Patent Application
20240382494
The COVID-19 pandemic is by far the worst pandemic since the 1918 Spanish flu. The etiological agent of COVID-19 is SARS-CoV-2, a single-stranded positive sense RNA virus that belongs to the beta coronavirus genus (Hu, B., et al., Nat Rev Microbiol 2021, 19, 141-154). Two additional coronaviruses within the same genus, SARS-CoV, and MERS-CoV, have caused epidemics in humans with mortality rates of 9.6% and 34.3%, respectively. Although SARS-CoV-2 has a lower mortality rate of 2.1% compared to SARS-CoV and MERS-CoV, it has led to a far greater death toll due to its higher transmission (Piroth, L, et al., The Lancet Respiratory Medicine 2021, 9, 251-259). SARS-CoV-2 differs from SARS-CoV and MERS-CoV in that it has a long incubation time after the initial infection (i to 2 weeks), and a large percentage of infected patients continue to shed the virus while being asymptomatic, presenting a daunting task for surveillance and containment (Bar-On, Y. M., et al., Elife 2020, 9, e57309).
Three mRNA vaccines developed by Pfizer/BioNtech, Moderna, and Johnson and Johnson have been approved by FDA in the United States (Li, Y., et al., A Comprehensive Review of the Global Efforts on COVID-19 Vaccine Development. ACS Central Science 2021). For small molecule antivirals, remdesivir received FDA approval on Oct. 22, 2020 (Eastman, R. T., et al., ACS Central Science 2020, 6, 672-683). Although the polymerase of SARS-CoV-2 has proof-reading function, it continues to mutate at a rate about 10−6 per site per cycle (Bar-On, Y. M., et al., Elife 2020, 9, e57309). Several variants have already emerged and widely circulated among humans since the beginning of the pandemic (Lauring, A. S.; Hodcroft, E. B., JAMA 2021, 325, 529-531). Therefore, there is a dire need for additional antivirals with a novel mechanism of action.
Antivirals are not substituents of vaccines, but rather an important complement that can be used for the treatment of infection from both wild-type (WT) and variant viruses. Among the viral proteins that have been actively pursued as SARS-CoV-2 antiviral drug targets, the main protease (Mpro) and papain-like protease (PLpro) are the most promising ones (Ma, C., et al., Cell Res 2020, 30, 678-692; and Sacco, M. D, et al., Sci Adv 2020, 6, eabe0751). Mpro and PLpro are involved in the proteolytic digestion of the viral polyproteins pp1a and pp1ab, yielding individual functional viral proteins for the replication complex formation. PLpro cleaves at three sites with the recognition sequence “LXGG↓XX” (Rut, W., et al., Sci Adv 2020, 6). PLpro has been shown to play additional roles in dysregulating host immune response and impairing the host type I interferon antiviral effect through its deubiquitinating and deISG15ylating (interferon-induced gene 15) activities, respectively (Freitas, B. T., et al., ACS Infect Dis 2020, 6, 2099-2109; Shin, D., et al., Nature 2020, 587, 657-662; and Klemm, T., et al., Embo J 2020, 39, e106275). SARS-CoV-2 PLpro cleaves ISG15 and polyubiquitin modifications from cellular proteins, and inhibition of PLP led to the accumulation of ISG15-conjugates and poly-ubiquitin-conjugates (Fu, Z., et al., Nat Commun 2021, 12, 488). While SARS-CoV PLpro prefers ubiquitinated substrates, SARS-CoV-2 PLpro prefers the ISGlyated proteins as substrates (Freitas, B. T., et al., ACS Infect Dis 2020, 6, 2099-2109; Shin, D., et al., Nature 2020, 587, 657-662; and Klemm, T., et al., Embo J 2020, 39, e106275). PLpro is part of a membrane anchored multi-domain protein named non-structural protein 3 (nsp-3), an essential component of the replicase-transcriptase complex. The pleiotropic roles of SARS-CoV-2 PLpro make it a promising antiviral drug target. Substantial morbidity and mortality associated with COVID-19 infection is caused by cytokine storm (Berlin, D. A.; Gulick, R. M.; Martinez, F. J., N Engl J Med 2020, 383, 2451-2460), and suppressing host immune response using dexamethasone and baricitinib has been shown to provide therapeutic benefits in the treatment of severe infections (Kalil, A. C., et al., New England Journal of Medicine 2020, 384, 795-807; and New England Journal of Medicine 2020, 384, 693-704).
