH (105 mg, 1.87 mmol) in dry DMSO (5 ml) was added 3-Fluor-phenol (106 mg, 0.94 mmol) and Compound 118 (260 mg, 0.62 mmol) . The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was quenched with H2O (15 ml) and then extracted with EtOAc (2x10 ml). The combined organic layer was washed with NaHCO3 solution, brine, dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The residue was purified by silica gel chromatography to give the desired product as a white solid (122.5 mg, 40% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.03-8.00 (d, 1H, J=6.9), 7.31-6.62 (m, 11H), 6.21 (s, 1H), 4.69-4.23 (m, 2H), 3.62-3.61 (m, 1H), 2.36 (s, 3H), 1.761.56 (m, 5H), 1.29 -1.00 (m, 5H); MS: 493.2 (M+1)+. The following compounds of the invention were also synthesized via Scheme 2 following the general procedure set out above for Compound 189. The corresponding HCl salt was synthesized following the general procedure set out in Example 1, step B. Compound 136
1H NMR (300 MHz, DMSO-d6): δ 8,01-7,99 (d, 1H, J=7,8), 7,10-6,71 (m, 10H), 6,19 (s, 1H), 4,61-4,17 (m, 2H), 3,62-3,59 (m, 1H), 2,34 (s, 3H), 1,75-1,49 (m, 5H), 1,28-1,00 (m, 5H); MS: 493,1 (M+1) +. 10 Composto 1961H NMR (300 MHz, DMSO-d6): δ8.02-8.00(d, 1H, J=6.9), 7.27-6.73(m, 11H), 6.22(s, 1H ), 4.63-4.20(m, 2H), 3.64-3.61(m, 1H), 2.37(s, 3H), 1.75-1.55(m, 5H), 1.291.00 (m, 5H); MS: 475.2(M+1)+. 5 Compound 194 1H NMR (300 MHz, DMSO-d6): δ 8.01-7.99 (d, 1H, J=7.8), 7.10-6.71 (m, 10H), 6.19 (s, 1H), 4.61-4.17 (m, 2H), 3.62-3.59 (m, 1H), 2.34 (s, 3H), 1.75-1.49 (m, 5H) , 1.28-1.00 (m, 5H); MS: 493.1 (M+1)+. 10 Compound 196
1H NMR (300 MHz, DMSO-d6): δ 8.02-8.01 (d, 1H, J = 7.2), 7.21-6.73 (m, 10H), 6.21 (s, 1H), 4.74-4.34 (m, 2H), 3.62-3.60 (m, 1H), 2.36 (s, 3H), 1.75-1.49 (m, 5H) , 1.25-0.95 (m, 5H); MS: 493.2 (M+1)+. 15 Compound 197 and its HCl Salt
1H NMR (300 MHz, DMSO-d6): δ8,50(m, 2H), 8,06-7,77(m, 3H), 7,15-6,74(m, 6H), 6,17(s, 1H), 4,96-4,50(m, 2H), 3,62(m, 1H), 2,36(s, 3H), 1,72-1,50(m, 5H), 1,34- 1,00(m, 5H); MS: 476,2 (M+1) +. Composto 198 1H NMR (300 MHz, DMSO-d6): δ 8,10-8,08 (m, 1H), 7,99-7,97 (m, 1H), 7,73-7,67 (m, 1H), 7,15-6,70 (m, 8H), 6,21(s, 1H), 4,73-4,43 (m, 2H), 3,63-3,61 (m, 1H), 2,39 (s, 3H), 1,75-1,50 (m, 5H), 1,28-0,96 (m, 5H); MS: 476,2 (M+1) +. Composto 199 1H NMR (300 MHz, DMSO-d6): δ 8,04-8,02 (m, 1H), 7,47-7,43 (m, 1H), 7,14-7,67 (m, 6H), 6,18 (s, 1H), 6,04-6,01 (m, 2H), 4,62-4,35 (m, 2H), 3,62-3,61 (m, 1H), 2,38 (s, 3H), 1,73-1,50 (m, 5H), 1,28-0,96 (m, 5H); MS: 476,2 (M+1) +. Composto 2601H NMR (300 MHz, DMSO-d6): δ 8.17-8.14 (m, 2H), 8.02-8.00 (m, 1H), 7.31-6.74 (m, 8H) , 6.21 (s, 1H), 4.75-4.31 (m, 2H), 3.63-3.61 (m, 1H), 2.36 (s, 3H), 1.75-1 .50 (m, 5H), 1.28-0.96 (m, 5H); MS: 476.2 (M+1)+. HCl salt: 1H NMR (300 MHz, DMSO-d6): δ8.50(m, 2H), 8.06-7.77(m, 3H), 7.15-6.74(m, 6H), 6.17( s, 1H), 4.96-4.50(m, 2H), 3.62(m, 1H), 2.36(s, 3H), 1.72-1.50(m, 5H), 1 .34-1.00(m, 5H); MS: 476.2 (M+1)+. Compound 198 1H NMR (300 MHz, DMSO-d6): δ 8.10-8.08 (m, 1H), 7.99-7.97 (m, 1H), 7.73-7.67 (m, 1H) , 7.15-6.70 (m, 8H), 6.21 (s, 1H), 4.73-4.43 (m, 2H), 3.63-3.61 (m, 1H), 2 .39 (s, 3H), 1.75-1.50 (m, 5H), 1.28-0.96 (m, 5H); MS: 476.2 (M+1)+. Compound 199 1H NMR (300 MHz, DMSO-d6): δ 8.04-8.02 (m, 1H), 7.47-7.43 (m, 1H), 7.14-7.67 (m, 6H) , 6.18 (s, 1H), 6.04-6.01 (m, 2H), 4.62-4.35 (m, 2H), 3.62-3.61 (m, 1H), 2 .38 (s, 3H), 1.73-1.50 (m, 5H), 1.28-0.96 (m, 5H); MS: 476.2 (M+1)+. Compound 260
1H NMR (300 MHz, DMSO-d6): δ 8.08-8.07 (d, 1H,J=2.4), 8.01 (s, 1H), 7.87 (br, 1H), 7 .72-7.67 (m, 1H), 7.15-6.69 (m, 8H), 6.21 (s, 1H), 4.71-4.44 (m, 2H), 3.61 -3.59 (m, 1H), 2.36 (s, 3H), 2.28 (s, 4H), 1.74-1.51 (m, 5H), 1.28-0.94 (m , 5H); MS: 494.1 (M+1)+. Example 7. Preparation of Compound 331. Compound 331 was prepared using the following protocol. The 2-[(2-Chloro-acetyl)-(3-fluoro-phenyl)-amino]-N-(4,4-difluoro-cyclohexyl)-2-o-tolyl-acetamide used in the protocol provided below was prepared from according to Scheme 4. The chloroacetyl compound was converted to Compound 331 was
Step A: (3-Fluoro-phenylamino)-o-tolyl-acetonitrile. A mixture of 2-Methyl-benzaldehyde (0.6 g, 5 mmol) and 3-Fluoro-phenylamine (0.56 g, 5 mmol) was stirred overnight at room temperature followed by the addition of TMSCN (0.6 g , 6 mmol). The reaction mixture was stirred for another 8 hours. Et2O (20 ml) was added and the solid was collected by filtration and dried in vacuo to give (3-Fluoro-phenylamino)-o-tolyl-acetonitrile, which was used directly without further purification (0.9 g, 77% income). 1H NMR (300 MHz, CDCl3): δ 7.70 (d, 1H, J = 6.9), 7.37-7.18 (m, 4H), 6.596.46 (m, 3H), 5.43 (d, 1H, J = 7.8), 3.95 (d, 1H, J = 7.8), 2.38 (s, 3H); MS: 214.1 (M-26)+. Step B: (3-Fluoro-phenylamino)-o-tolyl-acetic acid. To a mixture of (3-Fluoro-phenylamino)-o-tolyl-acetonitrile (0.48 g, 2 mmol) and K2CO3 (0.14 g, 1 mol) in DMSO (2.5 ml) was added H2O2 (30 %, 0.34 g) at 0°C.
The mixture was warmed to room temperature and stirred for 2 hours. The precipitate was collected by filtration, washed with cold water and dried under vacuum. The residue was dissolved in a mixture of MeOH/H2O (4:1, 5 ml) and NaOH (0.24 g, 6 mmol) was then added. The reaction mixture was refluxed for 5 hours and concentrated. Water (30 ml) was added. The resulting mixture was extracted with EtOAc (25ml) and the aqueous phase adjusted to pH=4 with conc. HCl, extracted with DCM (3x20 ml). The combined DCM layer was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo to give (3-Fluor-phenylamino)-o-tolyl-acetic acid (0.4 g, 80% yield), which was used directly for the next step. 1H NMR (300 MHz, CDCl3): δ 7.40 (d, 1H, J = 7.2), 7.37-7.21 (m, 4H), 7.05 (m, 1H), 6.40 -6.18 (m, 3H), 5.26 (s, 1H), 2.53 (s, 3H); MS: 214.1 (M-45)+. Step C: N-(4,4-Difluoro-cyclohexyl)-2-(3-fluoro-phenylamino)-2-o-tolyl-acetamide. To a solution of (3-Fluoro-phenylamino)-phenyl-acetic acid (259 mg, 1 mmol) in DCM (5 ml) was added HOBt (162 mg, 1.2 mmol), EDCI (240 mg, 1.2 mmol), Et3N (0.5 ml) and 4,4-Difluoro-cyclohexylamine (170 mg, 1.52 mmol) at 0°C. The reaction mixture was heated to 40°C for 48 hours. After cooling to room temperature, 30 ml of water was added. The organic layer was separated and the aqueous phase was extracted with DCM (3x10ml). The combined organic layer was washed with NaHCO3, brine, dried with Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was washed with Et2O to give N-(4,4-Difluoro-cyclohexyl)-2-(3-fluoro-phenylamino)-2-o-tolyl-acetamide, which was used directly without further purification (280 mg, 68% yield).
Step D: 2-[(2-Chloro-acetyl)-(3-fluoro-phenyl)-amino]-N-(4,4-difluoro-cyclohexyl)-2-o-tolyl-acetamide. To a mixture of N-(4,4-Difluoro-cyclohexyl)-2-(3-fluoro-phenylamino)-2-o-tolyl-acetamide (280 mg, 0.74 mmol)) in toluene (5 ml) was added chloroacetyl chloride (100 mg, 0.9 mmol) dropwise at 0°C. The reaction mixture was heated to 100°C for 2 hours and then cooled to room temperature. 10 ml of ethyl acetate was added and the solvent was washed with NaHCO3 solution, brine, dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The residue was washed with Et2O to give 2-[(2-Chloro-acetyl)-(3-fluoro-phenyl)-amino]-N-(4,4-difluoro-cyclohexyl)-2-o-tolyl-acetamide (230mg, 68% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.18-7.11 (m, 3H), 6.94-6.88 (m, 2H), 6.75 (d, 1H), 6.32(s , 1H), 5.33 (d, 1H), 3.97 (br, 1H), 3.86 (q, H), 2.39 (s, 3H), 2.09-1.79 (m, 6H), 1.56-1.39 (m, 2H); MS: 452.8 (M+1)+.
Step E: Compound 331. A mixture of 2-[(2-Chloro-acetyl)-(3-fluoro-phenyl)-amino]-N-(4,4-difluoro-cyclohexyl)-2-o-tolyl acetamide ( 100mg, 0.22mmol), K2CO3 (90mg, 0.66mmol) and pyridin-2-ol (42mg, 0.44mol) in MeCN (5ml) was warmed to 40°C and stirred during night. The resulting mixture was evaporated under vacuum. The residue was suspended in water (25 ml) and extracted with DCM (3x10 ml). The combined organic layer was washed with NaHCO3 solution, brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by TLC (DCM/MeOH=20/1) to give the desired product (20 mg, 17% yield). 1H-NMR(CDCl3, 400MHz), δ 8.08 (d, 1H), 7.56 (m, 1H), 7.26-6.82 (m, 9H), 6.32 (s, 1H), 5.50 (d, 1H), 4.6 (dd, 2H), 3.96 (br, 1H), 2.41 (s, 3H), 2.07-1.59 (m, 6H), 1.51-1.25 (m, 2H); MS: 512.2 (M+1) + The following compounds of the invention were also synthesized from the appropriate chloroacetyl compound and following the general procedure set out in step E.
1H), 4,70 (d, 1H, J=14,4 MHz), 4,43 (d, 1H, J=15,2 MHz), 4,16 (m, 1H), 2,38 (s, 3H), 2,15-2,08 (m, 2H), 1,62-1,49 (m, 2H), 1,21-1,09 (m, 2H), 0,36-0,34 (m, 1H), 0,00--0,03 (m, 1H); MS: 474,2 (M+1) +. Os compostos seguintes foram sintetizados de acordo com o Esquema 4 (e etapas A-D, acima), usando a amina R apropriada e derivado cloroacetil de R4. Composto 1861H NMR(400 MHz, CDCl3), δ8.07 (dd, 1H, J=4.8, 12), 7.56 (td, 1H, J=6.8, 1.6), 7.18-7 .10 (m, 3H), 6.93-6.83 (m, 5H), 5.39(s, 1H), 4.74 (d, 1H, J=14.8), 4.55 (d , 1H, J=15.2), 2.41 (s, 3H); MS: 487.3 (M+1)+. 1H), 4.70 (d, 1H, J=14.4 MHz), 4.43 (d, 1H, J=15.2 MHz), 4.16 (m, 1H), 2.38 (s, 3H), 2.15-2.08 (m, 2H), 1.62-1.49 (m, 2H), 1.21-1.09 (m, 2H), 0.36-0.34 ( m, 1H), 0.00--0.03 (m, 1H); MS: 474.2 (M+1)+. The following compounds were synthesized according to Scheme 4 (and steps AD, above), using the appropriate amine R and chloroacetyl derivative of R4. Compound 186
1H NMR (300 MHz, DMSO-d6): δ 8.09 (m, 1H), 7.77-6.50 (m, 11H), 6.32 (s, 1H), 4.01-3.89 (m, 1H), 3.65-3.56 (m, 2H), 2.36 (s, 3H), 2.11-0.75 (m, 10H); MS: 477.2 (M+1) +
1H NMR (400 MHz, DMSO-d6): δ 8,35 (s, 1H), 7,46(s, 1H), 7,36-7,34 (m, 1H), 7,12-6,44 (m, 9H), 4,25-4,23 (m, 1H), 3,69-3,52 (m, 2H), 2,35 (s, 3H), 2,19-2,12 (m, 2H), 1,92-1,88 (m, 1H), 1,71-1,57 (m, 3H); MS: 437,1 (M+1) +. 20 Composto 1591H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 7.74 (s, 1H), 7.36-6.28 (m, 11H), 3.76-2.87 (m, 7H), 2.31 (s, 3H), 1.86-1.23 (m, 4H); MS: 467.1 (M+1)+. Compound 178 1H NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1H), 7.46(s, 1H), 7.36-7.34 (m, 1H), 7.12-6.44 (m, 9H), 4.25-4.23 (m, 1H), 3.69-3.52 (m, 2H), 2.35 (s, 3H), 2.19-2.12 (m , 2H), 1.92-1.88 (m, 1H), 1.71-1.57 (m, 3H); MS: 437.1 (M+1)+. 20 Compound 159
1H NMR (300 MHz, DMSO-d6): δ 8.13 (d, 1H, J=5.4), 7.70-6.50 (m, 11H), 6.25 (s, 1H), 3 1.84-3.49 (m, 5H), 3.32 (m, 2H), 2.34 (s, 3H), 1.74 (m, 2H), 1.43 (m, 1H), 1. 23 (m, 1H); MS: 467.2 (M+1)+. 5 Compound 211
1H NMR (300 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.76-6.66 (m, 11H), 6.27 (s, 1H), 3.69-3.51 (m, 2H), 3.08-3.03 (m, 1H), 2.34 (s, 3H), 1.59-0.81 (m, 12H); MS: 479.2 (M+1) + . 10 Compound 190
1H NMR (300 MHz, CDCl3): δ 7.16-6.72 (m, 9H), 6.37 (s, 1H), 5.59 (m, 1H), 4.51 (m, 1H), 3.66 (m, 3H), 3.34-3.18 (m, 3H), 2.34 (s, 3H), 2.08 (m, 1H), 1.72 (m, 1H), 1 .43 (s, 9H); MS: 569.3 (M+18)+, 452.2 (M-100)+. Example 8. Preparation of Compound 341. Compound 341 was prepared according to Scheme 5, using the following protocol
Step A: {[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-methyl}-methyl-carbamic acid tert-butyl ester. The title compound was synthesized via the
Scheme 1, as described in Step A of Example 1. 1H NMR (400 MHz, CDCl3): δ 7.16-7.07 (m, 3.5H), 6.91-6.76 (m, 3.5H) ), 5.49 (d, 0.5H), 5.29 (d, 0.5H), 4.05 (d, 0.5), 3.95-3.80 (br, 1H), 3. 73 (d, 0.5H), 3.56-3.44 (m, 1H), 2.90 (d, 3H), 0.29 (d, 3H), 1.97-1.89 (m , 2H), 1.71-1.57 (m, 4H), 1.44 (s, 9H), 1.37-1.32 (br, 2H), 1.16-1.01 (m, 4H) ); MS: 511.9 (M+1)+. Step B: N-Cyclohexyl-2-[(3-fluoro-phenyl)-(2-methylamino-acetyl)-amino]-2-o-tolyl-acetamide (hydrochloride). A mixture of {[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-methyl}-methyl-carbamic acid tert-butyl ester (150 mg, 0.29 mmol) in HCl/ Et2O (30% w/w, 5 ml) was stirred for 5 hours at room temperature. The resulting mixture was evaporated under vacuum to give the desired product, which was used directly without further purification (135 mg, 100% yield).