Significant progress has been made in developing SARS-CoV-2 Mpro inhibitors (Ma, C., et al., Cell Res 2020, 30, 678-692; Sacco, M. D, et al., Sci Adv 2020, 6, eabe0751; Qiao, J., et al., Science 2021, 371, 1374-1378; Zhang, L., et al., Science 2020, 368, 409-412) and the Pfizer's nirmatrelvir is approved by FDA. In comparison, PLpro represents a more challenging drug target, and GRL0617 remains one of the most potent PLpro inhibitors reported to date despite several high-throughput screening and medicinal chemistry optimization campaigns (Rut, W., et al., Sci Adv 2020, 6; Freitas, B. T., et al., ACS Infect Dis 2020, 6, 2099-2109; Shin, D., et al., Nature 2020, 587, 657-66; Klemm, T., et al., Embo J 2020, 39, e106275; Osipiuk, J., et al., Nat Commun 2021, 12, 743; and Ratia, K., et al., Proc. Natl. Acad. Sci. U.S.A 2008, 105, 16119-24). GRL0617 was originally developed as a deubiquitinase inhibitor and was later identified as a SARS-CoV PLpro inhibitor through a high-throughput screening (Ratia, K., et al., Proc. Natl. Acad. Sci. U.S.A 2008, 105, 16119-24). As SARS-CoV-2 and SARS-CoV PLpro share a sequence identity of 83% and similarity of 90%, GRL0617 was also repurposed for SARS-CoV-2 PLpro and it was reported to inhibit SARS-CoV-2 PLpro with IC50 values of around 2 μM and SARS-CoV-2 viral replication with EC50 values around 20 μM from multiple studies (Klemm, T., et al., Embo J 2020, 39, e106275; Fu, Z., et al., Nat Commui 2021, 12, 488; Osipiuk, J., et al., Nat (Commun 2021, 12, 743; and Gao, X., et al., Acta Pharm Sin B 2021, 11, 237-245). Currently there is a need for SARS-CoV-2 antiviral agents that can be used alone or in combination with other drugs (e.g., protease inhibitors).
The invention provides SARS-CoV-2 antiviral agents that can be used alone or in combination with other drugs (e.g., antiviral agents, such as, for example, protease inhibitors).
Accordingly, in one embodiment, the invention provides a compound of the invention, which is a compound of formula (I):
or a salt thereof, wherein:
The invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
The invention also provides a method for promoting an antiviral effect in an animal, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal.
The invention also provides a method for inhibiting a papain-like protease in an animal in need thereof, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal.
The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.
The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a viral infection.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a viral infection in an animal.
The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.
The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
The term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8 means one to eight carbons). Examples include (C1-C5)alkyl, (C2-C5)alkyl, C1-C6)alkyl, (C2-C6)alkyl and (C3-C6)alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and and higher homologs and isomers.
The term “alkoxy” refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).
The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C5)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms, about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.
The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
The term “heterocycle” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, and 1,4-dioxane. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle comprising 1 to 3 nitrogen atoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle comprising 1 to 2 nitrogen atoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle comprising 1 nitrogen atom.
The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur, “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl. In one embodiment the heteroaryl is a 5-membered heteroaryl. In one embodiment the heteroaryl is a 6-membered heteroaryl. In one embodiment the heteroaryl is a 5-membered heteroaryl that comprises one or two heteroatoms selected from O, N, and S. In one embodiment the heteroaryl is a 6-membered heteroaryl that comprises one or two heteroatoms selected from O, N, and S.
As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006.
As used herein a wavy line “” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.
The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention,
The phrase “therapeutically effective amount” or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
The term “animal” includes mammals.
The term “mammal” as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human.
The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient In one embodiment, the patient is a human patient. In one embodiment, the mammal is a human.
The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a —CH3 group may be substituted with —CD3.
The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.
Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded.
Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(C1-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C1-C6)alkanoyl can be formyl, acetyl, propanoyl or butanoyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
A specific compound or salt of formula (I) is a compound of formula (Ia):
or a salt thereof A specific compound or salt of formula (I) is a compound of formula (Ib):
or a salt thereof.
In one embodiment, R1 is halo.
In one embodiment, R1 is NRaRb.
In one embodiment, R1 is phenyl that is optionally substituted with one or more groups Rx independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, NRaRb, oxo, 5-membered heteroaryl, 6-membered heterocycle, —C(═O)NRaRb, 4-membered heterocycle, 5-membered heterocycle, methylenedioxy, and (C1-C6)alkyl sulfonyl, wherein any Rx is optionally substituted with one or more groups Ry independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, NRcRd—C(═O)NRcRd (C3-C6)cycloalkyl, carboxy, 6-membered heterocycle, and phenyl, wherein any Ry is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, and halo.