Step C: Compound 341. To a mixture of N-Cyclohexyl-2-[(3-fluoro-phenyl)-(2-methylamino-acetyl)-amino]-2-o-tolyl-acetamide (hydrochloride, 132 mg, 0 .29 mmol) and Et3N (85 mg, 0.6 mmol) in DCM (5 ml) was added methyl chloroformate (30 mg, 0.3 mmol) at 0°C. The reaction was stirred for 3 hours at the same temperature. 10 ml of water was added and the mixture was extracted with DCM (3x5 ml). The combined organic layer was washed with saturated NaHCO3 solution, brine, dried with Na2SO4, filtered and the solvent was evaporated under vacuum. The residue was purified by TLC to give pure product (30 mg, 22% yield). 1H NMR (400MHz, CDCl 3 ) δ 7.17-7.07 (m, 3H), 6.89-6.76 (m, 4H), 6.42 (s, 0.5H), 6.39 (s , 0.5H), 5.53 (d, 0.5H, J=7.6), 5.29 (d, 0.5H, J=8.4), 4.01-3.79 (3, 3H), 3.65-3.48 (m, 4H), 2.96 (s, 3H), 2.39 (s, 3H), 1.97-1.90 (br, 2H), 1.72 -1.68 (br, 1H), 1.63-1.58 (br, 1H), 1.36-1.25 (br, 3H), 1.17-1.11 (m, 3H); MS: 470.2 (M+1) + The following compounds were synthesized according to Scheme 5, following the above protocol. Compound 334
1H NMR (400 MHz, CDCl3), δ 7.16-6.74 (m, 6H), 6.34 (s, 1H), 5.54 (s, 1H), 5.54-5.26 (m , 1H), 3.88-3.64 (m, 6H), 2.38 (s, 3H), 1.98-1.62 (m, 4H), 1.42-0.98 (m, 6H) ); MS: 456.2 (M+1)+. Compound 352
1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.94-7.92 (d, 1H, J=6.8), 7.18-7.04 (m, 3H), 6.98-6.64 (m, 5H), 6.23 (s, 1H), 3.58-3.56 (m, 1H), 3.34-3.32 (m, 1H) , 3.25-3.21 5 (m, 1H), 2.29 (s, 3H), 1.75-1.48 (m, 5H), 1.32 (s, 9H), 1.28- 0.89 (m, 5H); MS: 498.2 (M+1)+. Compound 357
F1H NMR (400 MHz, DMSO-d6): δ 8.15-8.11 (m, 1H), 7.99-7.97 (d, 1H, J=7.6), 10 7.29-6 .90 (m, 6H), 6.79-6.75 (m, 1H), 6.68-6.66 (d, 1H, J = 7.2), 6.27 (s, 1H), 3 .61-3.40 (m, 5H), 3.30 (s, 1H), 2.34 (s, 3H), 1.78-1.52 (m, 5H), 1.28-0.91 (m, 5H); MS: 456.1 (M+1)+. Compound 353 F
1H NMR (400 MHz, DMSO-d6): δ 7.94-7.92 (d, 2H, J = 7.2), 7.15-6.98 (m, 4H), 6.82-6, 78 (m, 2H), 6.63-6.56 (m, 2H), 6.17 (s, 1H), 3.58-3.45 (m, 5H), 3.25-3.19 ( m, 1H), 2.32 (s, 3H), 1.73-1.48 (m, 5H), 1.25-0.88 (m, 5H); MS: 456.2 (M+1)+. Compound 358
1H NMR (400 MHz, DMSO-d6): δ 8.21-8.19 (m, 1H), 7.01-7.99 (d, 1H, J=7.6), 7.30-6, 97 (m, 5H), 6.84-6.80 (m, 1H), 6.66-6.64 (d, 1H, J=7.2), 6.26 (s, 1H), 3. 62-3.39 (m, 5H), 3.34-3.32 (m, 1H), 2.36 (s, 3H), 1.77-1.52 (m, 5H), 1.28- 0.92 (m, 5H); MS: 474.0 5 (M+1) +.Compound 369
1H NMR (400 MHz, DMSO-d6): δ7,80 (br, 1H), 7,72 (br, 0,8H), 7,09-7,06 (d, 2H), 15 7,02-6,94 (m, 3H), 6,84 (t, 1H), 6,70 (d, 1H), 6,22 (s, 1H), 3,63 (m, 1H), 3,46 (s, 3H), 3,20- 3,08 (m, 2H), 2,34 (s,3H), 2,30-2,24 (m, 1H), 2,06-2,01 (m, 1H), 1,77-1,52 (m, 6H), 1,29- 1,23 (br, 1H), 1,19-0,94 (m, 3H); MS: 470,1 (M+1) +. Composto 3721H NMR (400 MHz, DMSO-d6): δ7.80-7.72 (br, 1.7H), 7.10-7.08 (d, 2H), 7.02-6.94 (m, 2H) ), 6.84 (t, J = 8.1H), 6.69 (d, J = 7.6, 1H), 6.61 (s, 1H), 6.22 (s, 1H), 3. 62 (m, 10 1H), 3.13-2.50 (m, 2H), 2.34 (s, 3H), 2.27-2.23 (m, 1.5H), 2.04-2 .00 (br, 1.3H), 1.78-1.52 (m, 5.5H), 1.52-1.11 (m, 12H); MS: 512.1 (M+1)+. Compound 374 1H NMR (400 MHz, DMSO-d6): δ7.80 (br, 1H), 7.72 (br, 0.8H), 7.09-7.06 (d, 2H), 15 7.02-6 .94 (m, 3H), 6.84 (t, 1H), 6.70 (d, 1H), 6.22 (s, 1H), 3.63 (m, 1H), 3.46 (s, 3H), 3.20-3.08 (m, 2H), 2.34 (s,3H), 2.30-2.24 (m, 1H), 2.06-2.01 (m, 1H) , 1.77-1.52 (m, 6H), 1.29-1.23 (br, 1H), 1.19-0.94 (m, 3H); MS: 470.1 (M+1)+. Compound 372
1H NMR (300 MHz, DMSO-d6): δ 8.16-8.02 (m, 1H), 7.36-7.08 (m, 6H), 6.81-6.62 (m, 1, 5H), 6.30 (s, 0.5H), 5.87 (s, 0.5H), 5.62 (s, 0.5H), 4.96-4.85 (m, 1H), 4 .72 (d, J = 13.2, 0.5H), 4.44 (d, J = 13.2, 0.5H), 4.09-4.03 (m, 1H), 3.84- 3.80 (m, 1H), 3.69-3.58 (m, 4H), 2.24 (s, 1.5H), 2.05 (s, 1.5H), 1.82-1, 57 (m, 5H), 1.37-1.00 (m, 6H); MS: 458.0 (M+1)+. Compound 306
1H NMR (400 MHz, DMSO-d6): δ 8.02-7.94 (m, 1H), 7.79-7.32 (m, 1H), 7.39-6.48 (m, 7H) , 6.24 (s, 1H), 4.02 (m, 1H), 3.61-3.58 (m, 4H), 3.40-3.30 (m, 2H), 2.37 (s , 3H), 1.79-1.52 (m, 7H), 1.29-1.06 (m, 7H); MS: 496.1 (M+1)+. Example 9. Preparation of Compounds 225, 226, 236 and 241. The title compound were prepared according to the following Scheme
Step A: Compound 224. Compound 224 was synthesized according to Scheme 1 and following the protocol set forth in Example 1, Step A. 1H-NMR (300MHz, DMSO-d6), δ 9.48-9.25 (m , 1H), 7.99 (m, 1H), 7.53-7.30 (m, 4H), 7.08-6.47 (m, 5H), 6.10 (s, 1H), 4. 98-4.62 (m, 2H), 3.59 (m, 1H), 2.45 (s, 3H), 2.36 (s, 3H), 1.73-1.46 (m, 14H) , 1.25-1.22 (m, 5H); MS: 560.3 (M+1)+.
Step B: Compound 226. Compound 226 was prepared following the protocol set forth in Example 8, step B. 1H-NMR (300MHz, DMSO-d6), δ 14.43 (m, 1H), 7.98 (s, 1H ), 7.72-7.53 (m, 2H), 7.23-6.71 (m, 6H), 6.12 (s, 1H), 5.00-4.66 (m, 2H), 3.59 (m, 1H), 2.47 (s, 3H), 2.37 (s, 3H), 1.72-1.50 (m, 4H), 1.24-1.23 (m, 6H); MS: 460.3 (M+1)+.
Step C: Compound 236. To a mixture of Compound 226 HCl salt in DCM (5 ml) was added acetyl chloride (20 mg, 0.24 mmol) at 0°C. The reaction was stirred for 3 hours and the resulting mixture was washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by TLC (DCM/MeOH=15/1) to give pure product (30 mg, 31% yield). 1H NMR (400 MHz, MeOD-d4): δ 7.95 (s, 1H), 7.57-6.69 (m, 10H), 6.22 (s, 1H), 4.58-4.42 (m, 2H), 3.65-3.61 (m, 1H), 2.34 (s, 3H), 2.15 (s, 3H), 2.02-1.95 (m, 3H), 1.79-1.49 (m, 5H), 1.28-0.95 (m, 5H); MS: 502.3 (M+1)+.
Step D: Compound 241. Compound 241 was synthesized following the protocol set forth in Example 8, step C. 1H NMR (400 MHz, MeOD-d4): δ 8.04 (m, 1H), 7.626.45 (m, 10H) ), 6.34 (s, 1H), 4.76-4.61 (m, 2H), 3.76-3.73 (m, 4H), 2.46 (s, 3H), 2.33 ( s, 3H), 1.91-1.63 (m, 5H), 1.40-1.07 (m, 5H); MS: 518.3 (M+1)+.
Example 10. Preparation of Compound 328. Compound 328 was prepared according to the following scheme
Step A: (SR, RS)-2-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-carboxylic acid tert-butyl ester.
Step A was carried out following Scheme 1 and the protocol provided in Example 1, Step A and generated two pairs of separate enantiomers by chromatography. (SR, RS)-2-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-carboxylic acid tert-butyl ester. (PE/EtOAc=5/1; Rf1=0.35). 1H NMR (400 MHz, DMSO-d6): δ 8.02 (br, 1H), 7.82 (d, 1H), 7.10-6.82 (m, 8H), 4.45-4.45 (q, 1H), 3.78 (br, 0.5H), 3.635 (br, 1.5H), 3.45 (br, 0.5H), 2.30 (s, 1H), 1.75- 1.42 (m, 7H), 1.42-1.02 (m, 18H); MS: 552.1 (M+1)+.
(RS, RS)-2-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (PE/EtOAc=5/1; Rf1 = 0.3). 1H NMR (400 MHz, DMSO-d6): δ 7.92-7.52 (m, 2H), 7.45-6.59 (m, 6H), 6.54-6.19 (m, 2H) , 4.37-4.45 (m, 1H), 3.78-3.61 (m, 2H), 3.29-3.25 (m, 1H), 2.34 (s, 3H), 3.175 -1.51 (m, 7H), 1.39-0.51 (m, 18H); MS: 552.1 (M+1)+.
Step B1: (SR, RS)Piperidine-2-carboxylic acid (cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-amide (hydrochloride). The title compound was synthesized from (SR, RS)-2-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-acid tert-butyl ester carboxylic using the protocol provided in Example 8, step B. 1H NMR (400 MHz, DMSO-d6): δ 9.12 (br, 1H), 8.11 (q, 1H), 7.75 (d, 1H) , 7.34 (m, 0.4H), 7.16 (m, 0.4H), 7.07-6.73 (m, 6H), 6.28 (d, 1H), 6.16 (br , 2H), 3.64 (d, 1H), 3.15 (d, 1H), 1.78 (br, 1H), 2.35 (d, 3H), 1.75-1.56 (m, 9H), 1.46-1.05 (m, 7H); MS: 452.1 (M+1)+.
Step B2: (RS, RS)Piperidine-2-carboxylic acid (cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-amide (hydrochloride). The title compound was synthesized from (RS, RS)-2-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-carboxylic acid tert-butyl ester through the protocol provided for in Example 8, step B also through the protocol provided for in Example 8, step B. 1H NMR (400 MHz, DMSO-d6): δ 8.48 (br, 1H), 8.06 (br, 1H) ), 7.83 (br, 1H), 7.18 (br, 1H), 7.09-7.07 (br, 2.66H), 6.86 (t, 1H), 6.61 (d, 1H), 6.16 (br, 2H), 3.63 (br, 1H), 3.54 (d, 1H), 3.08 (d, 1H), 2.73 (br, 1H), 2, 37 (s, 3H), 1.84-1.43 (m, 9H), 1.28-0.90 (m, 6H); MS: 452.1 (M+1)+.
Step C: Compound 328. To (SR, RS)-Piperidine-2-carboxylic acid (cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-amide (200 mg, 0.41 mmol) in DCM ( 10 ml) propionyl chloride (50 mg, 0.53 mmol) was added at 0°C. The reaction was stirred for 3 hours at the same temperature. The resulting mixture was washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by TLC (DCM/MeOH=15/1) to give pure product (60 mg, 29% yield); 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.77 (m, 2H), 7.26-6.72 (m, 7H), 6.26-6.23 (d, 1H, J=13.6 MHz), 4.86-4.79 (m, 1H), 3.68-3.53 (m, 3H), 2.41-2.27 (m, 5H), 1.75 -0.93 (m, 19H); MS: 508.2 (M+1)+.
The following compounds were also synthesized according to the Scheme provided for in that Example.
Compound 293 (from (SR, RS)-2-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-carboxylic acid tert-butyl ester)
1H NMR (400 MHz, DMSO-d6): δ 8.05-7.79 (m, 2H), 7.29-6.30 (m, 8H), 4.60-4.53 (m, 1H) , 3.72-3.46 (m, 6H), 2.29 (s, 3H), 1.75-0.99 (m, 16H); MS: 510.1 (M+1)+. Example 11: Preparation of Stereospecific Compounds of Formula A where 5 R 4 is an Optionally Substituted Piperidin-2-yl. Compounds of Formula A where R4 is optionally substituted piperidin-2-yl were prepared according to the following scheme exemplified for specific compounds of the invention.
Step A: Compound 332. Step A was carried out according to Scheme 110 using the protocol set forth in Example 1, Step A and Compound 332 and its isomer (R,R)-2-[(Cyclohexylcarbamoyl acid) tert-butyl ester -o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-carboxylic acid. These two isomers were separated by chromatography (PE/EtOAc=5/1; Rf1=0.35, Rf2=0.3). Compound 332 was the high polarity isomer. 1H NMR (300 MHz, DMSO-d6): δ7.92-7.78 (m, 2H), 7.28-6.08 (m, 8H), 6.21 (s, 1H), 15 4.66 -4.50 (m, 1H), 3.75-3.56 (m, 2H), 2.38-2.29 (m, 3H), 1.75-1.51 (m, 9H), 1 .39 (m, 9H), 1.31-0.94 (m, 9H); MS: 552.3 (M+1)+.
Step B: (S,R)-Piperidine-2-carboxylic acid (cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-amide (hydrochloride) (Compound 337). The title compound was synthesized via the general protocol set forth in Example 8, step B. 1H NMR (300 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.85-7.82 (br, 1H) ), 7.20-6.60 (m, 5H), 6.23-6.21 (br, 1H), 6.14 (s, 1H), 3.62-3.60 (m, 1H), 3.45-3.42 (m, 1H), 3.08-3.05 (m, 1H), 2.37 (s, 3H), 1.83-1.42 (m, 9H), 1. 31-0.95 (m, 7H); MS: 452.2 (M+1)+.
Step C: (S,R)-2-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]-piperidine-1-carboxylic acid methyl ester (R=methyl). The title compound was synthesized via the general protocol set forth in Example 8, step C. Step D: Compound 346
To Compound 337 (hydrochloride; 150 mg, 0.31 mmol) in DCM (5 ml) was added methanesulfonyl chloride (45 mg, 0.4 mmol) at 0°C. The reaction mixture was stirred for 3 hours. The resulting mixture was washed with brine, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by TLC (DCM/MeOH=20/1) to give pure product (80 mg, 48% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.96-7.78 (m, 2H), 7.20-6.20 (m, 7H), 6.11 (s, 1H), 4.30 -4.24 (m, 1H), 3.82-3.77 (m, 1H), 3.59-3.54 (m, 1H), 3.47-3.44 (m, 1H), 2 .87 (s, 3H), 2.29 (s, 3H), 1.84-1.51 (m, 8H), 1.42-0.95 (m, 9H); MS: 530.2 (M+1)+. Step E: Compound 347.
Ao Composto 337 (cloridrato; 150 mg, 0,31 mmol) em DCM (10 ml) foi adicionada cloreto de dimetilcarbamil (100 mg, 0,93 mmol) e Et3N (95 mg, 0,93 mmol). A reação foi agitada durante a noite em temperatura ambiente. A mistura resultante foi lavada com água, salmoura, seca com Na2SO4, filtrada e o solvente foi evaporado sob vácuo. O resíduo foi purificado por TLC (PE/EtOAc=1/1) para gerar o produto desejado (100 mg, 62% de rendimento). 1H NMR (400 MHz, DMSO-d6): δ 7,99-7,98 (d, 1H, J=8), 7,63 (s, 1H), 7,14-6,99 (m, 4H), 6,84-6,80 (m, 1H), 6,56 (s, 1H), 6,26 (s, 1H), 3,77 (s, 1H),3,66-3,63 (m, 1H), 3,53-3,48 (m, 1H), 2,89 (s, 1H), 2,72 (s, 6H), 2,29 (s, 3H), 1,841,38 (m, 9H), 1,36-0,87 (m, 7H); MS:521,1 (M-1)-. Etapa G: Composto 364 A uma mistura de Et3N (160 mg, 1,6 mmol) e Composto 337 (380 mg, 0,78 mmol) em THF (20 ml) foi adicionada uma solução de trifosgênio (230 mg, 0,78 mmol) em THF (20 ml). Após agitação durante 10 minutos, metilamina (1 M em THF, 1,3 ml, 1,3 mmol) foi adicionada em uma porção. A reação foi agitada durante 1,5 horas em temperatura ambiente. Água (50 ml) foi adicionada. A mistura resultante foi extraída com EtOAc (2x20 ml). A camada orgânica combinada foi lavada com salmoura, seca com Na2SO4, filtrada e o solvente foi evaporado sob vácuo. O resíduo foi purificado através de coluna de cromatografia flash eluída com DCM/MeOH (30/1) para gerar o produto desejado (40 mg, 10% de rendimento); 1H NMR (400 MHz, DMSO-d6): δ7,96-7,94 (d, 1H, J=7,6), 7,67(s, 1H), 7,17-6,83 (m, 4H), 6,59-6,57 (d, 1H, J=7,6), 6,34 (s, 1H), 6,19 (s, 1H), 4,51 (s, 1H),3,61-3,56 (m, 1H), 3,46-3,41 (m, 2H), 2,54 (s, 3H), 2,45(s, 3H), 1,76-1,44 (m, 9H), 1,30-0,84 (m, 8H); MS: 509,2 (M+1) +. Os análogos seguintes foram sintetizados através dos procedimentos gerais previstos nesse Exemplo Composto 343 1H NMR (400 MHz, DMSO-d6): δ 8,04-7,96 (m, 1H), 7,80-7,74 (m, 1H), 7,33-6,27 (m, 8H), 4,09-3,94 (m, 1H), 3,61 (m, 1H), 3,40-3,26 (m, 2H), 2,37 (d, 3H, J=6 MHz), 1,74-0,94 (m, 23H); MS: 538,3 (M+1) +. Composto 340 Compound 347 was synthesized from Compound 337 via the protocol provided in Example 10, step C. 1H NMR (300 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.85-7.76 ( m, 1H), 7.30-6.72 (m, 6H), 6.35-6.34 (br, 1H), 6.29(s, 1H), 5.13-5.04 (m, 1H), 4.47-4.27 (m, 1H), 3.69-3.59 (m, 2H), 2.45-2.40 (m, 3H), 2.67-1.61 ( m, 11H), 1.37-1.02 (m, 8H), 0.91(s, 3H); MS: 508.2 (M+1)+. Step F: Compound 365 To Compound 337 (hydrochloride; 150 mg, 0.31 mmol) in DCM (10 ml) was added dimethylcarbamyl chloride (100 mg, 0.93 mmol) and Et3N (95 mg, 0.93 mmol). The reaction was stirred overnight at room temperature. The resulting mixture was washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by TLC (PE/EtOAc=1/1) to give the desired product (100 mg, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.99-7.98 (d, 1H, J=8), 7.63 (s, 1H), 7.14-6.99 (m, 4H) , 6.84-6.80 (m, 1H), 6.56 (s, 1H), 6.26 (s, 1H), 3.77 (s, 1H), 3.66-3.63 (m , 1H), 3.53-3.48 (m, 1H), 2.89 (s, 1H), 2.72 (s, 6H), 2.29 (s, 3H), 1.841.38 (m, 9H), 1.36-0.87 (m, 7H); MS:521.1 (M-1)-. Step G: Compound 364 To a mixture of Et3N (160 mg, 1.6 mmol) and Compound 337 (380 mg, 0.78 mmol) in THF (20 ml) was added a solution of triphosgene (230 mg, 0.78 mmol) in THF ( 20 ml). After stirring for 10 minutes, methylamine (1M in THF, 1.3 ml, 1.3 mmol) was added in one portion. The reaction was stirred for 1.5 hours at room temperature. Water (50 ml) was added. The resulting mixture was extracted with EtOAc (2x20ml). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography eluting with DCM/MeOH (30/1) to give desired product (40 mg, 10% yield); 1H NMR (400 MHz, DMSO-d6): δ7.96-7.94 (d, 1H, J=7.6), 7.67(s, 1H), 7.17-6.83 (m, 4H ), 6.59-6.57 (d, 1H, J=7.6), 6.34 (s, 1H), 6.19 (s, 1H), 4.51 (s, 1H),3, 61-3.56 (m, 1H), 3.46-3.41 (m, 2H), 2.54 (s, 3H), 2.45(s, 3H), 1.76-1.44 ( m, 9H), 1.30-0.84 (m, 8H); MS: 509.2 (M+1)+. The following analogs were synthesized using the general procedures set forth in that Example Compound 343 1H NMR (400 MHz, DMSO-d6): δ 8.04-7.96 (m, 1H), 7.80-7.74 (m, 1H), 7.33-6.27 (m, 8H) , 4.09-3.94 (m, 1H), 3.61 (m, 1H), 3.40-3.26 (m, 2H), 2.37 (d, 3H, J=6 MHz), 1.74-0.94 (m, 23H); MS: 538.3 (M+1)+. Compound 340