In one embodiment, R1 is a 5-membered heteroaryl that is optionally substituted with one or more groups Rx independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, NRaRb, oxo, 5-membered heteroaryl, 6-membered heterocycle, —C(═O)NRaRb, 4-membered heterocycle, 5-membered heterocycle, methylenedioxy, and (C1-C6)alkyl sulfonyl, wherein any Rx is optionally substituted with one or more groups Ry independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, NRcRd—C(═O)NRcRd (C3-C6)cycloalkyl, carboxy, 6-membered heterocycle, and phenyl, wherein any Ry is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, and halo.
In one embodiment, R1 is a 6-membered heteroaryl that is optionally substituted with one or more groups Rx independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, NRaRb, oxo, 5-membered heteroaryl, 6-membered heterocycle, —C(═O)NRaRb, 4-membered heterocycle, 5-membered heterocycle, methylenedioxy, and (C1-C6)alkyl sulfonyl, wherein any Rx is optionally substituted with one or more groups Ry independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, NRcRd—C(═O)NRcRd (C3-C6)cycloalkyl, carboxy, 6-membered heterocycle, and phenyl, wherein any Ry is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, and halo.
In one embodiment, R1 is a 5-membered heterocycle that is optionally substituted with one or more groups Rx independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, NRaRb, oxo, 5-membered heteroaryl, 6-membered heterocycle, —C(═O)NRaRb, 4-membered heterocycle, 5-membered heterocycle, methylenedioxy, and (C1-C6)alkyl sulfonyl, wherein any Rx is optionally substituted with one or more groups Ry independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, NRcRd—C(═O)NRcRd (C3-C6)cycloalkyl, carboxy, 6-membered heterocycle, and phenyl, wherein any Ry is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, and halo.
In one embodiment, R1 is a 6-membered heterocycle that is optionally substituted with one or more groups Rx independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, NRaRb, oxo, 5-membered heteroaryl, 6-membered heterocycle, —C(═O)NRaRb, 4-membered heterocycle, 5-membered heterocycle, methylenedioxy, and (C1-C6)alkyl sulfonyl, wherein any Rx is optionally substituted with one or more groups Ry independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, NRcRd—C(═O)NRcRd (C3-C6)cycloalkyl, carboxy, 6-membered heterocycle, and phenyl, wherein any Ry is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, and halo.
In one embodiment, R1 is a 9-membered bicyclic heterocycle that is optionally substituted with one or more groups Rx independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, NRaRb, oxo, 5-membered heteroaryl, 6-membered heterocycle, —C(═O)NRaRb, 4-membered heterocycle, 5-membered heterocycle, methylenedioxy, and (C1-C6)alkyl sulfonyl, wherein any Rx is optionally substituted with one or more groups Ry independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, NRcRd—C(═O)NRcRd (C1-C6)cycloalkyl, carboxy, 6-membered heterocycle, and phenyl, wherein any Ry is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, and halo.
In one embodiment, R1 is a 9-membered bicyclic heteroaryl that is optionally substituted with one or more groups Rx independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, NRaRb, oxo, 5-membered heteroaryl, 6-membered heterocycle, —C(═O)NRaRb, 4-membered heterocycle, 5-membered heterocycle, methylenedioxy, and (C1-C6)alkyl sulfonyl, wherein any Rx is optionally substituted with one or more groups Ry independently selected from the group consisting of halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, NRcRd—C(═O)NRcRd (C3-C6)cycloalkyl, carboxy, 6-membered heterocycle, and phenyl, wherein any Ry is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, and halo.
In one embodiment, R1 is selected from the group consisting of chloro,
In one embodiment, R1 is selected from the group consisting of:
In one embodiment, R2 is —ORe.
In one embodiment, R2 is —SRe.
In one embodiment, R2 is —NRgRh.
In one embodiment, R2 is —OCH2CH2N(CH3)2.
In one embodiment, R2 is selected from the group consisting of amino, methylamino, dimethylamino, 2-aminoethoxy,
In one embodiment, R2 is selected from the group consisting of
In one embodiment, A is a 9-membered bicyclic heteroaryl that is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from halo.
In one embodiment, A is a 90-membered bicyclic heteroaryl that is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from halo.
In one embodiment, A is a 9-membered bicyclic heteroaryl.
In one embodiment, A is a 10-membered bicyclic heteroaryl.
In one embodiment, A is:
wherein * designates the point of attachment to R1 and ** designates the point of attachment to:
In one embodiment, A is selected from the group consisting of:
wherein * designates the point of attachment to R1 and ** designates the point of attachment to:
In one embodiment, A is:
wherein * designates the point of attachment to R1 and ** designates the point of attachment to:
In one embodiment, A is selected from the group consisting of:
wherein * designates the point of attachment to R1 and * * designates the point of attachment to:
In one embodiment, a compound of formula (I) or salt thereof, wherein:
In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other agents that are useful for the treatment of viral infections (e.g., protease inhibitors). Examples of such agents include nirmatrelvir, ensitrelvir, molnupiravir, VV116, and remdesivir. Accordingly, in one embodiment the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier. The invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat a viral infection.
The invention will now be illustrated by the following non-limiting Examples.
To a solution of compound methyl 5-hydroxy-2-methylbenzoate (1.0 equiv) in dry toluene in a sealed tube 2-(dimethylamino)ethan-1-ol (1.5 equiv) and cyanomethylene trimethyl-phosphorane (CMMP) (2.0 equiv) were added. The reaction mixture was degassed and purged with argon, and then the tube was sealed and heated to 110° C. overnight. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=20:1) to provide the desired product A-1 for the next step without purification.
A solution of methyl 5-(2-(dimethylamino)ethoxy)-2-methylbenzoate A-1 (4.00 g, 16.8 mmol, 1.0 equiv) in HCl (2 M aqueous, 30 mL) was stirred at 110° C. for 16 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature, basified to pH 6 using NaOH (2 M aqueous) the mixture was concentrated under vacuum to give the desired product 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (A-2, 3.8 g, 90%) as a white solid.
Prepared as described in the General procedure for ester hydrolysis above. White solid, 90% yield, 1H NMR (400 MHz, CD3OD) δ 7.03 (d, J=2.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.72 (dd, J=8.4, 2.8 Hz, 1H), 4.10 (t, J=4.9 Hz, 2H), 3.31 (t, J=5.0 Hz, 2H), 2.71 (s, 6H), 2.24 (s, 3H). 13C NMR (101 MHz, CD3OD) δ 175.99, 156.81, 132.84, 130.39, 116.50, 115.35, 63.65, 57.41, 43.86, 20.10 LCMS calcd for C15H18NO3 (M+H+): 224.1208; Found: 224.1209.
To a solution of 2-chloroquinoline-4-carboxylic acid (1.0 equiv), N,O-dimethylhydroxylamine hydrochloride (1.2 equiv), HOBt (1.3 equiv) and EDCI (1.3 equiv) in DCM (0.1 M) was added dropwise of triethylamine (3.0 equiv) at 0° C. The mixture was stirred at rt for 24 hours. After the reaction was completed, the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the product A-3 for the next step without purification.
To a solution of 2-chloro-N-methoxy-N-methylquinoline-4-carboxamide (A-3, 1.0 equiv) in dry ether at −78° C. under N2, the methyl magnesium bromide (3 M solution in diethyl ether, 2.0 equiv) was added slowly. After warming to room temperature and stirred for 2 hours, the reaction mixture was quenched with ice-cold saturated NH4Cl and washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude residue, which was purified by silica gel column chromatography (Hexanes/EtOAc=5:1) to provide the desired product A-4. 1-(2-chloroquinolin-4-yl)ethan-1-one (A-4) White solid, 75% yield for two steps. 1H NMR (400 MHz, CDCl3) δ 8.48-8.33 (m, 1H), 8.07 (dd, J=8.5, 1.3 Hz, 1H), 7.79 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.65 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.60 (s, 1H), 2.75 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 199.72, 150.10, 148.96, 145.72, 131.03, 129.08, 128.49, 125.56, 122.55, 121.27, 30.07. LCMS calcd for C11H9ClNO (M+H+): 206.0294; Found: 206.0297.
To a solution of 1-(2-chloroquinolin-4-yl)ethan-1-one (20.0 g, 97.5 mmol) in toluene (500.0 mL) under N2 were added (S)-2-methylpropane-2-sulfinamide (35.4 g, 292.5 mmol) and Ti(O-iPr)4 (110.9 g, 390.0 mmol) at 20° C. The reaction mixture was stirred at 100° C. under N2 for 15 h. LCMS showed a peak with a desired mass. The reaction mixture was then evaporated in vacuo to afford a crude, which was purified by silica gel chromatography using a Biotage (330 g column, petroleum ether/ethyl acetate=1/0 to 0/1) to afford (A-5, 27.3 g) as a yellow oil.