1H NMR (400 MHz, DMSO-d6): δ 8,06-8,05 (d, J = 0,8, 1H), 7,85 (s, 1H), 7,16- 6,82 (m, 8H), 6,66-6,12 (m, 2H), 3,62-3,58 (m, 2H), 3,33-3,29 (m, 1H), 3,10-2,81 (m, 1H), 2,45 (s, 3H), 1,77-1,52 (m, 8H), 1,29-0,47 (m, 6H); MS: 437,8 (M+1) +. Composto 3381H NMR (400 MHz, DMSO-d6): δ8.03-7.94 (m, 2H), 7.15-6.69(m, 6H), 6.29-6.20(m, 2H), 3.93-3.92(t, 1H), 3.60-3.58(t, 1H), 3.37-3.25(m, 2H), 2.37-2.33(m, 3H) ), 2.08-0.95(m, 23H); MS: 538.3 (M+1)+. Compound 376 1H NMR (400 MHz, DMSO-d6): δ 8.06-8.05 (d, J = 0.8, 1H), 7.85 (s, 1H), 7.16-6.82 (m, 8H), 6.66-6.12 (m, 2H), 3.62-3.58 (m, 2H), 3.33-3.29 (m, 1H), 3.10-2.81 ( m, 1H), 2.45 (s, 3H), 1.77-1.52 (m, 8H), 1.29-0.47 (m, 6H); MS: 437.8 (M+1)+. Compound 338
1H NMR (300 MHz, DMSO-d6): δ 7,93-7,78 (m, 2H), 7,20-6,13 (m, 8H), 4,66-4,46 (m, 1H), 3,95-3,93 (m, 2H), 3,78-3,74 (m, 1H), 3,59-3,57 (m, 1H), 3,41-3,39 (m, 1H), 2,36 (s, 3H), 1,78-1,45 (m, 9H), 1,31-0,95 (m, 10H); MS: 524,3 (M+1) +. Composto 3591H NMR (300 MHz, DMSO-d6): δ 7.92-7.78 (m, 2H), 7.28-6.12 (m, 8H), 4.74-4.49 (m, 2H) , 3.79-3.41 (m, 3H), 2.38 (s, 3H), 1.75-1.52 (m, 7H), 1.39-0.96 (m, 15H); MS: 538.3 (M+1)+. Compound 345 1H NMR (300 MHz, DMSO-d6): δ 7.93-7.78 (m, 2H), 7.20-6.13 (m, 8H), 4.66-4.46 (m, 1H) , 3.95-3.93 (m, 2H), 3.78-3.74 (m, 1H), 3.59-3.57 (m, 1H), 3.41-3.39 (m, 1H), 1H), 2.36 (s, 3H), 1.78-1.45 (m, 9H), 1.31-0.95 (m, 10H); MS: 524.3 (M+1)+. Compound 359
1H NMR (300 MHz, DMSO-d6): δ8.03-8.01 (m, 1H), 7.81-7.78 (m, 1H), 7.20-6.66(m, 7H), 6.25(s, 1H), 4.07-4.00(m, 3H), 3.63-3.61(m, 1H), 3.38-3.37(m, 1H), 3. 32-3.30(m, 1H), 2.36(s, 3H), 1.83-1.52(m, 9H), 1.30-0.95(m, 9H); MS: 510.1(M+1)+. Compound 336
1H NMR (400 MHz, DMSO-d6): δ 8,06-7,80 (m, 2H), 7,30-6,50 (m, 7H), 6,34 (s, 1H), 4,79-4,60 (m, 2H), 3,81-3,45 (m, 3H), 2,28 (s, 3H), 1,78-1,33 (m, 7H), 1,27-1,10 (m, 15H); MS: 538,3 (M+1) +. Composto 348 1H NMR (400 MHz, DMSO-d6): δ 8,05-7,97 (m, 1H), 7,80-7,78 (m, 1H), 7,32-6,42 (m, 7H), 6,31 (s, 1H), 4,60-4,53 (m, 1H), 4,06-4,01 (m, 2H), 3,80-3,51 (m, 2H), 3,47-3,39 (m, 1H), 2,29(s, 3H), 1,75-1,52 (m, 8H), 1,44-0,96 (m, 11H); MS: 524,3 (M+1) +. Composto 355 1H NMR (300 MHz, DMSO-d6): δ 7,96-6,15 (m, 10H), 3,97-3,88 (m, 1H), 3,63- 3,57 (m, 4H), 3,32-3,25 (, 2H), 2,35-2,08 (m, 3H), 1,94-1,49 (m, 9H), 1,28-0,85 (m, 5H); MS:496,2 (M+1) +. Composto 3601H NMR (400 MHz, DMSO-d6): δ 8.05-7.81 (m, 2H), 7.28-6.28 (m, 8H), 4.60-4.50 (m, 1H) , 3.73-3.59 (m, 6H), 2.29 (s, 3H), 1.75-0.83 (m, 16H); MS: 510.2 (M+1)+. Compound 339 1H NMR (400 MHz, DMSO-d6): δ 8.06-7.80 (m, 2H), 7.30-6.50 (m, 7H), 6.34 (s, 1H), 4.79 -4.60 (m, 2H), 3.81-3.45 (m, 3H), 2.28 (s, 3H), 1.78-1.33 (m, 7H), 1.27-1 .10 (m, 15H); MS: 538.3 (M+1)+. Compound 348 1H NMR (400 MHz, DMSO-d6): δ 8.05-7.97 (m, 1H), 7.80-7.78 (m, 1H), 7.32-6.42 (m, 7H) , 6.31 (s, 1H), 4.60-4.53 (m, 1H), 4.06-4.01 (m, 2H), 3.80-3.51 (m, 2H), 3 .47-3.39 (m, 1H), 2.29(s, 3H), 1.75-1.52 (m, 8H), 1.44-0.96 (m, 11H); MS: 524.3 (M+1)+. Compound 355 1H NMR (300 MHz, DMSO-d6): δ 7.96-6.15 (m, 10H), 3.97-3.88 (m, 1H), 3.63-3.57 (m, 4H) , 3.32-3.25 (, 2H), 2.35-2.08 (m, 3H), 1.94-1.49 (m, 9H), 1.28-0.85 (m, 5H ); MS:496.2 (M+1)+. Compound 360
1H NMR (400 MHz, DMSO-d6): δ 8.03-7.95 (m, 1H), 7.81-7.74 (m, 1H), 7.33-6.52 5 (m, 7H) ), 6.25 (s, 1H), 4.09-4.00 (m, 3H), 3.63-3.41 (d, 1H, J = 2.8), 3.41-3.29 (m, 2H), 2.36 (s, 3H), 1.87-1.52 (m, 9H), 1.29-0.98 (m, 8H); MS: 510.2 (M+1)+. Compound 356
1H NMR (400 MHz, DMSO-d6): δ 8,03-7,95 (m, 1H), 7,77-7,75 (m, 1H), 7,26-6,70 15 (m, 7H), 6,27-6,24 (m, 1H), 4,88-4,78 (m, 1H), 3,68-3,53 (m, 3H), 2,43-2,20 (m, 5H), 1,75-0,99 (m, 16H), 0,85 (t, 3H, J=7,4 Hz); MS: 508,3 (M+1) +. Composto 371 1H NMR (400 MHz, DMSO-d6): δ 7,81-7,79 (d, J = 10,4 1H), 7,10-6,61 (m, 8H), 6,22 (s, 1H), 4,04-3,99 (d, J = 22,4, 1H), 3,64-3,33 (m, 3H), 2,33 (s, 3H), 1,99-1,53 (m, 12H), 1,32-0,63 (m, 5H); MS: 480,1 (M+1) +. Composto 370 1H NMR (400 MHz, DMSO-d6): δ 7,99-7,75 (m, 2H), 7,29-6,59 (m, 7H), 6,22 (s, 1H), 4,12-4,04 (m, 1H), 3,63-3,62 (m, 1H), 3,51-3,42 (m, 2H), 2,35 (s, 3H), 1,99 (s, 3H), 1,73-1,52 (m, 8H), 1,29-0,85 (m, 7H); MS: 480,1 (M+1) +. Composto 3661H NMR (400 MHz, DMSO-d6): δ 8.00-7. 94 (m, 1H), 7.79-7.74 (m, 1H), 7.35-10 6.48 (m, 7H), 4.05-4.02 (m, 1H), 3.61 -3.58 (m, 4H), 3.39-3.30 (m, 2H), 2.37 (s, 3H), 1.84 1.52 (m, 9H), 1.29-0, 96 (m, 5H); MS: 496.2 (M+1)+. Compound 350 F 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.95 (m, 1H), 7.77-7.75 (m, 1H), 7.26-6.70 (m, 7H) ), 6.27-6.24 (m, 1H), 4.88-4.78 (m, 1H), 3.68-3.53 (m, 3H), 2.43-2.20 (m) , 5H), 1.75-0.99 (m, 16H), 0.85 (t, 3H, J=7.4 Hz); MS: 508.3 (M+1)+. Compound 371 1H NMR (400 MHz, DMSO-d6): δ 7.81-7.79 (d, J = 10.4 1H), 7.10-6.61 (m, 8H), 6.22 (s, 1H ), 4.04-3.99 (d, J = 22.4, 1H), 3.64-3.33 (m, 3H), 2.33 (s, 3H), 1.99-1.53 (m, 12H), 1.32-0.63 (m, 5H); MS: 480.1 (M+1)+. Compound 370 1H NMR (400 MHz, DMSO-d6): δ 7.99-7.75 (m, 2H), 7.29-6.59 (m, 7H), 6.22 (s, 1H), 4.12 -4.04 (m, 1H), 3.63-3.62 (m, 1H), 3.51-3.42 (m, 2H), 2.35 (s, 3H), 1.99 (s , 3H), 1.73-1.52 (m, 8H), 1.29-0.85 (m, 7H); MS: 480.1 (M+1)+. Compound 366
1H NMR (400 MHz, CDCl3): δ7.71 (br, 1H), 7.10 (br, 2H), 6.87-6.68 (m, 4H), 6.36-6.32 (br, 2H), 4.68-4.66 (m, 0.5H), 4.64-4.59 (br, 0.5H), 3.85-3.84 (br, 1H), 3.60 ( s, 2H), 3.40-3.34 (br, 1H), 2.90-2.88 (br, 3H), 2.38 (s, 3H), 1.96-1.93 (br, 2H), 1.68-1.65 (br, 2H), 1.36-1.26 (br, 6H), 1.11-1.07 (br, 3H); MS: 484.1 (M+1)+. Compound 335
1H NMR (400 MHz, DMSO-d6): δ 8,20-7,81(m, 2H), 7,36-6,39 (m, 8H), 4,40-4,25 (m, 1H), 3,82-3,51 (m, 5H), 3,28-3,21 (m, 2H), 2,33-2,32 (m, 3H), 1,77-0,94 (m, 19H); 10 MS: 554,1 (M+1)+. Composto 3951H NMR (300 MHz, DMSO-d6): δ 7.92 (s, 1H), 7.76-7.70 (br, 1H), 7.30-6.83 (m, 5H), 6.64 -6.62 (d, 1H, J=5.7), 6.32 (br, 1H), 6.15(s, 1H), 4.68-4.62 (m, 1H), 3.73 -3.70 (m, 1H), 3.59-3.58 (m, 1H), 3.47 (s, 3H), 2.35 (s, 3H), 1.80-1.45 (m , 9H), 1.31-0.95 (m, 7H); 5 MS: 510.3 (M+1)+. Compound 396 1H NMR (400 MHz, DMSO-d6): δ 8.20-7.81(m, 2H), 7.36-6.39 (m, 8H), 4.40-4.25 (m, 1H) , 3.82-3.51 (m, 5H), 3.28-3.21 (m, 2H), 2.33-2.32 (m, 3H), 1.77-0.94 (m, 19H); 10 MS: 554.1 (M+1)+. Compound 395
1H NMR (400 MHz, DMSO-d6): δ 9.86 (m, 1H), 9.30 (s, 1H), 8.21-8.13 (m, 1H), 7.73-7.71 (m, 1H), 7.36-6.79 (m, 6H), 6.28-6.25 (m, 1H), 3.99 (m, 1H), 3.78-3.44 (m) , 5H), 15 3.14 (m, 2H), 2.36-2.34 (d, 3H, J = 8.8), 1.76-1.74 (m, 4H), 1.30- 1.11 (m, 6H); MS: 454.1 (M+1)+. Compound 349
1H NMR (400 MHz, DMSO-d6): δ 8.09-8.00 (m, 1H), 7.84-7.79 (m, 1H), 7.32-6.96 (m, 4H) , 6.89-6.65 (m, 3H), 6.31-6.27 (m, 1H), 4.43-4.36 (m, 1H), 3.77-3.61 (m, 1H), 2H), 3.41-3.38 (m, 1H), 2.90 (s, 3H), 2.31 (s, 1H), 2.30 (s, 2H), 1.75-1.46 (m, 8H), 1.40-0.86 (m, 8H); MS: 530.2 (M+1)+. Compound 363
1H NMR (400 MHz, DMSO-d6): δ 7.78-7.55 (m, 2H), 7.13-6.08 (m, 7H), 5.94 (s, 1H), 3.79 (s, 1H), 3.40-3.39 (m, 1H), 3.17-3.11 (m, 2H), 2.63 (s, 3H), 2.14 (s, 3H), 1.781.29 (m, 9H), 1.08-0.61 (m, 5H); MS: 516.2 (M+1)+. Compound 362
1H NMR (400 MHz, DMSO-d6): δ 8.04-7.95 (m, 1H), 7.78-7.75 (d, 1H, J=10), 7.14-6.23 ( m, 8H), 4.06-4.02 (m, 1H), 3.62 (s, 1H), 3.39-3.36 (m, 1H), 3.28-3.26 (m, 1H), 2.89-2.86 (m, 3H), 2.36-2.34 (d, 3H, J=6), 1.93-1.52 (m, 9H), 1.30- 0.85 (m, 6H); MS: 516.0 (M+1)+. Compound 367
1H NMR (400 MHz, MeOD-d4): δ 8.03 (m, 0.77H), 7.77 (m, 0.65H), 7.31 (br, 1H), 7.10-7.01 (m, 3H), 6.86 (m, 1H), 6.72 (m, 1H), 6.22 (s, 1H), 3.66-3.62 (m, 2H), 2.99- 2.93(q, 2H), 2.36 (s, 3H), 1.79-1.52 (m, 4H), 1.29-0.98 (9H); MS: 490.2 (M+1)+. 5 Compound 375
1H NMR (400 MHz, DMSO-d6): δ 8.23-8.22 (d, J = 6.4 1H), 7.57-7.45 (m, 2H), 7.10-7.02 (m, 4H), 6.81 (s, 1H), 6.58 (s, 1H), 6.29-6.21 (m, 3H), 3.92-3.91 (m, 1H), 3.713.69 (m, 1H), 3.36-3.22 (m, 2H), 2.63-2.62 (d, J = 4.0, 3H), 2.28 (s, 3H), 2.08-1.33 (m, 10 9H), 1.29-0.51 (m, 5H); MS: 494.8 (M+1)+. Compound 385
1H NMR (400 MHz, DMSO-d6): δ 8.06-7.89 (m, 2H), 7.31-6.34 (m, 8H), 4.31-4.23 (m, 1H) , 3.84-3.48 (m, 8H), 3.29-3.26 (m, 2H), 2.30 (s, 3H), 1.77-1.53 (m, 5H), 1 .30-0.94 15 (m, 5H); MS: 512.0 (M+1)+. Example 12. Preparation of Compound 248. Compound 248 was produced using the following protocol.
1H NMR (300 MHz, DMSO-d6): δ 7,99 (s, 1H), 7,73 (br, 1H), 7,09-6,56 (m, 7H), 6,22 (s, 1H), 4,03-3,09 (m, 1H), 3,63-3,61 (m, 1H), 3,24 (s, 4H), 2,99-2,84 (m, 2H), 2,33(s, 3H), 2,28 (s, 4H), 1,78-1,52 (m, 5H), 1,29-0,95 (m, 8H); MS: 539,3 (M+1) +. Composto 250Step A: 2-[(2-Chloro-acetyl)-(3-fluoro-phenyl)-amino]-N-cyclohexyl-2-o-tolyl-acetamide. The title compound was synthesized using Scheme 1 and the general procedure set out in Example 1, step A. Step B: N-Cyclohexyl-2-[(3-fluoro-phenyl)-(2-piperazin-1-yl-acetyl) -amino]-2-o-tolyl-acetamide. The title compound was synthesized using Scheme 2 and the general procedure set out in Example 2. 1H NMR (300 MHz, DMSO-d6): δ9.12 (br, 2H), 8.02 (s, 1H), 7.11 -6.71 (m, 6H), 6.23 (s, 1H), 3.64-3.62 (m, 1H), 3.08-3.03 (m, 2H), 2.89 (m , 4H), 2.59 (s, 4H), 2.35 (s, 3H), 1.78-1.54 (m, 5H), 1.31-0.98 (m, 6H); MS: 467.1 (M+1)+. Step C: Compound 248. To a mixture of Et3N (40 mg, 0.39 mmol) and S-tetrahydro-furan-3-ol (35 mg, 0.39 mmol) in THF (10 ml) was added a solution of triphosgene (115 mg, 0.39 mmol) in THF (10 ml). After stirring for 10 minutes, N-Cyclohexyl-2-[(3-fluoro-phenyl)-(2-piperazin-1-yl-acetyl)-amino]-2-o-tolyl-acetamide (300 mg, 0.64 mmol) was added in one portion. The reaction was stirred for 1.5 hours at room temperature. Water (15 ml) was added. The resulting mixture was extracted with EtOAc (2x20 ml) and the combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography eluting with DCM/MEOH (30/1) to give the desired product (280 33 mg, 15% yield); 1H NMR (300 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.74 (br, 1H), 7.21-6.56 (m, 7H), 6.22 (s, 1H) ), 5.09 (s, 1H), 3.77-3.63 (m, 5H), 3.24 (s, 4H), 3.00-2.84 (m, 2H), 2.33 ( s, 3H), 2.28 (s, 4H), 2.10-1.52 (m, 7H), 1.30-0.96 (m, 5H); MS: 581.3 (M+1)+. The following compounds were synthesized from N-Cyclohexyl-2-[(3-fluoro-phenyl)-(2-piperazin-1-yl-acetyl)-amino]-2-o-tolyl-acetamide through step C of this Example Compound 249 1H NMR (300 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.73 (br, 1H), 7.09-6.56 (m, 7H), 6.22 (s, 1H) ), 4.03-3.09 (m, 1H), 3.63-3.61 (m, 1H), 3.24 (s, 4H), 2.99-2.84 (m, 2H), 2.33(s, 3H), 2.28 (s, 4H), 1.78-1.52 (m, 5H), 1.29-0.95 (m, 8H); MS: 539.3 (M+1)+. Compound 250
1H NMR (300 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.74 (br, 1H), 7.09-6.70 (m, 6H), 6.55 (br, 1H) ), 6.22 (s, 1H), 4.76-4.70 (m, 1H), 3.63-3.61 (m, 1H), 3.56 (s, 3H), 3.23 ( s, 4H), 2.99-2.83 (m, 2H), 2.34 (s, 3H), 2.28 (s, 4H), 1.78-1.52 (m, 5H), 1 .30-0.96 (m, 11H); MS: 553.3 (M+1)+. Compound 185 and its HCl Salt
1H NMR (300 MHz, DMSO-d6): δ 8,04-7,91 (m, 1H), 7,29-6,98 (m, 5H), 6,73-5,66 (m, 3H), 5,12-4,17 (m, 2H), 3,64-3,06 (m, 10H), 2,43-2,34 (m, 4H), 2,17 (s, 0,82H), 2,13 (s, 2,33H), 1,84-1,51 (m, 5H), 1,32-1,04 (m, 5H); MS: 527,2 (M+1) +. Exemplo 13. Preparação do Composto 299. O Composto 299 foi preparado de acordo com o protocolo seguinte 1H NMR (300 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.74 (br, 1H), 7.09-6.70 (m, 6H), 6.22 (s, 1H) ), 3.63-3.61 (m, 1H), 3.56 (s, 3H), 3.25 (s, 4H), 2.99-2.83 (m, 2H), 2.34( s, 3H), 2.28 (s, 4H), 1.78-1.52 (m, 5H), 1.30-0.96 (m, 5H); MS: 525.3 (M+1)+. HCl salt: 1H NMR (400 MHz, DMSO-d6): δ 10.25(s, 1H), 8.15(s, 1H), 7.87(m, 1H), 7.36-6.62(m , 8H), 6.22(s, 1H), 4.05-3.83 (m, 4H), 3.42-3.38(m, 7H), 3.00(m, 2H), 2. 38(s, 3H), 1.72-1.50(m, 5H), 1.38-1.00(m, 5H); MS: 525.3 (M+1)+. 1H NMR (300 MHz, DMSO-d6): δ 8.04-7.91 (m, 1H), 7.29-6.98 (m, 5H), 6.73-5.66 (m, 3H) , 5.12-4.17 (m, 2H), 3.64-3.06 (m, 10H), 2.43-2.34 (m, 4H), 2.17 (s, 0.82H) , 2.13 (s, 2.33H), 1.84-1.51 (m, 5H), 1.32-1.04 (m, 5H); MS: 527.2 (M+1)+. Example 13. Preparation of Compound 299. Compound 299 was prepared according to the following protocol
Step A: 2-{(3-Bromo-phenyl)-[2-(2-methyl-imidazol-1-yl)-acetyl]-amino}-N-cyclohexyl-2-o-tolyl-acetamide. The title compound was synthesized via Scheme 1 and the protocol set forth in Example 1, step A.
1H NMR (400 MHz, DMSO-d6): δ 8.228.00 (m, 2H), 7.38-6.88 (m, 7H), 6.73-6.66 (m, 2H), 6.19 (s, 1H), 4.66-4.34 (m, 2H), 3.60(s, 1H), 2.36 (s, 3H), 2.10 (s, 3H), 1.73- 1.52 (m, 5H), 1.28-0.92 (m, 5H); MS: 523.1 (M+1)+. Step B: Compound 299. A mixture of 2-{(3-Bromo-phenyl)-[2-(2-methyl-imidazol-1-yl)-acetyl]-amino}-N-cyclohexyl-2-o -tolyl-acetamide (209 mg, 0.4 mmol), (3-methoxyphenyl) boronic acid (0.3 g, 2 mmol), K2CO3 (0.17g, 1.2 mmol) and Pd(dppf)Cl2 (66m mg, 0.08 mmol) in DME (5 ml) was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified via flash chromatography to give the desired product as a yellow powder (130 mg, 59%). 1H NMR (400 MHz, DMSO-d6): δ 8.26-7.97 (m, 2H), 7.46-6.72 (m, 13H), 6.24 (s, 1H), 4.66 -4.35 (m, 2H), 3.84-3.74 (m, 3H), 3.63-3.61 (m, 1H), 2.46-2.39 (m, 3H), 2 .10 (s, 3H), 1.73-1.50 (m, 5H), 1.25-0.89 (m, 5H); MS: 551.1 (M+1)+. The following compounds were synthesized according to the procedures set forth in this Example. Compound 286
1H NMR (400 MHz, DMSO-d6): δ 9,25-9,09 (m, 2H), 8,81(s, 1H), 8,35-8,03 (m, 2H), 7,64-7,23 (m, 2H), 7,18-6,71 (m, 7H), 6,26 (s, 1H), 4,76-4,45 (m, 2H), 3,63-3,61 (m, 1H), 2,45 (s, 2H), 2,41 (s, 1H), 2,17 (s, 3H), 1,78-1,55 (m, 5H), 1,28-0,98 (m, 5H); MS: 10 523,1 (M+1) +. Composto 2921H NMR (400 MHz, CD3OD): δ 8.16-6.69 (m, 15H), 6.29 (d, 1H, J=9.6 Hz), 4.73-4.45 (m, 2H) ), 3.64-3.62 (m, 1H), 2.40 (d, 3H, J=24.4 Hz), 2.16 (s, 3H), 1.84-1.50 (m, 5H), 1.28-1.02 (m, 5H); MS: 521.2 (M+1)+. 5 Compound 300 1H NMR (400 MHz, DMSO-d6): δ 9.25-9.09 (m, 2H), 8.81(s, 1H), 8.35-8.03 (m, 2H), 7.64 -7.23 (m, 2H), 7.18-6.71 (m, 7H), 6.26 (s, 1H), 4.76-4.45 (m, 2H), 3.63-3 1.61 (m, 1H), 2.45 (s, 2H), 2.41 (s, 1H), 2.17 (s, 3H), 1.78-1.55 (m, 5H), 1. 28-0.98 (m, 5H); MS: 10 523.1 (M+1)+. Compound 292
1H NMR (400 MHz, DMSO-d6): δ 8.28-7.34 (m, 8H), 7.24-6.69 (m, 7H), 6.24 (d, 1H, J=6, 8 Hz), 4.86-4.56 (m, 2H), 3.61-3.59 (m, 1H), 2.47-2.35 (m, 3H), 2.30 (s, 3H) ), 15 1.72-1.50 (m, 5H), 1.28-0.96 (m, 5H); MS: 605.1 (M+1)+. Compound 315 5
1H NMR (400 MHz, DMSO-d6): δ 8.14-8.01 (m, 2H), 7.49-7.03 (m, 6H), 6.89-6.73 (m, 4H) , 6.38-6.14 (m, 2H), 4.69-4.40 (m, 2H), 3.83-3.53 (m, 4H), 2.42-2.40 (m, 2H), 3H), 2.17 (s, 3H), 1.73-1.51 (m, 5H), 1.28-0.95 (m, 5H); MS: 525.1 (M+1)+. Example 14. Preparation of Compound 344.
Step A: N-Cyclohexyl-2-{(3-fluoro-phenyl)-[2-(2-iodo-imidazol-1-yl)-acetyl]-amino}-2-o-tolyl-acetamide. The title compound was synthesized using Scheme 2, and the protocol provided in Example 2, step A. 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.93 (m, 2H), 7.28- 7.06 (m, 5H), 6.90-6.48 (m, 4H), 6.22 (s, 1H), 4.48-4.45 (m, 2H), 3.61-3, 60 (m, 1H), 2.33 (s, 3H), 1.76-1.51 (m, 5H), 1.28-0.93 (m, 5H); MS: 575.1 (M+1)+. Step B: Compound 344. A mixture of N-Cyclohexyl-2-{(3-fluoro-phenyl)-[2-(2-iodo-imidazol-1-yl)-acetyl]-amino}-2-o-tolyl -acetamide (144 mg, 0.25 mmol), KF (dry, 25 mg, 0.43 mol), CuI (75 mg, 0.39 mmol) and CF3SiC(CH3)3 (60 mg, 0.43 mmol) in dry NMP (2.5 ml) was stirred at 50°C for 27 hours under N 2 atmosphere. The resulting mixture was cooled to room temperature and diluted with DCM (15 ml), washed with water, brine, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified with prep-HPLC to give the desired product as a solid (40 mg, 31% yield), 1H NMR (400 MHz, DMSO-d6): δ 8.05-7.89 (m, 2H) , 7.42-6.38 (m, 9H), 6.19 (s,1H), 4.76-4.74 (m,2H), 3.60-3.57 (m, 1H), 2 .38 (s,3H), 1.74-1.51 (m, 5H), 1.28-0.93 (m, 5H); MS: 517.2 (M+1)+. Compound 373
Compound 373 was synthesized via the procedure described in that example. 1H NMR (400 MHz, DMSO-d6): δ 8.17-8.13 (m, 1H), 7.89-7.86 (m, 1H), 7.41-7.07 (m, 6H) , 6.87 (t, 1H, J=7.6Hz), 6.70-6.69 (m, 1H), 6.51-6.50 (m, 1H), 6.20 (s,1H) ), 4.82-4.76 (m,2H), 3.84 (s, 1H), 2.38 (s,3H), 2.01-1.76 (m, 6H), 1.51- 1.43 (m, 1H), 1.31-1.23 (m, 1H); MS: 552.6 (M+1)+. Example 15. Preparation of Compound 326.
Etapa A: Composto 368. O composto do título foi sintetizado usando Esquema 1 e o protocolo previsto no Exemplo 1, etapa A. 1H NMR (400 MHz, MeOD-d4): δ 7,73 (br, 1H), 7,15 (d, J = 7,6, 1H), 7,09-7,09 (m, 1), 6,99-6,94 (m, 1H). 6,80-6,78 (m, 1H), 6,57 (br, 0,7H), 6,38 (s, 1H), 3,78-3,68 (m, 2H), 3,50-3,39 (d, 1H), 2,33 (s, 3H), 1,9-1,93 (m, 1H), 1,80-1,71 (m, 4H), 1,46-1,04 (m, 12H); MS: 498,1 (M+1) +. Etapa B: 2-[(2-Amino-acetil)-(3-fluor-fenil)-amino]-N-ciclohexil-2-o-tolil- acetamida (cloridrato). O composto do título foi sintetizado usando o protocolo previsto no Exemplo 8, etapa B. 1H NMR (400 MHz, MeOD-d4): δ 8,1 (br, 1H), 7,66 (br, 1H), 7,03-6,70 (m, 6H), 6,29 (s, 1H), 4,16 (m, 1H), 3,43 (d, 1H), 3,26 (d, 1H), 2,34 (s, 3H), 1,69-1,64 (m, 1H), 1,52-1,50 (m, 3H), 1,29-1,00 (m, 3H), 0,80-0,76 (m, 3H); MS: 398,1 (M+1)+.Step A: N-Cyclohexyl-2-{(3-fluoro-phenyl)-[2-(2-nitro-imidazol-1-yl)-acetyl]-amino}-2-o-tolyl-acetamide. The title compound was synthesized using Scheme 2, and the protocol provided in Example 2, step A. Step B: Compound 326. A suspension of N-Cyclohexyl-2-{(3-fluoro-phenyl)-[2-(2 - nitro-imidazol-1-yl)-acetyl]-amino}-2-o-tolyl-acetamide (110 mg, 0.22 mmol) and 10% Pd/C (30 mg) in MeOH (8 ml) was stirred under 1 atm of hydrogen gas at room temperature for 16 h. The solids were removed by filtration and the solvent was concentrated, purified by prep-HPLC to give 30 mg of product (30 mg, 30% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.05-7.75 (m, 2H), 7.11-6.98 (m, 4H), 6.88-6.67 (m, 3H) , 6.43 (d, 1H), 6.31 (d, 1H), 6.19 (s, 1H), 5.07 (s, 2H), 4.39-4.35 d, 1H), 4 .13-4.08 (d, 1H), 3.63-3.58 (m, 1H), 2.38 (s, 3H), 1.76-1.49 (m, 5H), 1.31 -0.85(m, 5H); MS: 464.2 (M+1)+. Example 16. Preparation of Compound 319. Step A: Compound 368. The title compound was synthesized using Scheme 1 and the protocol provided in Example 1, step A. 1H NMR (400 MHz, MeOD-d4): δ 7.73 (br, 1H), 7.15 (d, J = 7.6, 1H), 7.09-7.09 (m, 1), 6.99-6.94 (m, 1H). 6.80-6.78 (m, 1H), 6.57 (br, 0.7H), 6.38 (s, 1H), 3.78-3.68 (m, 2H), 3.50- 3.39 (d, 1H), 2.33 (s, 3H), 1.9-1.93 (m, 1H), 1.80-1.71 (m, 4H), 1.46-1, 04 (m, 12H); MS: 498.1 (M+1)+. Step B: 2-[(2-Amino-acetyl)-(3-fluoro-phenyl)-amino]-N-cyclohexyl-2-o-tolyl-acetamide (hydrochloride). The title compound was synthesized using the protocol provided in Example 8, step B. 1H NMR (400 MHz, MeOD-d4): δ 8.1 (br, 1H), 7.66 (br, 1H), 7.03 -6.70 (m, 6H), 6.29 (s, 1H), 4.16 (m, 1H), 3.43 (d, 1H), 3.26 (d, 1H), 2.34 ( s, 3H), 1.69-1.64 (m, 1H), 1.52-1.50 (m, 3H), 1.29-1.00 (m, 3H), 0.80-0, 76 (m, 3H); MS: 398.1 (M+1)+.
Step C: N-Cyclohexyl-2-[{2-[3-(2,2-dimethoxy-ethyl)-ureido]-acetyl}-(3-fluoro-phenyl)-amino]-2-o-tolyl-acetamide . To a mixture of 2-[(2-Amino-acetyl)-(3-fluoro-phenyl)-amino]-N-cyclohexyl-2-o-tolyl-acet-amide (433 mg, 1 mmol) and Et3N (0 .2 ml, 1.5 mmol) in DCM was added 2-Isocyanato-1,1-dimethoxy-ethane (231 mg, 1.3 mmol). The reaction mixture was stirred for 8 hours. The resulting mixture was washed with HCl (1N), water, brine, dried over Na2SO4 and filtered. The solvent was evaporated under vacuum and the residue was washed with Et2O to give N-Cyclohexyl-2-[{2-[3-(2,2-dimethoxy-ethyl)-ureido]-acetyl}-(3-fluoro- crude phenyl)-amino]-2-o-tolyl-acetamide, which was used directly without further purification (350 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.12-7.78 (m, 2H), 7.35-6.20 (m, 10H), 4.41 (m, 1H), 3.66 (m, 2H), 3.30-3.24 (m, 7H), 3.05 (m, 2H), 2.35 (s, 3H), 1.78-1.50 (m, 5H), 1.25-0.95 (m, 5H); MS: 529.1 (M+1)+.
Step D: Compound 319. A mixture of N-Cyclohexyl-2-[{2-[3-(2,2-dimethoxy-ethyl)-ureido]-acetyl}-(3-fluoro-phenyl)-amino]-2 -o-tolyl-acetamide (100 mg, 0.19 mmol) in AcOH (1 ml) and HCOOH (0.7 ml) was heated to 65°C for 1 hour. The resulting mixture was concentrated in vacuo and the residue was suspended in saturated NaHCO3 (10 ml). The precipitate was collected by filtration and washed with Et2O to give the desired product (25 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 8.04-7.81 (m, 2H), 7.05-6.57 (m, 7H), 6.28 -6.19 (m, 3H), 4.02 (m, 2H), 3.58 (m, 1H), 2.33 (s, 3H), 1.70-1.50 (m, 5H), 1.34-1.02 (m, 5H); MS: 465.1 (M+1)+. Example 17. Preparation of Compound 163.
To a solution of 2-[(2-Chloro-acetyl)-(3-fluoro-phenyl)-amino]-N-cyclohexyl-2-o-tolyl-acetamide (208 mg, 0.50 mmol) in 1.2 -dichloroethane (10 ml) was added thiourea (54 mg, 0.71 mmol). The reaction mixture was stirred at 80°C for 8h and then cooled to room temperature. The precipitate was collected by filtration and purified by prep. 10 HPLC to generate the by-product as a white solid (60 mg, yield =26%). 1H NMR (300 MHz, DMSO-d6): δ 9.02 (br, 4H), 8.06-6.57 (m, 9H), 6.17 (s,1H), 4.16-3.85 (m,2H), 3.63-3.60 (m, 1H), 2.43 (s,3H), 1.78-1.51 (m, 5H), 1.32-0.93 (m , 5H); MS: 457.2 (M+1)+. Example 18. Preparation of Compounds 263 and 212.
1H NMR (400 MHz, DMSO-d6): δ 8,15 (m, 1H), 7,64-6,31 (m, 13H), 3,63 (m, 1H), 3,45-3,36 (m, 2H), 3,03 (s, 3H), 2,89 (s, 3H), 1,74-1,51 (m, 5H), 1,25-0,95 (m, 5H); MS: 550,1 (M+1) +. 5 Exemplo 19. Preparação dos Compostos 215 e 216 Éster fenil do ácido acético 4-[(ciclohexilcarbamoil-o-tolil-metil)-(3-fluor-fenil)- carbamoil]- (Composto 215) foi sintetizado através do Esquema 1, seguindo o procedimento geral previsto no Exemplo 1, etapa A e uma quantidade do subproduto-Ac 10 (Composto 216) foi isolado da reação. Step A: Compound 217. N-Cyclohexyl-2-{(3-fluoro-phenyl)-[2-(4-hydroxy-phenyl)-acetyl]-amino}-2-o-tolyl-acetamide (Compound 217) was synthesized according to Scheme 1, by the general procedure provided in Example 1, step A. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.96-7.71 (m , 2H), 7.09-6.23 (m, 12H), 3.62-3.57 (m, 20 1H), 3.33-3.21 (m, 2H), 2.32 (s, 3H), 1.76-1.52 (m, 5H), 1.29-0.93 (m, 5H); MS: 475.2 (M+1)+. Step B: Compound 263. A mixture of N-Cyclohexyl-2-{(3-fluoro-phenyl)-[2-(4-hydroxy-phenyl)-acetyl]-amino}-2-o-tolyl-acetamide (100 mg, 0.21 mmol), Dimethylcarbamyl chloride (46 mg, 0.42 mmol), Et3N (64 mg, 0.42 mmol) and DMAP (26 mg, 0.21 mol) in DCM (15 ml) was heated to 50°C for 10 hours. After cooling to room temperature, the resulting mixture was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The residue was purified by TLC (DCM/MeOH=20/1) to give pure product (45 mg, 40% yield). 1 H NMR (400 MHz, DMSO-d6): δ 7.99-7.65 (m, 2H), 7.26-6.24 (m, 12H), 3.81-3.32 (m, 3H) , 3.03 (s, 3H), 2.90 (s, 3H), 2.34 (s, 3H), 1.76-1.52 (m, 5H), 1.29-0.96 (m , 5H); MS: 546.1 (M+1)+. Step C: Compound 212. A mixture of N-Cyclohexyl-2-{(3-fluoro-phenyl)-[2-(4-hydroxy-phenyl)-acetyl]-amino}-2-o-tolyl-acetamide (200 mg, 0.42 mmol), Et3N (260 mg, 0.84 mmol) and acetyl chloride (70 mg, 0.84 mmol) in DCM (15 ml) was stirred for 10 hours at room temperature. The resulting mixture was washed with brine, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by TLC (PE/EtOAc=2/1) to give pure product (180 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.98-7.75 (m, 2H), 7.10-6.24 (m, 12H), 3.63-3.61 (m, 1H) , 3.47-3.37 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 1.77-1.52 (m, 5H), 1.28-0 .83 (m, 5H); MS: 517.3 (M+1)+. The following compounds were synthesized using the general procedure set out in that example. Compound 264 1H NMR (400 MHz, DMSO-d6): δ 8.15 (m, 1H), 7.64-6.31 (m, 13H), 3.63 (m, 1H), 3.45-3.36 (m, 2H), 3.03 (s, 3H), 2.89 (s, 3H), 1.74-1.51 (m, 5H), 1.25-0.95 (m, 5H); MS: 550.1 (M+1)+. 5 Example 19. Preparation of Compounds 215 and 216 4-[(Cyclohexylcarbamoyl-o-tolyl-methyl)-(3-fluoro-phenyl)-carbamoyl]- acetic acid phenyl ester (Compound 215) was synthesized via Scheme 1, following the general procedure set forth in Example 1, step A and an amount of the by-product-Ac 10 (Compound 216) was isolated from the reaction.
1H NMR (300 MHz, DMSO-d6): δ 8.12 (d, 1H, J=8.1 MHz), 7.29-6.75 (m, 12H), 6.47 (s, 1H), 3.66 (m, 1H), 2.38 (s, 3H), 1.98 (s, 3H), 1.79-1.51 (m, 5H), 1.29-1.03 (m, 15 5H); MS: 503.2 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8.13 (d, 1H, J=7.6 MHz), 7.11-6.49 (m, 12H),
3.68-3.66 (m, 1H), 2.35 (s, 3H), 1.78-1.54 (m, 5H), 1.31-1.01 (m, 5H); MS: 461.2 (M+1)+. Example 20. Synthesis of 3-Isocyanobicido[3.1.0]hexane. The title intermediate was synthesized following the scheme below and used for synthesis of Compound 333 and Compound 377 following Scheme 1
Step A: For Cyclopent-3-enyl-carbamic acid benzyl ester. To a solution of Cyclopent-3-ene carboxylic acid (5 g, 44.6 mmol) in toluene (50 ml) was added a solution of DPPA (13.5 g, 49 mmol) and Et3N (5.4 g, 53 .5 mmol) in toluene (50 ml) dropwise at room temperature. The mixture was heated to reflux for 2 hours and then benzyl alcohol (7 ml, 66.9 mmol) was added. The reaction mixture was refluxed overnight then cooled to room temperature, washed with NaHCO3 solution, brine, dried with Na2SO4, and filtered. The organic solvent was evaporated under vacuum and the residue was purified by flash column chromatography eluted with PE/EtOAc (50/1 to 5/1) to give pure cyclopent-3-enyl-carbamic acid benzyl ester (5 g , 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.46 (d, J = 8.0, 1H), 7.367.30 (m, 5H), 5.66 (s, 2H), 5.00 (s , 2H), 4.11 (m, 1H), 2.59-2.49 (m, 2H), 2.19-2.14 (m, 2H) Step B: Bicyclo[3.1 acid benzyl ester ,0]hex-3-yl-carbamic. To a solution of Cyclopent-3-enyl-carbamic acid benzyl ester in DCM (30 ml) was added ZnEt2 (1M, 30.4 ml, 30.4 mmol) at 0°C under N2 atmosphere. CH2I2 (2.5 ml, 30.4 mmol) was added dropwise under the same condition. The reaction mixture was warmed to room temperature and stirred for 4 hours. The resulting mixture was washed with brine, dried over Na2SO4, filtered and the solvent was concentrated. The residue was purified by flash column chromatography eluted with PE/EtOAc (50/1 to 5/1) to give pure Bicyclo[3.1.0]hex-3-yl-carbamic acid benzyl ester (1 .5 g, 46% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.37-7.31 (m, 5H), 7.50 (d, J = 4.6, 1H), 4.99 (s, 2H), 3 .98-3.96(m, 1H), 1.59-1.55 (m, 2H), 1.23-1.14 (m, 2H), 0.50 (m, 1H), 0.27 (m, 1H). Step C: For Bicyclo[3.1.0]hex-3-ylamine. A solution of Bicyclo[3.1.0]hex-3-yl-carbamic acid benzyl ester (1.5 g, 6.5 mmol) in MeOH (20 ml) was hydrogenated with Pd/C (10%, 0 .3 g) as a catalyst under atmospheric pressure for 2 hours. The resulting mixture was filtered and the filtrate was evaporated in vacuo to give Bicyclo[3.1.0]hex-3-ylamine as a white solid which was used directly without further purification (0.45 g, 71% yield) . 1H NMR (400 MHz, CDCl3): δ 4.353.64 (m, 3.8H), 2.23-2.18 (m, 2H), 1.53-1.50 (m, 2H), 1.23 -1.13(m, 4H), 0.56-0.51 (m, 2H), 0.00 (br, 1H).