To a solution of (S)—N-(1-(2-chloroquinolin-4-yl)ethylidene)-2-methylpropane-2-sulfinamide (27.3 g, 88.61 mmol) in THF (500 mL) under N2, was added L-selectride (159.5 mL, 1 M, 159.5 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. under N2 for 5 h before being quenched by 100 mL sat. aq. NH4Cl at 0° C. The reaction mixture was then partitioned between ethyl acetate and water (500/500 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (500 mL). The combined organic layer was washed with brine, dried and evaporated in vacuo before being purified by silica gel chromatography using a Biotage (330 g column, petroleum ether/ethyl acetate=1/0 to 0/1, ethyl acetate/methanol=1/0 to 0/1) to afford (A-6, 20.6 g). White solid, 75% yield. 1H NMR (400 MHz, CDCl3) δ 8.10-7.97 (m, 2H), 7.74 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.58 (ddd, J=8.5, 6.9, 1.3 Hz, 1H), 7.47 (s, 1H), 5.29 (qd, J=6.6, 2.9 Hz, 1H), 3.80 (d, J=3.0 Hz, 1H), 1.66 (d, J=6.6 Hz, 3H), 1.28 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 152.39, 150.86, 148.29, 130.56, 129.56, 127.35, 124.21, 122.86, 119.19, 55.98, 48.51, 22.64, 21.89. LCMS calcd for C15H20ClN2OS (M+H+): 311.0907; Found: 311.0909.
To a solution of (S)—N—((R)-1-(2-chloroquinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (14.5 g, 46.7 mmol) in MeOH (100 mL) was added HCl/MeOH (58.4 mL, 233.5 mmol, 4M in MeOH). The reaction was stirred at 20° C. for 8 h. TLC (petroleum ether/ethyl acetate=3/1) showed that starting material was consumed and a new spot was detected. The mixture was filtered and the filter cake was dissolved in water (20 mL). The solution was basified with sat. aq. NaHCO3 to pH=8 and extracted with dichloromethane/MeOH (v/v=10/1, 5 Ř200 mL). The organic layers were combined, dried over Na2SO4, filtered, evaporated under reduced pressure to A-7 as a yellow liquid, which was used for the next step without further purification.
5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (1.1 equiv), HATU (1.1 equiv) and DIPEA (3.0 equiv) were dissolved in DMF (0.2 M) and stirred for 15 min. After that ((R)-1-(2-chloroquinolin-4-yl)ethan-1-amine (A-9, 1.0 equiv) was added and stirred at room temperature overnight. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with EtOAc and was then washed with saturated aq. NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by Prep-HPLC to give the final product. White solid, 61% yield. 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.91-7.78 (m, 1H), 7.71 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.56 (s, 1H), 7.19-7.13 (m, 1H), 6.97-6.90 (m, 2H), 5.96 (q, J=7.0 Hz, 1H), 4.11 (t, J=5.3 Hz, 2H), 2.81 (t, J=5.4 Hz, 2H), 2.37 (s, 6H), 2.27 (s, 3H), 1.68 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.52, 156.52, 154.15, 150.60, 147.90, 136.81, 131.56, 130.56, 128.31, 127.50, 127.17, 124.77, 123.43, 118.25, 115.65, 113.06, 65.15, 57.57, 45.04, 44.32, 19.70, 17.44. LCMS calcd for C23H27ClN3O2 (M+H+): 412.1714; Found: 412.1717.
To a solution of compound (R)—N-(1-(2-chloroquinolin-4-yl)ethyl)-5-(2-(dimethylamino)-ethoxy)-2-methylbenzamide (1.0 equiv) in dioxane/H2O (4:1) in a microwave reaction vial was added corresponding boronic acid or ester (1.2 equiv) and potassium carbonate (1.8 equiv). The mixture was purged with nitrogen for 5 min. Then Pd(dppf)Cl2 (0.1 equiv) was added, and the solution was heated in the biotage microwave reactor at 130° C. for 90 min. The reaction mixture was diluted with EtOAc and extracted with aqueous NaHCO3 solution and brine. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by Prep-HPLC to give the final product.
(R)-5-(2-(dimethylamino)ethoxy)-2-methyl-N-(1-(2-(thiophen-2-yl)quinolin-4-yl)ethyl) benzamide. White solid, 72% yield. 1H NMR (400 MHz, CD3OD) δ 8.25 (d, J=8.5 Hz, 1H), 8.14-8.00 (m, 2H), 7.85 (d, J=3.7 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.61 (t, J=6.7 Hz, 2H), 7.23-7.12 (m, 2H), 6.96 (dt, J=8.1, 2.8 Hz, 2H), 6.02 (q, J=7.0 Hz, 1H), 4.11 (t, J=5.3 Hz, 2H), 2.86 (t, J=5.3 Hz, 2H), 2.41 (s, 6H), 2.29 (s, 3H), 1.72 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.56, 156.45, 152.28, 150.66, 148.21, 144.72, 137.15, 131.52, 129.62, 129.12, 128.56, 127.86, 127.49, 126.16, 126.09, 124.96, 122.98, 115.71, 113.78, 112.89, 64.89, 57.45, 45.04, 44.14, 19.91, 17.39. LCMS calcd for C27H30N3O2S (M+H+): 460.6080; Found: 460.6.