Step D: N-Bicyclo[3.1.0]hex-3-yl-formamide. A mixture of Bicyclo[3.1.0]hex-3-ylamine (0.45 g, 4.6 mmol) in ethyl formate (2 ml) was refluxed for 8 hours. The resulting mixture was evaporated in vacuo and the residue was purified by chromatography eluting with PE/EtOAc (20/1 to 2/1) to give N-Bicyclo[3.1.0]hex-3-yl-formamide . (460 mg, 80% yield) 1H NMR (400 MHz, DMSO-d6): δ 7.67-7.59 (m, 2H), 3.93 (m, 1H), 1.94-1.88 (m, 2H), 1.32-1.28(m, 2H), 1.03-1.00 (m, 2H), 0.30-0.26 (m, 1H), 0.00 (m , 1H).
Step E: 3-Isocyano-bicyclo[3.1.0]hexane. A mixture of N-(Tetrahydro-pyran-4-yl)-formamide (0.46 g, 3.7 mmol), PPh3 (1.06 g, 4 mmol), CCl4 (0.57 g, 3.7 mmol) ), Et3N (0.38 g, 3.7 mmol) in DCM (10 ml) was heated to 45°C for 8 hours. The resulting mixture was evaporated under vacuum and the residue was suspended in Et2O (25 ml). The solid was filtered and the solvent was concentrated and purified by flash chromatography column eluted with PE/EtOAc (100/1 to 20/1) to give pure 3-Isocyano-bicyclo[3.1.0]hexane ( 0.1 g, 25% yield). 1H NMR (400 MHz, CDCl3): δ 4.01 (m, 1H), 2.22-2.17 (m, 2H), 2.08-2.04 (m, 2H), 0.66-0 .60(m, 2H).
The following intermediates were synthesized through Steps D and E of the procedure provided in this example and purified by flash chromatography eluting with Et2O or PE to generate the desired product as a solution of Et2O or PE, which was concentrated under 1 atm pressure and used directly. 1,1-Difluoro-4-isocyano-cyclohexane (PE solution) used for synthesis of Compound 342
D11-Isocyano-cyclohexane (Et2O solution) used for the synthesis of Compound 361
Example 21. Synthesis of 4-Isocyano-tetrahydro-pyran. The title compound was synthesized following the scheme below and used for synthesis of Compound 179 following Scheme 1.
Step A: N-(Tetrahydro-pyran-4-yl)-formamide. A mixture of Tetrahydro-pyran-4-ylamine (25 g, 247.5 mmol) in ethyl formate (25 g, 338 mmol) was refluxed for 8 hours. The resulting mixture was evaporated in vacuo to give crude N-(Tetrahydro-pyran-4-yl)-formamide, which was used directly without further purification (29 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.10 (br, 1H), 5.77 (br, 1H), 4.19-4.02 (m, 1H), 3.98-3.90 (m , 2H), 3.50-3.84 (m, 2H), 1.92-1.80 (m, 2H), 1.62-1.41 (m, 2H). Step B: For 4-Isocyano-tetrahydro-pyran. A mixture of N-(Tetrahydro-pyran-4-yl)-formamide (29 g, 224 mmol), PPh3 (64.8 g, 247 mmol), CCl4 (34.5 g, 224 mmol), Et3N (22, 6 g, 224 mmol) in DCM (300 ml) was heated to 45°C for 8 hours. The resulting mixture was evaporated under vacuum and the residue was suspended in Et2O (250 ml). The solid was filtered and the solvent was purified by flash column chromatography eluting with PE/EtOAc to give 4-Isocyano-tetrahydro-pyran (15 g, 60% yield). 1H NMR (400 MHz, CDCl3): δ 3.90-3.82 (m, 3H), 3.57-3.50 (m, 2H), 1.95-1.91 (m, 2H), 1 .84-1.77 (m, 2H).
Example 22. Synthesis of U-Difluoro-3-isocyano-tidobutane. The title compound was synthesized following the scheme below and used for synthesis of Compound 379 according to Scheme 1.
Step A: (3-Oxo-cyclobutyl)-carbamic acid benzyl ester. A solution of 3-Oxo-cyclobutane carboxylic acid (1.01 g, 8.8 mmol) and Et3N (1.5ml, 10.5mmol) in THF/Toluene (1:1, 30ml) was treated with DPPA (1, 9 ml, 8.8 mmol). The mixture was stirred for 3 hours at 60°C and then BnOH (1 ml, 9.7mmol) added. The reaction mixture was stirred for another 3 hours at the same temperature. The resulting mixture was concentrated in vacuo to remove most of the THF and then diluted with EtOAc (50 20 ml). This mixture thus obtained was washed with saturated NaHCO3 solution, brine, dried with Na2SO4 and filtered. The solvent was evaporated and the residue was purified by chromatography eluting with PE/EtOAc (4:1) to give the desired product as a white solid (yield: 0.48g, 25% yield). 1H NMR (400 MHz, CDCl3): δ 7.35 (m, 5H), 5.12 (m, 3H), 4.33 (m, 1H), 3.41 (m, 2H), 3.07 ( m, 2H).
Step B: For (3,3-Difluoro-cyclobutyl)-carbamic acid benzyl ester. To a solution of (3-Oxo-cyclobutyl)-carbamic acid benzyl ester (0.3 g, 1.37 mmol) in CHCl3 (3 ml) was added DAST (0.88 g, 5.48 mmol) dropwise. drop. The reaction mixture was stirred overnight at room temperature and then quenched with saturated NaHCO3 solution (25 ml). The resulting mixture was extracted with DCM (3x15 ml) and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by TLC (PE/EA=5:2) to give the desired product (0.23g, 69% yield). 1H NMR (400 MHz, CDCl3): δ 7.35 (m, 5H), 5.10 (s, 2H), 4.97 (br, 1H), 4.11 (m, 1H), 2.97 ( m, 2H), 2.47 (m, 2H).
Step C: 3,3-Difluoro-cyclobutylamine (hydrochloride). A mixture of (3,3-Difluoro-cyclobutyl)-carbamic acid benzyl ester (1.47 g, 6.1 mmol) and 10% Pd/C (1 g) in MeOH (20 ml) was stirred overnight. under H2 atmosphere (1 atm) at room temperature. The resulting mixture was filtered through a pad of celite and washed with MeOH. The combined filtration with 2ml of conc. HCl and evaporated under vacuum to give desired product (0.81g, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (m, 3H), 3.64 (m, 1H), 2.89 (m, 4H).
Step D: N-(3,3-Difluoro-cyclobutyl)-formamide. The title compound was synthesized via the general procedure set forth in Example 20, step D. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (br, 1H), 8.01 (s, 1H), 4, 11 (m, 1H), 2.96-2.87(m, 2H), 2.63-2.51 (m, 2H).
Step E: 1,1-Difluoro-3-isocyano-cyclobutane. The title compound was synthesized via the general procedure set out in Example 20, step E and purified by chromatography eluting with Et2O to give the desired product as an Et2O solution, which was concentrated under 1 atm pressure and used directly. 1H NMR (400 MHz, DMSO-6): δ 4.28 (m, 1H), 3.19-3.12 (m, 2H), 2.96-2.91 (m, 2H).
Example 23. Synthesis of (4-Fluoro-Benzyloxy)-Acetic Acid. The title compound was synthesized following the scheme below and used for the synthesis of Compound 214 according to Scheme 1
Step A: (4-Fluoro-Benzyloxy)-acetic acid tert-butyl ester. To a mixture of (4-Fluor-phenyl)-methanol (0.6 g, 5.12 mmol) and Bu4N+Cl- (174 mg, 0.512 mmol) in toluene (100 ml) was added NaOH solution (50% 100 ml) at 0°C. Bromo-acetic acid tert-butyl ester (2.0 g, 10.25 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. The organic phase was separated, washed with water, brine, dried over Na2OS4, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography eluting with PE/EtOAc (3/1) to give (4-Fluoro-benzyloxy)-acetic acid tert-butyl ester as a colorless oil (1.18 g, 96% yield) 1H NMR (400 MHz, CDCl3): δ 7.36-7.31 (m, 2H), 7.01 (t, 2H), 4.56 (s, 2H), 3.96 (s, 2H), 1.47 (s, 9H).
Step B: (4-Fluoro-Benzyloxy)-Acetic Acid. A solution of (4-Fluoro-benzyloxy)-acetic acid tert-butyl ester (1.1 g, 4.58 mmol) in TFA/DCM (1/1, 30 ml) was stirred for 3 hours at room temperature. The resulting mixture was evaporated in vacuo and the residue washed with an EtOAc/hexane mixture to give (4-Fluoro-benzyloxy)-acetic acid as a solid, which was used directly without further purification (0.8 g, 94). % yield).
Ácido (Tetrahidro-piran-4-iloxi)-acético foi usado para síntese do Composto 259 Ácido (S)-(Tetrahidro-furan-3-iloxi)-acético foi usado para síntese do Composto Ácido (2-Fluor-benziloxi)-acético foi usado para síntese do Composto 222 Ácido (Piridin-4-ilmetoxi)-acético foi usado para síntese do Composto 229 Ácido Ciclopentiloxi-acético foi usado para síntese do Composto 230 Ácido (Piridin-3-ilmetoxi)-acético foi usado para síntese do Composto 233 Ácido (3-Fluor-benziloxi)-acético foi usado para síntese do Composto 234 Ácido (Piridin-2-ilmetoxi)-acético foi usado para síntese do Composto 281 Ácido (Pirazin-2-ilmetoxi)-acético foi usado para síntese do Composto 282 Ácido (4-Trifluormetil-piridin-3-ilmetoxi)-acético foi usado para síntese do Composto 303The following intermediate carboxylic acids were synthesized using the general procedures set out in this example. (2-Fluoro-cyclohexyloxy)-acetic acid used for synthesis of Compound 235 (Tetrahydro-pyran-4-yloxy)-acetic acid was used for synthesis of Compound 259 (S)-(Tetrahydro-furan-3-yloxy)-acetic acid was used for Compound synthesis (2-Fluoro-benzyloxy)-acetic acid was used for synthesis of Compound 222 (Pyridin-4-ylmethoxy)-acetic acid was used for synthesis of Compound 229 Cyclopentyloxy-acetic acid was used for the synthesis of Compound 230 (Pyridin-3-ylmethoxy)-acetic acid was used for synthesis of Compound 233 (3-Fluoro-benzyloxy)-acetic acid was used for synthesis of Compound 234 (Pyridin-2-ylmethoxy)-acetic acid was used for synthesis of Compound 281 (Pyrazin-2-ylmethoxy)-acetic acid was used for synthesis of Compound 282 (4-Trifluoromethyl-pyridin-3-ylmethoxy)-acetic acid was used for synthesis of Compound 303
Ácido (Piridazin-3-iloxi)-acético foi usado para síntese do Composto 273 Exemplo 24. Síntese de Ácido 3-Fluor-piridin-2-ilamino)-acético. O composto do título foi sintetizado seguindo o esquema abaixo e usado para a síntese do Composto 361, Composto 342, Composto 333, Composto 301 e Composto 379. (6-Trifluoromethyl-pyridin-3-yloxy)-acetic acid was used for Compound synthesis (Pyridazin-3-yloxy)-acetic acid was used for synthesis of Compound 273 Example 24. Synthesis of 3-Fluoro-pyridin-2-ylamino)-acetic acid. The title compound was synthesized following the scheme below and used for the synthesis of Compound 361, Compound 342, Compound 333, Compound 301 and Compound 379.
Step A: (3-Fluoro-pyridin-2-ylamino)-acetic acid methyl ester. To a mixture of 40% aqueous glyoxal solution (1.5 ml) in MeOH (10 ml) was added a slurry of 3-Fluoro-pyridin-2-ylamine (1.17 g, 10.5 mmol) in HClO4 ( 3 ml). The reaction mixture was heated to 70°C for 48 hours. The resulting mixture was adjusted to pH>8 with saturated NaHCO3 solution after being cooled to room temperature. The basic solution was extracted with ethyl acetate (3x10 ml). The combined organic layer was washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column to give the (3-Fluor-pyridin-2-ylamino)-acetic ester methyl acid as a white solid (600 mg, 31% yield). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, 2H, J = 4.8), 7.17 (m, 1H), 6.59 (m, 1H), 5.12 (br, 1H ), 4.26 (d, 2H, J = 6.4), 3.78 (s, 3H).
Step B: (5-Fluoro-pyridin-2-ylamino)-acetic acid. A mixture of (3-Fluor-pyridin-2-ylamino)-acetic acid methyl ester (280 mg, 1.5 mmol) in 5 N HCl (5 ml) was heated to reflux for 3 hours. The resulting mixture was evaporated in vacuo to give (5-Fluor-pyridin-2-ylamino)-acetic acid, which was used directly without further purification (300 mg, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.82 (m, 2H), 7.68 (m, 1H), 6.75 (m, 1H), 4.13 (s, 2H).
The following intermediate carboxylic acids were synthesized using the general procedure set out in this example.
(5-Fluoro-pyridin-2-ylamino)-acetic acid (hydrochloride) was used for Compound 287
(Pyridin-2-ylamino)-acetic acid (hydrochloride) was used for Compound 316
1H NMR (400 MHz, DMSO-d6): δ 13.65 (br, 2H), 8.94 (br, 1H), 7.94 (m, 2H), 7.17 (d, 1H, J = 7 .2), 6.91 (t, 1H, J = 6.4). Example 25. Synthesis of 1H-Pyrrolo[2,3-b]pyridin-3-yl)-acetic acid (hydrochloride). The title compound was synthesized following the scheme below and used for synthesis of Compound 276, Compound 203 and Compound 213.
Step A: Oxo-(1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid ethyl ester (bb). To a solution of aluminum chloride (28.2 g, 0.212 mol) in DCM (50 ml) was added 7-azaindole (aa; 5.0 g, 0.042 mol) in one portion at room temperature (25°C) under N2. After 1h at room temperature, the resulting mixture was cooled to 0°C and a solution of chloro-oxo-acetic acid ethyl ester (28.9 g, 0.212 mol) in DCM (20 ml) was added dropwise over 1h. . After stirring for 30 min at the same temperature, the reaction was warmed to room temperature and stirred overnight. The reaction was cooled to 0°C and ethanol (100 ml) was added dropwise. After a period of 30 min at room temperature, the solvent was evaporated. DCM (250 ml) and saturated NaHCO3 (300 ml) were added, the aqueous phase was extracted with DCM twice, the organics were combined, washed with brine, dried with Na2SO4, concentrated to give the crude product. The crude product was washed with PE (20 ml), filtered and the filter cake was dried to give bb (2.1 g, 23% yield) as yellow solid. 1H NMR (400 MHz, CDCl3): δ 12.51 (s, 1H), 8.77-8.69 (m, 2H), 8.46-8.44 (m, 1H), 7.37-7 .33 (m, 1H), 4.49-4.42 (q, 2H), 1.48-1.43 (t, 3H); MS: 219.0 (M+1)+.
Step B: (1H-Pyrrolo[2,3-b]pyridin-3-yl)-acetic acid ethyl ester (cc). To a mixture of triethylsilane (2.0 g, 17.2 mmol) in TFA (20 ml) was added bb (1.0 g, 4.9 mmol) in one portion at room temperature. After a period of 16 h at 55°C, the solvent was removed and saturated NaHCO3 was added, followed by DCM. The organic layer was collected, dried with Na 2 SO 4 and concentrated to give cc (400 mg, 43% yield) as yellow solid without further purification for next step. 1H NMR (400 MHz, CDCl3): δ 12.81 (s, 1H), 8.42-8.37 (m, 2H), 7.45 (s, 1H), 7.37-7.32 (m , 1H), 4.18-4.16 (q, 2H), 3.81 (s, 2H), 1.28-1.24 (t, 3H); MS: 205.0 (M+1)+.
Ácido (1H-Pirrolo[2,3-c]piridin-3-il)-acético foi usado para síntese do Composto 25 276 Ácido (1H-Pirrolo[3,2-c]piridin-3-il)-acético foi usado para síntese do Composto 261Step C: (1H-Pyrrolo[2,3-b]pyridin-3-yl)-acetic acid (dd). A mixture of cc (0.4 g, 2.1 mmol) and LiOH 3 O (0.35 g, 8.4 mmol) in THF/H 2 O (10 ml, v/v=1:1) was stirred at temperature room for 1 h. 4 M aq HCl was added at 0°C until pH=5, the solvent was removed and the residue was washed with methanol, filtered and the organic layer was dried and concentrated to give crude dd (400 mg) without further purification for next step . 1H NMR (400 MHz, DMSO-d6): δ 12.06 (s, 1H), 8.29-8.15 (m, 2H), 7.45-7.44 (m, 1H), 7.23 -7.18 (m, 1H), 3.72 (s, 2H); MS: 177.1 (M+1)+. The following carboxylic acid reagents were synthesized by the general procedure of this example (1H-Pyrrolo[3,2-b]pyridin-3-yl)-acetic acid was used for synthesis of Compound 275 (1H-Pyrrolo[2,3-c]pyridin-3-yl)-acetic acid was used for synthesis of Compound 25 276 (1H-Pyrrolo[3,2-c]pyridin-3-yl)-acetic acid was used for synthesis of Compound 261
Example 26. Synthesis of 2-Methyl-imidazol-1-yl)-acetic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 176 following Scheme 1.
Step A: (2-Methyl-imidazol-1-yl)-acetic acid ethyl ester. To a solution of 2-Methyl-1H-imidazole (20.52 g, 250 mmol) in THF (500 ml) was added K 2 CO 3 (41.46 g, 300 mmol). The mixture was stirred at room temperature for 0.5 hour. Bromoacetic acid ethyl ester (27.6 ml, 250 mmol) was added and the mixture was stirred overnight at room temperature. The resulting mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by flash column chromatography eluted with PE/EtOAc (20/1 to 3/1) to give (2-Methyl-imidazol-1-yl)-acetic acid ethyl ester as a colorless oil ( 23.4 g, 56% yield). 1H NMR (400 MHz, CDCl3): δ 6.93 (s, 1H), 6.83 (s, 1H), 4.58 (s, 2H), 4.25 (q, 2H, J = 6.8 ), 2.35 (s, 3H), 1.29 (t, 3H, J=6.8). Step B: (2-Methyl-imidazol-1-yl)-acetic acid. A mixture of (2-Methyl-imidazol-1-yl)-acetic acid ethyl ester (23.4 g, 0.14 mol) and NaOH (12 g, 0.3 mol) in a mixture of H2O (100 ml) ), THF (150 ml) and MeOH (150 ml) was stirred for 3 h at room temperature. The organic solvents were evaporated and the resulting aqueous solution was extracted with 10% MeOH/DCM. The aqueous layer was acidified with conc. HCl to pH=4 and all solvent was evaporated. The residue was extracted with 40% MeOH/DCM and the solvent was evaporated in vacuo to give (2-Methyl-imidazol-1-yl)-acetic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (d, 1H, J=1.6), 7.39 (d, 1H, J=1.6), 4.75 (s, 2H) , 2.48 (s, 3H). Example 27. Synthesis of 5-Fluoro-pyridin-3-ylamino)-acetic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 310.