White solid, δ 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J=8.5 Hz, 1H), 8.10-7.98 (m, 2H), 7.85 (d, J=3.7 Hz, 1H), 7.80-7.71 (m, 1H), 7.61 (t, J=6.8 Hz, 2H), 7.27-7.09 (m, 2H), 7.01-6.90 (m, 2H), 6.01 (q, J=7.0 Hz, 1H), 4.10 (t, J=5.4 Hz, 2H), 2.82 (t, J=5.4 Hz, 2H), 2.38 (s, 6H), 2.28 (s, 3H), 1.72 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.58, 156.49, 152.29, 150.68, 148.21, 144.71, 137.12, 131.52, 129.62, 129.11, 128.56, 127.87, 127.46, 126.16, 126.11, 124.96, 122.98, 115.72, 113.80, 112.90, 65.07, 57.51, 45.05, 44.24, 19.92, 17.39. LCMS calcd for C27H30N3O2S (M+H+): 460.6080; Found: 460.1.
White solid 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.41 (s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.81-7.72 (m, 1H), 7.66-7.61 (m, 1H), 7.19-7.12 (m, 1H), 6.95 (d, J=7.1 Hz, 2H), 6.03 (q, J=7.0 Hz, 1H), 4.13 (t, J=5.3 Hz, 2H), 2.94 (t, J=5.2 Hz, 2H), 2.47 (s, 6H), 2.26 (s, 3H), 1.73 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.50, 156.35, 151.03, 150.50, 148.18, 140.56, 137.12, 131.54, 131.49, 129.75, 128.86, 127.61, 126.78, 126.37, 125.70, 125.00, 123.11, 115.67, 115.59, 115.26, 113.02, 110.89, 108.40, 64.53, 57.31, 45.02, 43.93, 43.90, 19.83, 17.33. 19F NMR (376 MHz, CD3OD) δ −96.32, −96.48. LCMS calcd for C27H30F2N5O2 (M+H+): 494.5588; Found: 494.6.
White solid 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.77 (dd, J=8.3, 4.6 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.32 (d, J=3.5 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.98-6.88 (m, 2H), 6.67 (dd, J=3.5, 1.8 Hz, 1H), 6.00 (q, J=7.0 Hz, 1H), 4.11 (t, J=5.3 Hz, 2H), 2.85 (t, J=5.3 Hz, 2H), 2.40 (s, 6H), 2.28 (s, 3H), 1.71 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.57, 156.44, 153.18, 151.09, 148.80, 147.96, 144.44, 137.11, 131.51, 129.82, 128.71, 127.55, 126.36, 124.98, 123.10, 115.69, 113.38, 112.97, 112.16, 110.28, 64.94, 57.48, 47.42, 47.21, 46.99, 45.10, 44.18, 19.80, 17.40. LCMS calcd for C27H30N3O3 (M+H+): 444.5470; Found: 444.2.
White solid 1H NMR (400 MHz, CD3OD) δ 9.10 (s, 1H), 8.58 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.07 (d, J=7.7 Hz, 2H), 7.78 (t, J=7.6 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.01-6.92 (m, 2H), 6.03 (q, J=6.9 Hz, 1H), 4.15 (t, J=5.3 Hz, 2H), 2.95 (t, J=5.3 Hz, 2H), 2.48 (s, 6H), 2.27 (s, 3H), 1.74 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.56, 156.46, 156.39, 151.16, 149.94, 148.34, 141.20, 140.83, 137.10, 131.55, 129.86, 129.44, 127.60, 126.81, 125.24, 123.08, 115.77, 114.18, 113.06, 113.02, 64.67, 57.36, 57.35, 45.11, 44.00, 19.94, 17.36. LCMS calcd for C26H29N4O2S (M+H+): 461.5960; Found: 461.6.