Step A: Bis-(5-fluoro-pyridin-3-ylamino)-acetic acid ethyl ester. To a solution of 3-amino-5-fluropyridine (2.24 g, 20 mmol) in dry DMF (30 ml) was added Oxoacetic acid ethyl ester (2.04 g, 40 mmol) in toluene (30 ml). HCl/dioxane (3M, 6.6 ml) was added dropwise below 15°C. The reaction mixture was stirred at 50°C for 70 hours and the solvent removed under reduced pressure. The residue was neutralized with saturated aqueous NaHCO3 to pH>8, extracted with DCM, purified by silica gel chromatography with MeOH/DCM (5%) to give Bis-(5-fluoro-pyridin-3-acid ethyl ester) ylamino)-acetic (1.0 g, 32% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 2H), 7.80 (s,2H), 7.18 (s, 2H, J = 7.2), 7.02 (d , 2H, J = 12), 5.63 (m, 1H), 4.20 (q, 2H, J = 6.8), 1.53 (t, 3H, J = 6.8). Step B: (5-Fluoro-pyridin-3-ylamino)-acetic acid (hydrochloride). A mixture of Bis-(5-fluoro-pyridin-3-ylamino)-acetic acid ethyl ester (1 g, 3.2 mmol) and Pd/C (5%, 0.9 g) in HCl (6N, 20 ml) was stirred overnight under H2 atmosphere at room temperature. The resulting mixture was basified with 20% aqueous NaOH to pH>8 and extracted with ether. The aqueous phase was adjusted to pH=4 and evaporated to dryness under reduced pressure. The residual solid was triturated in 20% MeOH/DCM, filtered and the filtrate evaporated in vacuo to give (5-Fluoro-pyridin-3-ylamino)-acetic acid (hydrochloride) which was used directly without further purification (0, 5g, 74% yield). Example 28. Synthesis of (1H-Indol-3-yl)-oxo-acetic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 262 following Scheme 1.
Step A: (1H-Indol-3-yl)-oxo-acetic acid ethyl ester. The title compound was synthesized via the general procedure set forth in Example 25, step A. 1H NMR (400 MHz, DMSO-d6): δ 12.42 (br, 1H), 8.44 (s, 1H), 8, 17 (d, 1H, J = 6.4), 7.57 (d, 1H, J = 6.4), 7.27 (m, 2H), 4.37 (q, 2H, J = 14.5 .1), 1.35 (t, 3H, J = 5.1). Step B: (1H-Indol-3-yl)-oxo-acetic acid. To a mixture of (1H-Indol-3-yl)-oxo-acetic acid ethyl ester (2.66 g, 12.2 mmol) in THF (300 ml) was added a solution of NaOH (1.0 g, 24 .2mmol) in water (20ml). The reaction mixture was stirred for 2h at room temperature. The resulting mixture was concentrated in vacuo to remove most of the THF. The aqueous phase was acidified to pH=3 with conc. HCl and then the precipitate was collected by filtration, washed with water and dried to give the desired product (2.3 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.86 (br, 1H), 12.36 (s, 1H), 8.42 (s, 1H), 8.17 (d, 1H, J = 6 .4), 7.54 (d, 1H, J = 6.4), 7.27 (m, 2H), 4.37 (q, 2H, J = 14, 5.1), 1.35 (t , 3H, J=5.1). Example 29. Synthesis of N-Pyridin-4-ylmethyl-oxalamic Acid Ethyl Ester. The title compound was synthesized following the scheme below and used for synthesis of Compound 270 following Scheme 1.
Step A: N-Pyridin-4-ylmethyl-oxalamic acid ethyl ester. To a solution of 4-aminomethylpyridine (7.5 g, 69.4 mmol) in dry THF (200 ml) was added ethyl chlorooxacetate (8.55 ml, 76.3 mmol) and Et3N (14.5 ml) at 0oC. The mixture was stirred for 3 hours at the same temperature and then concentrated. The residue was diluted with saturated aqueous NaHCO3 (100 ml), extracted with EtOAc (3x45 ml) and the combined extracts were washed with brine, dried with Na2SO4 and filtered. The organic solvent was evaporated to dryness to give N-Pyridin-4-ylmethyl-oxalamic acid ethyl ester as brown oil (12.6g, 87% yield). 1H NMR (400 MHz, CDCl3): δ 8.57 m, 2H), 7.74 (br, 1H), 7.22 (m, 2H), 4.54 (d, 2H, J = 6.4, 14.4), 1.40 (t, 3H, J = 5.1). Step B: N-Pyridin-4-ylmethyl-oxalamic acid. The title compound was synthesized using the general procedure set out in Example 28, step B. 1H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.87 (m, 2H), 7. 93 (m, 2H), 4.61 (d, 2H, J = 6). Example 30. Synthesis of 1-Methyl-1H-imidazol-2-yl)-oxo-acetic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 284 following Scheme 1.
Ácido Oxo-(1H-pirrolo[3,2-c]piridin-3-il)-acético foi sintetizado através do procedimento geral previsto no Exemplo 25, etapa C. 1H NMR (400 MHz, DMSO-d6): δ 13,71 (br, 1H), 9,53 (s, 1H), 9,00 (s, 1H), 8,63 (d, 1H, J = 6,4), 8,14 (d, 1H, J = 6,4). Exemplo 32. Síntese de 4,4-Difluor-cidohexilamma. O composto do título foi sintetizado seguindo o esquema abaixo e usado para síntese do Composto 331, Composto 330, Composto 378 e Composto 373, todos seguindo o Esquema 1. Step A: (1-Methyl-1H-imidazol-2-yl)-oxo-acetic acid ethyl ester. To a solution of 1-methylimidazole (2.65g, 32.3mmol) in MeCN (30ml) was added ethyl chlorooxacetate (4.41g, 32.3mmol) dropwise at 0°C followed by Et3N (5.8 ml). The reaction mixture was stirred overnight and then filtered. The filtrate was evaporated to dryness, purified by flash chromatography eluting with PE/EtOAc (2/1) to give pure (1-Methyl-1H-imidazol-2-yl)-oxo-acetic acid ethyl ester (5.0 g, 85% yield). 1H NMR (400 MHz, CDCl3): δ 7.31 (s, 1H), 7.17 (s, 1H), 4.47 (q, 2H, J=6.8), 4.05 (s, 1H ), 1.41 (t, 3H, J = 6.8) Step B: (1-Methyl-1H-imidazol-2-yl)-oxo-acetic acid. The title compound was synthesized using the general procedure set out in Example 28, step B Example 31. Synthesis of Oxo-(1H-pyrrolo[3,2-c]pyridin-3-yl)-acetic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 269 following Scheme 1. Oxo-(1H-pyrrolo[3,2-c]pyridin-3-yl)-acetic acid was synthesized via the general procedure set out in Example 25, step C. 1H NMR (400 MHz, DMSO-d6): δ 13, 71 (br, 1H), 9.53 (s, 1H), 9.00 (s, 1H), 8.63 (d, 1H, J = 6.4), 8.14 (d, 1H, J = 6.4). Example 32. Synthesis of 4,4-Difluoro-cidohexylamine. The title compound was synthesized following the scheme below and used for synthesis of Compound 331, Compound 330, Compound 378 and Compound 373, all following Scheme 1.
Step A: (4,4-Difluoro-cyclohexyl)-carbamic acid tert-butyl ester. To a solution of (4-Oxo-cyclohexyl)-carbamic acid tert-butyl ester (10 g, 47 mmol) in DCM (50 ml) was added DAST (12.8 g, 80 mmol) dropwise at 0° Ç. The reaction mixture was stirred overnight at room temperature. The resulting mixture was washed with NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from Et2O and PE to (4,4-Difluoro-cyclohexyl)-carbamic acid tert-butyl ester as a solid (4.0 g, 32% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.91-6.89 (d, 1H), 3.44-3.43 (d, 1H), 1.99-1.74 (m, 6H) , 1.49-1.36 (m, 11H).
Step B: 4,4-Difluoro-cyclohexylamine (hydrochloride). A mixture of (4,4-Difluoro-cyclohexyl)-carbamic acid tert-butyl ester (4.0 g, 17 mmol) in Et 2 O/HCl (saturated, 50 ml) was stirred for 3 hours. The precipitate was collected by filtration and dried under vacuum to give the 4,4-Difluoro-cyclohexylamine (hydrochloride) which was used directly without further purification (2.0 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 3H), 3.19-3.18 (s, 1H), 2.06-1.85 (m, 6H), 1.65 -1.59 (m, 2H). Example 33. Synthesis of 4-(1H-Tetrazol-5-yl)-phenylamine. The title compound was synthesized following the scheme below and used for synthesis of Compound 285 via Scheme 1.
To a solution of 4-amino-benzonitrile (2.36 g, 20 mmol) in dry DMF (20 ml) was added NaN3 (1.6 g, 30 mmol) and NH4Cl (1.6 g, 30 mmol) and the reaction mixture was refluxed overnight. After cooling to room temperature, the resulting mixture was diluted with 40 ml of water and extracted with EtOAc (3x30 ml). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and evaporated to give 4-(1H-Tetrazol-5-yl)-phenylamine (1.5 g, 54% yield). 1H NMR (400 MHz, DMSO-d6): δ 16.26 (s, 1H), 7.70-7.68 (d, 2H, J = 8.4), 6.70-6.67 (d, 2H, J = 8.4), 5.79-5.76 (s, 2H). Example 34. Synthesis of 4-[1,3,4]Oxadiazol-2-yl-phenylamine. The title compound was synthesized following the scheme below and used for synthesis of Compound 290 via Scheme 1
Step A: 4-Nitro-benzoic acid methyl ester. To a solution of p-nitrobenzoic acid (8 g, 50 mmol) in MeOH (100 ml) was added conc.H 2 SO 4 (10 ml) dropwise. The reaction mixture was refluxed overnight and then concentrated in vacuo. The residue was dissolved in EtOAc (10 ml), washed with water, brine, dried with Na2SO4, filtered and the solvent was concentrated to give 4-Nitro-benzoic acid methyl ester which was used directly without further purification (7.2 g, 84% yield). Step B: 4-Nitro-benzoic acid hydrazide. To a solution of 4-Nitro-benzoic acid methyl ester (3.6g, 20mmol) in MeOH (100ml) was added Hydrazine hydrate (2.0g, 40mmol).
The reaction mixture was stirred overnight at room temperature. The resulting mixture was evaporated in vacuo to give 4-Nitro-benzoic acid hydrazide which was used directly without further purification (2.9 g, 81% yield). Step C: 2-(4-Nitro-phenyl)-[1,3,4]oxadiazole. A mixture of 4-Nitrobenzoic acid hydrazide (1.8 g, 10 mmol) in orthoformic acid Triethylester (30 ml) was refluxed overnight. The resulting mixture was concentrated under reduced pressure and the residue was washed with Et2O to give pure 2-(4-Nitro-phenyl)-[1,3,4]oxadiazole (1.2 g, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.42-8.40 (d, 2H, J =9.2), 8.32-8.30 (d, 2H, J = 8.8).
Step D: For 4-[1,3,4]Oxadiazol-2-yl-phenylamine. A mixture of 2-(4-Nitrophenyl)-[1,3,4]oxadiazole (1.2 g, 6 mmol) in MeOH (10 ml) was hydrogenated overnight under atmospheric pressure with 10% Pd/C (400 mg) as a catalyst at room temperature. The resulting mixture was filtered. The filtration was concentrated and purified by flash chromatography eluting with PE/EtOAc (30/1 to 2/1) to give the pure 4-[1,3,4]Oxadiazol-2-yl-phenylamine (0.8 g, 71% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.25-8.23 (d, 2H, J = 9.2), 7.97-7.95 (d, 2H, J = 8.8), 6.09 (s, 2H). Example 35. Synthesis of 4-[1,2,4]Oxadiazol-3-yl-phenylamine. The title compound was synthesized following the scheme below and used for the synthesis of Compound 291 via Scheme 1.
Step A: N-Hydroxy-4-nitro-benzamidine. Hydroxylamine hydrochloride (18g, 200mol) and K 2 CO 3 (5.53g, 400mmol) were added to a solution of 4-Nitro-benzonitrile (8g, 55mmol) in EtOH (200ml). The reaction mixture was refluxed overnight and the hot mixture was filtered. The filtrate was collected and concentrated in vacuo to furnish N-Hydroxy-4-nitro-benzamidine which was used directly without further purification (9.4 g, 87% yield).
Step B: For 3-(4-Nitro-phenyl)-[1,2,4]oxadiazole. A mixture of N-Hydroxy-4-nitro-benzamidine (5.2 g, 30 mmol) in orthoformic acid triethyl ester (50 ml) was refluxed overnight. The resulting mixture was concentrated in vacuo and the residue was washed with Et2O to give the 3-(4-Nitro-phenyl)-[1,2,4]oxadiazole which was pure enough to be used directly (4.6 g, 92 % yield). 1H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.39-8.32 (m, 4H).
Step C: For 4-[1,2,4]Oxadiazol-3-yl-phenylamine. A mixture of 3-(4-Nitrophenyl)-[1,2,4]oxadiazole (2.3 g, 16 mmol) in MeOH (20 ml) was hydrogenated overnight under atmospheric pressure with 10% Pd/C (400 mg) as a catalyst at room temperature. The resulting mixture was filtered. The filtrate was concentrated and purified by flash chromatography eluting with PE/EtOAc (30/1 to 2/1) to give the pure 4-[1,2,4]Oxadiazol-3-yl-phenylamine (1.5 g, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 7.68-7.66 (d, 2H, J = 8.4), 6.69-6.67(d, 2H, J = 8.4), 5.95 (s, 2H). Example 36. Synthesis of 3,4-Dihydro-2H-benzo[1,4]oxazine. The title compound was synthesized following the scheme below and used for synthesis of Compound 202 via Scheme 1
3-Bromo-fenilamina (0,83 g, 4,8mmol) foi dissolvida em 30 ml de tolueno seco com agitação, e 15 ml de EtOH foram adicionados. Em seguida, uma solução de Na2CO3 (3,3 g, 31,2 mmol) em água (15 ml) foi adicionada seguido de 4-(4,5-Dimetil- [1,3,2]dioxaborolan-2-il)-1-metil-1H-pirazol (1,0 g, 4,8 mmol) e Pd(PPh3)4 (0,28 g, 0,24 mmol). A mistura de reação foi aquecida para refluxo com agitação durante a noite. A mistura resultante foi resfriada para temperatura ambiente, filtrada e a solução foi extraída com EtOAc (3x30 ml). A camada orgânica foi lavada com salmoura, seca com Na2SO4, filtrada e concentrada. O resíduo foi purificado por cromatografia em gel flash eluída com PE/EtOAc (de 2/1 a 1/3) para gerar 3-(1-Metil-1H-pirazol-4-il)-fenilamina como um sólido branco (0,56 g, 67% de rendimento). Exemplo 38. Síntese de 6,7-Dihidro-5H-[1]pirindin-6-ilamina. O composto do título foi sintetizado seguindo o esquema abaixo e usado para síntese do Composto 318 através do Esquema 1. Step A: For 4H-Benzo[1,4]oxazin-3-one. To a mixture of 2-aminophenol (5.45 g, 49.98 mmol), TEBA (11.4 g, 50.00 mmol) and NaHCO3 (16.8 g, 200.00 mmol) in CHCl3 (30 ml) a solution of acetyl 2-chlorochloride (8.16 g, 72.21 mmol) in CHCl3 (5 ml) was added dropwise at 0°C. The reaction mixture was stirred for a further 1 h at the same temperature and then heated to 55°C for 10 hours with stirring. The resulting mixture was concentrated in vacuo and then 50 ml of water was added. The precipitate was collected, purified by recrystallization to give the 4H-Benzo[1,4]oxazin-3-one as a white solid (3.6 g, 48% yield). 1H NMR (300MHz, DMSO-d6): δ 6.97-6.86 (m, 4H), 4.55 (s, 2H). Step B: 3,4-Dihydro-2H-benzo[1,4]oxazine. To a mixture of LAH (3.6 g, 94.74 mmol) in THF (80 ml) was added a solution of 4H-Benzo[1,4]oxazin-3-one (5.7 g, 38.22 mmol) ) in THF (21 ml) dropwise at room temperature. The reaction mixture was refluxed overnight. The resulting mixture was cooled to 0°C and then quenched by the addition of 3.6 ml of H2O, followed by 10.8 ml of 15% NaOH solution. The precipitate was filtered off and the solvent was extracted with EtOAc (2x50 ml). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 3,4-dihydro-2H-benzo[b][1,4]oxazine as red oil which was pure enough to be used directly (1, 5g, 50% yield). 1H NMR (300 MHz, DMSO-d6): δ 6.67-6.41 (m, 4H), 5.68 (s, 1H), 4.11-4.07 (m, 2H), 3.27 -3.24 (m, 2H). Example 37. Synthesis of 3-(1-Methyl-1H-pyrazol-4-yl)-phenylamine. The title compound was synthesized following the scheme below and used for synthesis of Compound 223 via Scheme 1. 3-Bromo-phenylamine (0.83 g, 4.8mmol) was dissolved in 30 ml of dry toluene with stirring, and 15 ml of EtOH was added. Then a solution of Na 2 CO 3 (3.3 g, 31.2 mmol) in water (15 ml) was added followed by 4-(4,5-Dimethyl-[1,3,2]dioxaborolan-2-yl) -1-methyl-1H-pyrazole (1.0 g, 4.8 mmol) and Pd(PPh3)4 (0.28 g, 0.24 mmol). The reaction mixture was heated to reflux with stirring overnight. The resulting mixture was cooled to room temperature, filtered and the solution extracted with EtOAc (3x30ml). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash gel chromatography eluting with PE/EtOAc (2/1 to 1/3) to give 3-(1-Methyl-1H-pyrazol-4-yl)-phenylamine as a white solid (0, 56 g, 67% yield). Example 38. Synthesis of 6,7-Dihydro-5H-[1]pyrindin-6-ylamine. The title compound was synthesized following the scheme below and used for the synthesis of Compound 318 via Scheme 1.
Step A: For (3-Hydroxymethyl-pyridin-2-yl)-methanol. To a solution of pyridine-2,3-dicarboxylic acid dimethyl ester (35 g, 179 mmol) in EtOH (400 ml) was added NaHB4 (35 g, 921 mmol) in increments. The reaction mixture was refluxed overnight and the resulting mixture was filtered and the filtrate was evaporated to give the crude product. The residue was purified by flash chromatography eluting with DCM/MeOH/Et3N (from 51/1/0.2 to 100/1/0.5) to give pure (3-Hydroxymethyl-pyridin-2-yl)-methanol as brown oil (6 g, 24% yield). 1H NMR (400 MHz, CDCl3): δ8.42(d, 1H, J=4), 7.74(d, 1H, J=7.6), 7.27-7.22(m, 1H), 4.75 (s, 2H), 4.66 (s, 2H), 4.19(br, 2H). Step B: 2,3-Bis-chloromethyl-pyridine. To a mixture of (3-Hydroxymethyl-pyridin-2-yl)-methanol (5.5 g, 43 mmol) in DCM (50 ml) was added SOCl2 (5 ml) at 0°C. The reaction was stirred for 2 hours at 75°C and then evaporated in vacuo to give the crude 2,3-Bis-chloromethyl-pyridine (hydrochloride) which was used directly without further purification (6 g, 71% yield). 1H NMR (400 MHz, DMSO-d6): δ15.86 (br, 0.6H), 8.69(d, 1H), 7.69-7.66 (m, 1H), 5.05 (s, 2H), 5.02 (s, 2H). Step C: For 5,7-Dihydro-[1]pyrindine-6,6-dicarboxylic acid diethyl ester. To 100 ml of EtOH was added Na (1.6 g, 68 mmol) bit by bit. After the solid dissolved, Malonic acid diethyl ester (4.94 g, 30.86 mmol) was added, followed by a solution of 2,3-Bis-chloromethyl-pyridine (hydrochloride, 5.4 g, 30.86 mol) in EtOH (100 ml). The reaction mixture was refluxed overnight. The resulting mixture was concentrated and diluted with water (100 ml). The mixture thus obtained was extracted with EtOAc (3x30 ml) and the organic layer was washed with NaHCO3 solution, brine, dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The residue was purified by flash chromatography eluting with (PE/EtOAc 50/1 to 10/1) to give pure 5,7-Dihydro-[1]pyrindine-6,6-dicarboxylic acid diethyl ester as a colorless oil . (2.9 g, 35% yield). 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.49 (d, 1H), 7.09-7.06 (m, 1H), 4.25-4.20 (q, 4H), 3.70 (s, 2H), 3.60 (s, 2H), 1.27 (t, 3H).
Step D: For 6,7-Dihydro-5H-[1]pyrindine-6-carboxylic acid. A mixture of 5,7-Dihydro-[1]pyrindine-6,6-dicarboxylic acid diethyl ester (2 g, 7.6 mmol) in conc. HCl (200 ml) was refluxed for 2 hours and then evaporated in vacuo to give crude 6,7-Dihydro-5H-[1]pyrindine-6-carboxylic acid (hydrochloride) as a black solid which was used directly without further purification. (1.6 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ8.64 (d, 1H), 834(d, 1H), 7.76 (m, 1H), 3.55-3.28 (m, 5H).
Step E: For (6,7-Dihydro-5H-[1]pyrindin-6-yl)-carbamic acid tert-butyl ester. To a solution of crude 6,7-Dihydro-5H-[1]pyrindine-6-carboxylic acid (hydrochloride, 0.66 g, 3.32 mmol), Et3N (1.7 g, 16.6 mmol) and t -BuOH (15ml) in dioxane (15ml) was added DPPA (1.05g, 4.32mmol) dropwise. The reaction mixture was heated to 100°C and stirred overnight. The resulting mixture was concentrated and dissolved in EtOAc (50 ml). The organic layer was washed with NaHCO3, brine, dried with Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography eluting with (PE/EtOAc 5/1) to give (6,7-Dihydro-5H-[1]pyrindin-6-yl)-carbamic acid tert-butyl ester (0.35 g, 35% yield). 1H NMR (400 MHz, DMSO-d6): δ8.28 (d, 1H), 7.56(d, 1H), 7.23 (d, 1H), 7.11 (q, 1H), 4.24 (m, 1H), 3.19-3.10 (m, 2H), 2.86-2.75 (m, 2H), 1.39 (s, 9H).
Step F: For 6,7-Dihydro-5H-[1]pyrindin-6-ylamine. A mixture of (6,7-Dihydro-5H-[1]pyrindin-6-yl)-carbamic acid tert-butyl ester (0.2 g, 0.85 mmol) in HCl/Et2O (3M, 5 ml) ) was stirred overnight at room temperature, then evaporated in vacuo to give 6,7-Dihydro-5H-[1]pyrindin-6-ylamine (hydrochloride) as a solid (0.16 g, 100% yield ). 1H NMR (400 MHz, DMSO-d6): δ8.65 (d, 1H), 8.36(m, 1H), 7.783 (m, 1H), 3.66-3.26 (m, 5H). Example 39. Synthesis of 2-(1H-Indol-3-yl)-propionic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 283 via Scheme 1.
Step A: For (1H-Indol-3-yl)-acetic acid ethyl ester. To a solution of (1H-Indol-3-yl)-acetic acid (5.0 g, 28.6 mmol) in EtOH (50 ml) was added SOCl2 (6.1 g, 51.4 mmol) dropwise at room temperature. The reaction mixture was refluxed overnight. The solution was cooled to room temperature and the solvent removed to give (1H-Indol-3-yl)-acetic acid ethyl ester as a brown solid (5.5 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.63-7.61 (d, 1H, J=8 Hz), 7.34-7.32 (d, 1H, J =8 Hz), 7.21-7.11 (m, 3H), 4.19-4.14 (q, 2H, J=7.2 Hz), 3.76 (s, 2H), 1.28 -1.24 (t, 2H, J = 7.2); MS: 204.1 (M+1)+. Step B: 3-Ethoxycarbonylmethyl-indole-1-carboxylic acid methyl ester. To a solution of (1H-Indol-3-yl)-acetic acid ethyl ester (5.5 g, 27.1mmol) and TBAI (0.08g, 0.2mmol) in a mixture of 30% NaOH (80 ml ) and DCM (80ml) was added methyl chloroformate (3.8g, 40.6mmol) at -4°C for 15 minutes. The reaction was stirred at 0°C for 2 h. The mixture of the two layers was separated and the aqueous layer was extracted once with DCM. The combined DCM layer was washed with brine and concentrated in vacuo, purified by flash chromatography eluting with PE/EtOAc (20/1 to 15/1) to give 3-Ethoxycarbonylmethyl-indole-1-carboxylic acid methyl ester as a solid (5.0 g, 71% yield). 1H NMR (400 MHz, CDCl3): δ 8.18-8.16 (m, 1H), 7.60-7.53 (m, 2H), 7.37-7.25 (m, 2H), 4 .20-4.15 (q, 2H, J=6.8), 4.02 (s, 3H), 3.70 (s, 2H), 1.28-1.24 (t, 2H, J= 7.2 Hz); MS: 262.1 (M+1)+. Step C: 3-(1-Ethoxycarbonyl-ethyl)-indole-1-carboxylic acid methyl ester. To a solution of 3-Ethoxycarbonylmethyl-indole-1-carboxylic acid methyl ester (2.0g, 7.7mmol) in dry THF (10ml) was added LDA (15ml, in THF, 11.5mmol) dropwise dropwise at -78°C for 30 min under N 2 . Then the solution was stirred at -78°C for a further 1 h, a solution of Iodomethane (1.6 g, 11.5mmol) in dry THF (5 ml) was added dropwise at -78°C. After stirring at -78°C for 1.5 h, the reaction was quenched with saturated NH 4 Cl solution at room temperature, extracted with EtOAc (2x30 ml). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with PE/EtOAc (20/1) to give 3-(1-Ethoxycarbonyl-ethyl)-indole-1-carboxylic acid methyl ester as a white solid (0.4 g, 19 % yield). 1H NMR (400 MHz, CDCl3): δ 8.18-8.17 (m, 1H), 7.62-7.55 (m, 2H0, 7.36-7.24 (m, 2H), 4. 18-4.11 (m, 2H), 4.03 (s, 3H), 3.96-3.91 (m, 1H), 1.61-1.59 (d, 3H), 1.24- 1.20 (t, 2H, J = 7.2); MS: 276.1 (M+1) +.
Step D: 2-(1H-Indol-3-yl)-propionic acid. A solution of KOH (575 mg, 8.7 mmol) in water (10 ml) was added to a solution of 3-(1-Ethoxycarbonyl-ethyl)-indole-1-carboxylic acid methyl ester (400 mg, 1, 45 mmol) in methanol (40 ml) at room temperature. The mixture was stirred at 70°C for 1 h and concentrated. The residual oil was adjusted to pH=1 with aq.HCl (1M) and the precipitate was filtered. The aqueous phase was extracted with EtOAc (2x, 30 ml) and the organic layer was washed with brine, dried with Na2SO4, filtered and concentrated to give 2-(1H-Indol-3-yl)-propionic acid as a clear oil (250 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.12 (s, 1H), 10.93 (s, 1H), 7.56-7.55 (d, 1H, J=7.6Hz), 7.35-7.33 (d, 1H, J = 8.0), 7.21-7.20 (d, 1H, J=2.4 Hz), 7.087.05 (t, 1H, J = 6 .8, J=8.0), 6.99-6.95 (t, 1H, J=7.2, J=7.6), 3.87-3.85 (m, 1H), 1, 47-1.45 (d, 3H, J = 7.2); MS: 190.1 (M+1)+. Example 40. Synthesis of Indol-1-yl-acetic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 271 via Scheme 1.
Uma mistura de glicina (7,51 g, 100 mmol) e cloreto de benzenossulfonil (12,9 ml, 100 mmol) em solução de NaOH (1 M, 272 ml, 272 mmol) foi aquecida para 70°C durante 2 horas. A mistura resultante foi resfriada para 5°C e então ajustada para pH=6,5. O precipitado foi recolhido por filtração e seco sob vácuo para gerar o ácido Benzenessulfonilamino acético puro (10,5 g, 48% de rendimento). 1H NMR (300 MHz, H2O): δ 7,78 (d, 2H,), 7,62-7,53 (m, 3H), 3,69 (s, 2H). Exemplo 42. Síntese de Ácido (4-Ciano-fenilamino) acético. O composto do título foi sintetizado seguindo o esquema abaixo e usado para síntese do Composto 227 e Composto 228 através do Esquema 1. Uma suspensão de 4-Amino-benzonitrila (1,0 g, 8,5mmol) e ácido cloro acético (1,6 g, 16,9 mmol) em água (30 ml) foi refluxada durante 4 h. A mistura resultante foi resfriada para temperatura ambiente. O precipitado foi recolhido por filtração e lavado com EtOAc para gerar o ácido (4-Ciano-fenilamino) acético puro como um sólido branco (300 mg, 20% de rendimento). 1H NMR (400 MHz, DMSO-d6): δ 12,73 (s, 1H), 7,47-7,45 (d, 2H, J=8,8 Hz), 6,92 (m, 1H), 6,65-6,63 (d, 2H, J = 8,8), 3,91-3,89 (d, 2H, J = 6,0); MS: 177,1 (M+1) +. Exemplo 43. Síntese de Ácido [1,2,3]Triazol-1-il-acético. O composto do título foi sintetizado seguindo o esquema abaixo e usado para síntese do Composto 329 através do Esquema 1. Step A: Indol-1-yl-acetic acid tert-butyl ester. Indol-1-yl-acetic acid tert-butyl ester was synthesized via general procedure 19 (step A), except that the alcohol was replaced by the indole. 1H NMR (400 MHz, CDCl3): δ 7.631 (d, 1H, J = 8), 7.25-7.21 (m, 2H), 7.13-7.08 (m, 2H), 6.55 (d, 1H, J = 3.2), 4.74 (s, 2H), 1.43 (s, 9H). Step B: Indol-1-yl-acetic acid. To a stirred solution of indole-1-yl acetic acid tert-butyl ester (2 g, 8.6 mmol) in MeOH (12 ml) was added KOH (4 g, 71.4 mmol) and water (0.4 ml). The reaction mixture was stirred at room temperature for 16 hours, then diluted with water (100 ml). The resulting mixture was extracted with Et2O (25 ml) and the organic layer was discarded. The aqueous phase was acidified to pH 3-4 with HCl (6N) and extracted with Et2O (3x15 ml). The combined organic layer was dried with Na2SO4, filtered and concentrated to yield indole-1-yl acetic acid, which was used directly without further purification (1.2g, 79.7% yield). Example 41. Synthesis of Benzenesulfonylamino Acetic Acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 10, Compound 28 and Compound 29 via Scheme 1. A mixture of glycine (7.51 g, 100 mmol) and benzenesulfonyl chloride (12.9 ml, 100 mmol) in NaOH solution (1M, 272 ml, 272 mmol) was heated to 70°C for 2 hours. The resulting mixture was cooled to 5°C and then adjusted to pH=6.5. The precipitate was collected by filtration and dried under vacuum to give pure Benzenesulfonylaminoacetic acid (10.5 g, 48% yield). 1H NMR (300 MHz, H2O): δ 7.78 (d, 2H), 7.62-7.53 (m, 3H), 3.69 (s, 2H). Example 42. Synthesis of (4-Cyano-phenylamino)acetic acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 227 and Compound 228 via Scheme 1. A suspension of 4-Amino-benzonitrile (1.0g, 8.5mmol) and chloroacetic acid (1.6g, 16.9mmol) in water (30ml) was refluxed for 4h. The resulting mixture was cooled to room temperature. The precipitate was collected by filtration and washed with EtOAc to give pure (4-Cyano-phenylamino)acetic acid as a white solid (300 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.73 (s, 1H), 7.47-7.45 (d, 2H, J=8.8 Hz), 6.92 (m, 1H), 6.65-6.63 (d, 2H, J = 8.8), 3.91-3.89 (d, 2H, J = 6.0); MS: 177.1 (M+1)+. Example 43. Synthesis of [1,2,3]Triazol-1-yl-acetic Acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 329 via Scheme 1.
A uma solução de ácido cloroacético (2,37 g, 25 mmol) e NaOH (2,0 g, 50 mmol) em H2O foi adicionado benzotriazol (3,0 g, 25 mmol) em uma porção. A mistura de reação foi agitada durante 30 minutos em temperatura ambiente e então aquecida para refluxo durante 2 horas. A mistura resultante foi resfriada para 0°C, ajustada para pH=3 com HCl (0,5 M). O precipitado foi recolhido por filtração, lavado com água e seco sob vácuo para gerar o ácido Benzotriazol-1-il-acético que foi suficientemente puro para ser usado diretamente (3,1 g, 70% de rendimento). 1H NMR (300 MHz, DMSO-d6): δ 8,02 (d, 2H, J = 8,1), 7,74 (d, 1H, J = 8,1), 7,50-7,36 (m, 2H), 5,35 (s, 3H). Exemplo 45. Preparação do Composto 386.Step A: [1,2,3]Triazol-1-yl-acetic acid benzyl ester. A mixture of 1H-[1,2,3]Triazole (2.07 g, 30 mmol), CbzCl (6.9 g, 30 mmol) and DIEA (5.1 ml, 30 mmol) in DCM (40 ml) was stirred overnight at room temperature. 150 ml of Et2O was added. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by flash column chromatography eluting with DCM/PE (19/1) to give pure [1,2,3]Triazol-1-yl-acetic acid benzyl ester (1 g, 32% yield ). 1H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.77 (s, 1H), 7.40-7.35 (m, 5H), 5.54-5.50 (s, 2H), 5.29-5.10 (d, 2H). Step B: [1,2,3]Triazol-1-yl-acetic acid. A mixture of [1,2,3]Triazol-1-yl-acetic acid benzyl ester (1 g, 4.6 mmol) in MeOH was hydrogenated overnight under 50 psi pressure with PdOH/C (20%, 92 mg) as a catalyst. The catalyst was filtered and the solvent was concentrated under vacuum to give crude [1,2,3]Triazol-1-yl-acetic acid as a solid which was used directly without further purification (560 mg, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.37 (s, 1H), 8.13-8.11 (m, 1H), 7.777.74 (d, 1H), 5.31-5.23 (d, 2H). Example 44. Synthesis of Benzotriazol-1-yl-acetic Acid. The title compound was synthesized following the scheme below and used for synthesis of Compound 205, Compound 5, Compound 157 and Compound 151 via Scheme 1. To a solution of chloroacetic acid (2.37 g, 25 mmol) and NaOH (2.0 g, 50 mmol) in H 2 O was added benzotriazole (3.0 g, 25 mmol) in one portion. The reaction mixture was stirred for 30 minutes at room temperature and then heated to reflux for 2 hours. The resulting mixture was cooled to 0°C, adjusted to pH=3 with HCl (0.5M). The precipitate was collected by filtration, washed with water and dried under vacuum to give Benzotriazol-1-yl-acetic acid which was pure enough to be used directly (3.1 g, 70% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.02 (d, 2H, J = 8.1), 7.74 (d, 1H, J = 8.1), 7.50-7.36 ( m, 2H), 5.35 (s, 3H). Example 45. Preparation of Compound 386.
Step A: (R)-N-Cyclohexyl-2-hydroxy-2-phenyl-acetamide. To a stirred solution of D-Mandelic acid (34 g, 223.68 mmol) in DMF (200 ml) was added HOBT (45.2 g, 335.5 mmol), EDCI (68.4 g, 357.9 mmol) at 0°C. Cyclohexylamine (88 g, 894.7 mmol) was added slowly. The reaction mixture was stirred overnight at room temperature. Water (500 ml) was added to the reaction mixture below 5°C. The resulting mixture was extracted with ethyl acetate (2x1.5L) and the combined organic layer was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography to give (R)-N-Cyclohexyl-2-hydroxy-2-phenyl-acetamide (38 g, 73.1% yield, ee%=100%). 1H NMR (300 MHz, DMSO-d6): δ7.69-7.67 (m, 1H), 7.40-7.25 (m, 5H), 6.07-6.05 (m, 1H), 4.87-4.86 (m, 1H), 3.32 (s, 1H), 1.67-1.53 (m, 5H), 1.26-1.21 (m, 5H); MS: 234.2 (M+1)+. Step B: (R)-Methanesulfonic acid cyclohexylcarbamoyl-phenyl-methyl ester. To a solution of (R)-N-Cyclohexyl-2-hydroxy-2-phenyl-acetamide (38 g, 163 mmol) in pyridine (100 ml) was added MsCl (20.5 g, 179 mmol) dropwise. 0°C. the mixture of
The reaction was stirred for a further 1.5 hours at the same temperature and was then concentrated in vacuo. The residue was dissolved in EtOAc (200 ml), washed with water, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to give (R)-Methanesulfonic acid cyclohexylcarbamoyl-phenyl-methyl ester which was used directly without further purification (20 g, 39.4% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.30-8.28 (m, 1H), 7.54-7.36 (m, 5H), 5.87 (s,1H), 3.54 (s, 1H), 3.18 (s, 3H), 1.76-1.52 (m, 5H), 1.26-1.09 (m, 5H); MS: 312.1 (M+1)+. Step C: (S)-N-Cyclohexyl-2-(3-fluoro-phenylamino)-2-phenyl-acetamide. A mixture of (R)-Methanesulfonic acid cyclohexylcarbamoyl-phenyl-methyl ester (20 g, 64.3 mmol), DIEA (24.8 g, 192.9 mmol) and 3-fluoro-phenylamine (7.13 g, 64.3 mmol) in DMF (80 ml) was heated to 80°C for 4 hours. The resulting mixture was cooled to room temperature and water (150 ml) was added. This mixture was extracted with EtOAc (2x200ml). The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography eluted with DCM/ MeOH (20/1 to 1/1) to give (S)-N-Cyclohexyl-2-(3-fluoro-phenylamino)-2-phenyl- acetamide (6 g, 28.6% yield, ee%=100%). 1H NMR (300 MHz, DMSO-d6): δ 8.27-8.13 (m, 1H), 7.51-7.00 (m, 6H), 6.50-6.27 (m,3H) , 4.98 (s, 1H), 3.55 (s, 1H), 1.76-1.50 (m, 5H), 1.27-1.03 (m, 5H); MS: 327.1 (M+1)+.
Step D: Compound 386. To a mixture of (S)-N-Cyclohexyl-2-(3-fluoro-phenylamino)-2-phenyl-acetamide (120 mg, 0.37 mmol) and NaHCO3 (154 mg, 1, 84 mmol) in THF (6 ml) was added 2-(thiophen-2-yl) acetyl chloride (236 mg, 1.48 mmol) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. Water (20 ml) was added and the resulting mixture was extracted with DCM (3x10 ml). The combined organic layer was washed with saturated NaHCO3 solution, brine, dried with Na2SO4, filtered and the solvent was evaporated under vacuum. The residue was purified by prep-HPLC to give the desired product (35 mg, 21% yield, ee% = 99%). 1H NMR (300 MHz, DMSO-d6): δ 8.03-8.00 (d, 1H), 7.35-7.33 (d, 1H), 7.14-6.72 (m, 10H) , 6.07 (s, 1H), 3.59-3.56 (m, 3H), 1.70-1.55 (m, 5H), 1.30-0.97 (m, 5H); MS: 451.2 (M+1)+. Example 46: Preparation of Compounds 387-389.
Step A: [(Thiophen-2-ylmethyl)-amino]-o-tolyl-acetonitrile. [(Thiophen-2-ylmethyl)-amino]-o-tolyl-acetonitrile was synthesized by a procedure similar to that described in Example 7, step A. 5 Step B: [(Thiophen-2-ylmethyl)-amino]- acid o-tolyl-acetic. [(Thiophen-2-ylmethyl)-amino]-o-tolyl-acetic acid was synthesized by a procedure similar to that described in Example 7, step B. 1H NMR (300 MHz, DMSO-d6): δ 7.34- 7.31 (m, 2H), 7.08-7.01 (m, 3H), 9.94-6.85 (m, 2H), 4.10 (s, 1H), 3.80-3, 64 (m, 2H), 3.61-3.60 (m, 1H), 2.31(s, 1H). 10 Step C: N-Cyclohexyl-2-[(thiophen-2-ylmethyl)-amino]-2-o-tolyl-acetamide. N-Cyclohexyl-2-[(thiophen-2-ylmethyl)-amino]-2-o-tolyl-acetamide was synthesized via a similar procedure as described in Example 7, step C. 1H NMR (300 MHz, DMSO-d6 ): δ 7.84-7.8 2(d, 1H, J = 10.8), 7.41-7.40 (d, 1H, J = 1.2), 7.30-7.27 ( m, 3H), 6.95-6.92 (m, 2H), 4.32-4.30 (d, 1H, J = 8.7), 3.85-3.82 (m, 2H), 3.61-3.58 (m, 1H), 2.88-2.85 (m, 15 1H), 2.26 (s, 3H), 1.77-1.52 (m, 5H), 1 .30-1.10 (m, 5H). Step D: Compound 387.