White solid 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.76 (t, =7.7 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 6.98-6.92 (m, 2H), 6.02 (q, J=7.0 Hz, 1H), 4.40 (t, J=5.1 Hz, 2H), 4.13 (t, J=5.3 Hz, 2H), 3.80 (t, J=5.1 Hz, 2H), 3.34 (s, 3H), 2.92 (t, J=5.3 Hz, 2H), 2.46 (s, 6H), 2.27 (s, 3H), 1.73 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.51, 156.36, 151.87, 150.78, 148.15, 137.89, 137.16, 131.53, 130.29, 129.60, 128.40, 127.62, 125.84, 124.66, 123.10, 123.05, 115.70, 115.11, 113.01, 70.56, 64.57, 57.71, 57.32, 51.90, 45.02, 43.96, 19.88, 17.36. LCMS calcd for C29H36N5O3 (M+H+): 502.6310; Found: 502.6.
White solid. 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.45 (s, 1H), 8.33-8.23 (m, 2H), 8.08 (ddd, J=8.4, 6.9, 1.1 Hz, 1H), 7.90 (ddd, J=8.3, 7.0, 1.1 Hz, 1H), 7.21 (d, J1=8.4 Hz, 1H), 7.09 (d, J=2.7 Hz, 1H), 7.03 (dd, J=8.4, 2.8 Hz, 1H), 6.07 (q, J=7.0 Hz, 1H), 4.36 (t, J=5.0 Hz, 2H), 4.06 (s, 3H), 3.63-3.56 (m, 2H), 2.99 (s, 6H), 2.26 (s, 3H), 1.79 (d, J=7.1 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.55, 161.27, 155.60, 148.31, 139.42, 138.46, 136.55, 134.06, 133.46, 131.82, 128.70, 128.67, 124.41, 124.36, 120.76, 116.27, 116.02, 114.89, 113.36, 62.03, 56.29, 46.29, 42.50, 38.52, 19.52, 17.48.
LCMS calcd for C27H32N5O2 (M+H+): 458.5780; Found: 458.6.
White solid. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.67 (s, 1H), 8.83 (d, J=7.6 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.15 (s, 1H), 6.95-6.89 (m, 2H), 6.47 (s, 1H), 5.49 (p, J=7.1 Hz, 1H), 4.24 (t, J=4.9 Hz, 4H), 3.45 (q, J=5.1 Hz, 3H), 2.79 (d, J=3.9 Hz, 5H), 2.18 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.51, 158.83, 155.68, 151.07, 138.62, 138.17, 134.03, 132.06, 131.00, 130.68, 128.32, 126.82, 124.71, 124.11, 118.77, 116.08, 115.98, 114.14, 62.84, 55.93, 54.61, 44.98, 43.29, 21.44, 18.78, 6.83. LCMS calcd for C29H34N5O2 (M+H1): 484.6160; Found: 484.2.
White solid 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 9.91 (s, 1H), 9.10 (d, J=6.9 Hz, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.29 (dd, J=16.1, 8.4 Hz, 2H), 8.12 (t, J=8.0 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.64 (q, J=7.2, 6.4 Hz, 2H), 7.52 (s, 1H), 7.34 (t, J=6.4 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.09-6.73 (m, 2H), 5.81 (p, J=7.0 Hz, 1H), 4.33 (t, J=5.0 Hz, 2H), 3.56-3.51 (m, 2H), 2.87 (s, 6H), 2.24 (s, 3H), 1.62 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.58, 158.80, 158.47, 155.64, 152.29, 152.12, 137.72, 132.08, 131.71, 128.69, 124.43, 122.35, 118.91, 118.58, 116.03, 114.92, 114.51, 110.42, 62.91, 55.90, 45.48, 43.30, 20.83, 19.01. LCMS calcd for C28H32N5O2 (M+H+): 470.5890; Found: 470.2.
White solid. 11H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.39 (d, J=9.3 Hz, 2H), 8.20-8.08 (m, 1H), 8.04 (s, 1H), 7.88 (ddd, J=8.4, 6.8, 1.3 Hz, 1H), 7.73 (ddd, J=8.3, 6.9, 1.2 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.04 (d, J=8.2 Hz, 2H), 6.06 (td, J=7.2, 4.7 Hz, 1H), 5.13 (q, J=8.7 Hz, 2H), 4.45-4.30 (m, 2H), 3.65-3.55 (m, 2H), 2.98 (s, 6H), 2.29 (s, 3H), 1.77 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.37, 155.56, 153.17, 150.48, 146.17, 139.48, 137.17, 131.97, 131.72, 130.64, 128.49, 127.05, 126.71, 124.78, 123.35, 122.84, 115.82, 115.42, 113.19, 61.99, 56.27, 45.37, 42.48, 19.77, 17.39. LCMS calcd for C28H31F3N5O2 (M+H+): 526.5762; Found: 526.6.