To a mixture of N-cyclohexyl-2-[(thiophen-2-ylmethyl)-amino]-2-o-tolyl-acetamide (170 mg, 0.5 mmol) in dioxane (5 ml) was added NaHCO3 (294 mg). , 3.5 mmol) and phenylchloroformate (156 mg, 1 mmol). The reaction mixture was refluxed overnight and then quenched with water (20 ml) after being cooled to room temperature. The resulting mixture was extracted with DCM (3X15 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by TLC (PE/EtOAc = 8/1) to give the desired product (133 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.10-8.08 (d, 1H, J = 7.2), 7.46-7.43 (m, 2H), 7.30-7, 20 (m, 5H), 7.15-7.10 (m, H), 6.65-6.63 (m, 1H), 5.97-5.92 (m, 2H), 4.92- 4.56 (m, 2H), 3.44-3.34 (m, 1H), 2.11-2.03 (m, 3H), 1.78-1.54 (m, 5H), 1. 30-1.56 (m, 5H); MS: 463.2 (M+1)+. Step E: Compound 388.
A mixture of N-cyclohexyl-2-[(thiophen-2-ylmethyl)-amino]-2-o-tolyl-acetamide (100 mg, 0.29 mmol) and isocyanatomethyl-benzene (69.6 mg, 0.58 mmol) in DMF (2 ml) was stirred overnight at room temperature. The precipitate was collected by filtration and washed with ether to give the desired product as a white solid (63 mg, 46.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.80 (d, 1H), 7.26-7.07 (m, 10H), 6.76-6.67 (m, 2H), 6.40 (d, 1H), 6.01 (s, 1H), 4.80 (d, 1H), 4.45 (d, 1H), 4.40 (m, 1H), 4.20 (m, 1H) , 3.58 (m, 1H), 2.18 (s, 3H), 1.75-1.52 (m, 5H), 1.27-0.98 (m, 5H); MS: 476.2 (M+1)+. Step F: Compound 389.
A mixture of N-cyclohexyl-2-[(thiophen-2-ylmethyl)-amino]-2-o-tolyl-acetamide (86 mg, 0.25 mmol), (3-methyl-pyridin-4-acid phenyl ester) -yl)-carbamic (114 mg, 0.5 mmol) and DMAP (39 mg, 0.32 mmol) in MeCN (4 ml) was heated to 60° for 10 min and then cooled to room temperature. The precipitate was collected by filtration to give pure product (52 mg, 43% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.19-8.03 (m, 4H), 7.65 (d, 1H, J=5.7Hz), 7.32 (dd, 1H, J = 4.7, 1.4), 7.24-7.15 (m, 4H), 6.85-6.82 (m, 2H), 5.99 (s, 1H), 5.16 (d , 1H, J = 17.1), 4.57 (d, 1H, J = 16.8), 3.64-3.61 (m, 1H), 2.30 (s, 3H), 1.84 (s, 3H), 1.79-1.52 (m, 5H), 1.29-1.04 (m, 5H); MS: 477.2 (M+1)+
The following compounds were synthesized using procedures similar to those described in Example 46.
1H NMR (400 MHz, DMSO-d6): δ 8.22-8.00 (d, 1H, J = 7.2), 7.35-7.31 (m, 5H), 7.26-7, 05 (m, 5H), 6.60 (s, 1H), 5.89-5.82 (m, 2H), 5.27-5.16 (m, 2H), 4.77-4.30 ( m, 2H), 3.64-3.61 (m, 1H), 2.03-1.96 (m, 3H, J = 27.2), 1.76-1.53 (m, 5H), 1.29-1.10 (m, 5H); MS: 477.2 (M+1)+.
1H NMR (400 MHz, DMSO-d6): δ 8,02 (d, 1H), 7,40-7,33 (m, 4H), 7,23-7,00 (m, 8H), 6,89-6,81 (m, 2H), 6,06(s, 1H), 2,45 (s, 3H), 1,74-1,52 (m, 5H), 1,29-0,98 (m, 5H); MS: 443,2 (M+1) +. Exemplo 47: Preparação do Composto 393 1H NMR (400 MHz, CDCl3): δ 7.30-6.88 (m, 14H), 6.02 (s, 1H), 5.34 (d, 1H), 5.19 (m, 2H), 3.86 (m, 1H), 2.35 (s, 3H), 1.93-1.25 (m, 5H), 1.13-0.91 (m, 5H); MS: 457.2 (M+1)+. Compound 392 1H NMR (400 MHz, DMSO-d6): δ 8.02 (d, 1H), 7.40-7.33 (m, 4H), 7.23-7.00 (m, 8H), 6.89 -6.81 (m, 2H), 6.06(s, 1H), 2.45 (s, 3H), 1.74-1.52 (m, 5H), 1.29-0.98 (m , 5H); MS: 443.2 (M+1)+. Example 47: Preparation of Compound 393
Step A: N-(3-Fluoro-phenyl)-C-phenyl-methanesulfonamide. To a solution of 3-Fluor-phenylamine (1.15 g, 10.4 mmol) and TEA (1.6 g, 31.2 mmol) in DCM (10 ml) was added Phenyl-methanesulfonyl chloride (1 g, 7 mmol) dropwise at 0°C. The reaction mixture was stirred overnight at room temperature, concentrated and purified by chromatography to give the desired product (1 g, 36% yield). 1H NMR (400 MHz, CDCl3): δ 7.39-7.23 (m, 6H), 6.94-6.82 (m, 3H), 6.61 (brs, 1H), 4.35 (s , 2H).
Step B: N-Cyclohexyl-2-hydroxy-2-o-tolyl-acetamide. To a stirring solution of hydroxy-o-tolyl-acetic acid (500 mg, 3 mmol) in DMF (5 ml) was added HOBt (610 mg, 4.5 mmol), EDCI (922 mg, 4.8 mmol) at 0°C. Cyclohexylamine (1.2 g, 12 mmol) was added slowly. The reaction mixture was stirred overnight at room temperature and then poured into 20 ml of ice water. The precipitate was collected by filtration, dried and triturated with ether to give the desired product (300 mg, 40% yield). Step C: Compound 393
To a solution of triphenylphosphine (110 mg, 0.42 mmol) in THF (6 ml) was added DIAD (85 mg, 0.42 mmol) dropwise at 0°C. After slurrying, a solution of N-cyclohexyl-2-hydroxy-2-o-tolyl-acetamide (111 mg, 0.42 mmol) in THF (2 ml) was added, followed by a solution of N-( 3-fluoro-phenyl)-C-phenyl-methanesulfonamide (62 mg, 0.42 mmol) in THF (2 ml). The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated and purified by chromatography to give the desired product (65 mg, 31% yield). 1H NMR (400 MHz, CDCl3): δ 7.38-7.05 (m, 10H), 6.89-6.85 (m, 2H), 6.70 (d, 1H), 6.28 (s , 1H), 5.26 (d, 1H), 4.90 (d, 1H), 4.42 (d, 1H), 3.89 (m, 1H), 2.49 (s, 3H), 2 .04-1.55 (m, 5H), 1.42-1.03 (m, 5H); MS: 495.2 (M+1)+.
Example 48: In Vitro Assays for R132H IDH1 Inhibitors
Assays were conducted in a volume of 76 µl test buffer (150 mM NaCl, 10 mM MgCl 2 , 20 mM Tris pH 7.5, 0.03% bovine serum albumin) as follows in a standard 384-well plate: A 25 ul substrate mix (8 uM NADPH, 2 mM aKG), 1 μl test compound was added in DMSO. The plate was briefly centrifuged, and then 25 µl of enzyme mixture was added (0.2 µg/ml IDH1 R132H) followed by a brief centrifugation and shaking at 100 RPM. The reaction was incubated for 50 minutes at room temperature, then 25 μl of detection mixture (30 μM resazurin, 36 μg/ml) was added and the mixture was further incubated for 5 minutes at room temperature. Conversion of resazurin to resorufin was detected by fluorescence spectroscopy at Ex544 Em590 c/o 590.

Compounds of Formula I predicted in Table 1 and compounds predicted in Table 2 were tested in this assay and the results shown in Table 4A and 4B. As used in Table 4A and 4B, “A” refers to an inhibitory activity against R132H IDH1 with an IC50 < 0.1 µM; “B” refers to an inhibitory activity against R132H IDH1 with an IC50 between 0.1 µM and 1 µM; “C” refers to an inhibitory activity against R132H IDH1 with an IC50 between 1 µM and 10 µM; “D” refers to an inhibitory activity against R132H IDH1 with an IC50 between 10 μM and 100 μM; “E” refers to an inhibitory activity against R132H IDH1 with an IC50 > 100 μM.


Example 49: Cellular Assays for R132H IDH1 Inhibitors. Cells (HT1080 or U87MG) were grown in T125 flasks in DMEM containing 10% FBS, 1x penicillin/streptomycin and 500ug/ml G418 (present in U87MG cells only). They were collected by trypsin and advertisements in 96-well white-bottom plates at a density of 5000 cells/well in 100 ul/well in DMEM with 10% FBS.
No cells were placed in columns 1 and 12. Cells were incubated overnight at 37°C in 5% CO 2 . The next day of testing compounds were made up to 2x final concentration and 100ul was added to each cell well. The final concentration of DMSO was 0.2% and the DMSO control wells were plated 10 in row G. The plates were then placed in the incubator for 48 hours. Within 48 hours, 100ul of medium was removed from each well and analyzed by LC-MS for 2-HG concentration. Cell plates were placed back in the incubator for an additional 24 hours. Within 72 hours after addition of compounds, 10 mL/plate of Promega Cell Titer Glo reagent was thawed and mixed. The cell plate was removed from the incubator and left to equilibrate to room temperature. Then, 100ul of Promega Cell Titer Glo reagent was added to each medium well. The cell plate was then placed on an orbital shaker for 10 minutes and then allowed to stand at room temperature for 20 minutes. The plate was then read for luminescence with an integration time of 500ms.

The IC50 for inhibiting 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 the invention is shown in Tables 5A (HT1080 cells) and 5B (U87MG cells) below. As used in Tables 5A and 5B “A” refers to an IC50 for inhibition of 2-HG production < 0.25 µM; “B” refers to an IC50 for inhibiting 2-HG production between 0.25 μM and 1 μM; “C” refers to an IC50 for inhibiting 2-HG production between 1 μM and 5 μM; “D” refers to an IC50 for inhibiting 2-HG production > 5 μM. Table 5A. Inhibition of 2-HG Production in HT1080 Cells. Comp

权利要求:
Claims (10)
[0001]
ou um sal farmaceuticamente aceitável do mesmo, em que: R1 é selecionado de ciclohexil, ciclopentil, cicloheptil, 3,3-difluorciclobutil, 4,4,- difluorciclohexil, e biciclo[2.2.1]heptanil; R3 é selecionado de 3-fluorfenil, 3-metilfenil, 3-clorofenil e tien-2-ilmetil; R4 é selecionado de 1-(metilmetoxicarbonilamino)etil, 1,2,3,4-tetraidroquinolin-1-il, 1-etoxicarbonilpiperidin-2-il, 1-etoxicarbonilpirrolidin-2-il, 1H-benzimidazol-1-ilmetil, 1H-indazol-3-ilmetil, indolin-1-ilmetil, 1H-indol-3-ilmetil, 1H-indol-5-ilmetil, 1H-pirrolo[2,3-b]piridina-3-ilmetil, 1H-pirrolo[3,2-b]piridin-3-ilmetil, 1-metoxicarbonilpiperidin-2-il, 1-metoxicarbonilpirrolidin-2-il, 2-fluorpiridin-3-ilaminometil, 2-imino-4-fluorpiridin-1-ilmetil, 2-metoxifenilaminometil, 2-metil-1H-benzimidazol-1-ilmetil, 2-metilimidazol-1-ilmetil, 2-trifluormetil-1H-imidazol-1-il, 3-cianofenilaminometil, 3-fluorpiridin-2-ilaminometil, 3-metoxifenilaminometil, 4-(1,3,4-oxadiazol-2-il)fenilaminometil, 4-(dimetilaminocarboniloxi)fenilmetil, 4,5-dicloroimidazol-1-ilmetil, 4-cianofenilaminometil, 4-fluorfenilaminometil, 4-fluorpiridin-2-ilaminometil, 4-hidroxifenilmetil, 4-metoxicarbonilmorfolin-3-il, 4-metoxicarbonilpiperazin-1-ilmetil, 4-metoxifenilaminometil, 4-metilcarboniloxifenilmetil, 5-fluorpiridin-2-aminometil, 5-fluorpiridin-2-oximetil, 6-fluorpiridin-3-ilaminometil, benzomorfolin-4-ilmetil, metoxicarbonilaminometil, metilmetoxicarbonilaminometil, metilfenilaminometil, fenilaminometil, piridin-2-oximetil, piridin-2-ilaminometil, piridin-2-iloximetil, piridin-3-oximetil, piridin-3-ilmetil, piridin-4-ilmetil, tiazol-4-ilmetil, e tien-2-ilmetil; e R10 é selecionado de metil, hidrogênio, flúor, cloro, e bromo, em que: quando R1 é ciclopentil ou ciclohexil e R3 é tien-2-ilmetil, então, R4 é outro que não tien-2-ilmetil, 1H-benizimidazol-1-ilmetil, 1H-indol-3-ilmetil, ou 1H-benzotriazol-1- ilmetil; quando R1 é ciclopentil, R10 é hidrogênio, e R3 é 3-fluorfenil, 3-metilfenil, ou 3- clorofenil, então, R4 é outro que não tien-2-ilmetil; quando R1 é ciclopentil, R10 é metil e R3 é 3-fluorfenil, então, R4 é outro que não tien-2-ilmetil ou 1H-benzotriazol-1-ilmetil; 5 quando R1 é ciclopentil, R10 é fluor e R3 é 3-metilfenil, então, R4 é outro que não tien-2-ilmetil ou 1H-benzotriazol-1-ilmetil; quando R1 é ciclopentil, R10 é fluor e R3 é 3-fluorfenil, então, R4 é outro que não tien-2-ilmetil; quando R1 é ciclohexil, R10 é hidrogênio, e R3 é 3-metilfenil, ou 3-clorofenil, então, 10 R4 é outro que não tien-2-ilmetil; e quando R1 é ciclohexil, R10 é hidrogênio e R3 é 3-fluorfenil, então, R4 é outro que não 1H-benzotriazol-1-ilmetil.1. Compound, characterized by being of Formula II: or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from cyclohexyl, cyclopentyl, cycloheptyl, 3,3-difluorocyclobutyl, 4,4,-difluorocyclohexyl, and bicyclo[2.2.1]heptanyl; R3 is selected from 3-fluorophenyl, 3-methylphenyl, 3-chlorophenyl and thien-2-ylmethyl; R4 is selected from 1-(methylmethoxycarbonylamino)ethyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1-ethoxycarbonylpiperidin-2-yl, 1-ethoxycarbonylpyrrolidin-2-yl, 1H-benzimidazol-1-ylmethyl, 1H -indazol-3-ylmethyl, indolin-1-ylmethyl, 1H-indol-3-ylmethyl, 1H-indol-5-ylmethyl, 1H-pyrrolo[2,3-b]pyridin-3-ylmethyl, 1H-pyrrolo[3 ,2-b]pyridin-3-ylmethyl, 1-methoxycarbonylpiperidin-2-yl, 1-methoxycarbonylpyrrolidin-2-yl, 2-fluoropyridin-3-ylaminomethyl, 2-imino-4-fluoropyridin-1-ylmethyl, 2-methoxyphenylaminomethyl , 2-methyl-1H-benzimidazol-1-ylmethyl, 2-methylimidazol-1-ylmethyl, 2-trifluoromethyl-1H-imidazol-1-yl, 3-cyanophenylaminomethyl, 3-fluoropyridin-2-ylaminomethyl, 3-methoxyphenylaminomethyl, 4 -(1,3,4-oxadiazol-2-yl)phenylaminomethyl, 4-(dimethylaminocarbonyloxy)phenylmethyl, 4,5-dichloroimidazol-1-ylmethyl, 4-cyanophenylaminomethyl, 4-fluorophenylaminomethyl, 4-fluoropyridin-2-ylaminomethyl, 4 -hydroxyphenylmethyl, 4-methoxycarbonylmorpholin-3-yl, 4-methoxycarbonylpiperazin-1-ylmethyl, 4-methoxyphenylaminomethyl, 4-methylcarbonyloxyphenylmethyl, 5-flu orpyridin-2-aminomethyl, 5-fluoropyridin-2-oxymethyl, 6-fluoropyridin-3-ylaminomethyl, benzomorpholin-4-ylmethyl, methoxycarbonylaminomethyl, methylmethoxycarbonylaminomethyl, methylphenylaminomethyl, phenylaminomethyl, pyridin-2-oxymethyl, pyridin-2-ylaminomethyl, pyridin- 2-yloxymethyl, pyridin-3-oxymethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, thiazol-4-ylmethyl, and thien-2-ylmethyl; and R10 is selected from methyl, hydrogen, fluorine, chlorine, and bromine, where: when R1 is cyclopentyl or cyclohexyl and R3 is thien-2-ylmethyl, then R4 is other than thien-2-ylmethyl, 1H-benizimidazole -1-ylmethyl, 1H-indol-3-ylmethyl, or 1H-benzotriazol-1-ylmethyl; when R1 is cyclopentyl, R10 is hydrogen, and R3 is 3-fluorophenyl, 3-methylphenyl, or 3-chlorophenyl, then R4 is other than thien-2-ylmethyl; when R1 is cyclopentyl, R10 is methyl and R3 is 3-fluorophenyl, then R4 is other than thien-2-ylmethyl or 1H-benzotriazol-1-ylmethyl; 5 when R1 is cyclopentyl, R10 is fluoro and R3 is 3-methylphenyl, then R4 is other than thien-2-ylmethyl or 1H-benzotriazol-1-ylmethyl; when R1 is cyclopentyl, R10 is fluoro and R3 is 3-fluorophenyl, then R4 is other than thien-2-ylmethyl; when R1 is cyclohexyl, R10 is hydrogen, and R3 is 3-methylphenyl, or 3-chlorophenyl, then R4 is other than thien-2-ylmethyl; and when R1 is cyclohexyl, R10 is hydrogen and R3 is 3-fluorophenyl, then R4 is other than 1H-benzotriazol-1-ylmethyl.
[0002]
2. Compound according to claim 1, characterized in that R3 is 3-fluorophenyl.
[0003]

[0004]
4. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that it is for the preparation of a medicine to treat a cancer having a mutation in R132X IDH1.
[0005]
5. Use according to claim 4, characterized in that the R132X IDH1 mutation is a R132H IDH1 mutation.
[0006]
6. Use according to claim 4, characterized in that the R132X IDH1 mutation is a R132C IDH1 mutation.
[0007]
7. Use according to claim 4, characterized in that a sample from a subject is evaluated in vitro for the presence of an elevated level of 2HG.
[0008]
8. Use according to claim 4, characterized in that the effectiveness of cancer treatment comprises monitoring in vitro the level of 2HG in a sample from a subject during treatment.
[0009]
9. Use according to claim 4, characterized in that the effectiveness of cancer treatment comprises monitoring in vitro the level of 2HG in a sample of a subject following the end of treatment.
[0010]
10. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

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MX342951B|2016-10-18|

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BR112013001122A2|2017-07-11|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-03-10| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-06-09| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-04-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-05-11| B25G| Requested change of headquarter approved|Owner name: AGIOS PHARMACEUTICALS, INC. (US) |

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2021-06-08| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/07/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US36507210P| true| 2010-07-16|2010-07-16|

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US61/365,072|2010-07-16|

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PCT/US2011/044254|WO2012009678A1|2010-07-16|2011-07-15|Therapeutically active compositions and their method of use|

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