White solid 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.87-7.78 (m, 1H), 7.71 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.56 (s, 1H), 7.20-7.11 (m, 1H), 6.98-6.91 (m, 2H), 5.96 (q, J=7.0 Hz, 1H), 4.11 (t, J=5.3 Hz, 2H), 2.81 (t, J=5.4 Hz, 2H), 2.37 (s, 6H), 2.27 (s, 3H), 1.68 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.52, 156.52, 154.15, 150.60, 147.90, 136.81, 131.56, 130.56, 128.31, 127.50, 127.17, 124.77, 123.43, 118.25, 115.65, 113.06, 65.15, 57.57, 45.04, 44.32, 19.70, 17.44. LCMS calcd for C23H27ClN3O2 (M+H+): 412.9300; Found: 413.0.
White solid 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 8.28-8.22 (m, 1H), 8.05 (dd, J=8.5, 1.2 Hz, 1H), 7.86 (s, 1H), 7.75 (ddd, J=8.3, 6.8, 1.3 Hz, 1H), 7.59 (ddd, J=8.3, 6.8, 1.3 Hz, 1H), 7.19-7.11 (m, 1H), 6.93 (d, J=6.8 Hz, 2H), 6.01 (q, J=7.0 Hz, 1H), 4.35 (t, J=6.6 Hz, 2H), 4.07 (t, J=5.4 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 2.74 (t, J=5.4 Hz, 2H), 2.32 (s, 6H), 2.30 (s, 6H), 2.26 (s, 3H), 1.72 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.56, 156.61, 151.83, 150.68, 148.16, 137.93, 137.10, 131.48, 130.00, 129.59, 128.42, 127.34, 125.84, 124.69, 123.19, 123.07, 115.60, 115.12, 112.99, 65.37, 58.33, 57.64, 49.67, 44.98, 44.41, 44.21, 19.82, 17.36. LCMS calcd for C30H39N6O2 (M+H+): 515.6740; Found: 515.3.
White solid 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.95 (d, J=7.5 Hz, 2H), 6.86 (d, J=2.1 Hz, 1H), 6.04 (q, J=7.0 Hz, 1H), 4.34 (s, 3H), 4.12 (t, J=5.3 Hz, 2H), 2.88 (t, J=5.3 Hz, 2H), 2.43 (s, 6H), 2.27 (s, 3H), 1.72 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 174.46, 160.40, 154.97, 153.14, 151.73, 145.44, 141.75, 141.00, 135.48, 133.72, 133.69, 131.42, 130.97, 128.67, 126.94, 120.51, 119.61, 116.92, 110.98, 68.87, 61.40, 49.00, 48.12, 42.58, 23.89, 21.36. LCMS calcd for C27H32N5O2 (M+H+): 458.5780; Found: 458.5.
White solid. 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.76 (dd, J=8.5, 7.0 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.95 (d, J=7.4 Hz, 2H), 6.02 (q, J=7.0 Hz, 1H), 4.66-4.57 (m, 1H), 4.12 (t, J=5.3 Hz, 2H), 2.89 (t, J=5.3 Hz, 2H), 2.44 (s, 6H), 2.27 (s, 3H), 1.73 (d, J=7.0 Hz, 3H), 1.57 (d, J=6.7 Hz, 6H). 13C NMR (101 MHz, CD3OD) δ 170.48, 156.43, 152.00, 150.67, 148.15, 137.43, 137.15, 131.53, 129.60, 128.37, 127.49, 127.05, 125.81, 124.66, 123.08, 122.71, 115.61, 115.17, 113.03, 64.83, 57.43, 54.21, 44.99, 44.12, 21.72, 19.88, 17.41. LCMS calcd for C29H36N5O2 (M+H+): 486.6320; Found: 486.6.
White solid. 1H NMR (400 MHz, CD3OD) δ 8.27 (d, J=8.5 Hz, 2H), 8.14 (d, J=8.4 Hz, 1H), 7.82-7.74 (m, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.18-7.08 (m, 2H), 6.99 (d, J=2.8 Hz, 1H), 6.92 (dd, J=8.4, 2.8 Hz, 1H), 6.01 (q, J=7.0 Hz, 1H), 4.14 (t, J=5.5 Hz, 2H), 2.93 (t, J=5.4 Hz, 2H), 2.46 (s, 6H), 2.27 (s, 3H), 1.72 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.63, 156.42, 150.63, 148.03, 137.15, 131.45, 129.51, 129.02, 127.57, 126.37, 125.41, 123.07, 115.90, 114.72, 112.76, 103.84, 64.92, 57.46, 45.01, 44.13, 19.68, 17.32. LCMS calcd for C26H30N5O2 (M+H+): 444.5510; Found: 444.5.
White solid. 1H NMR (400 MHz, CD3OD) δ 8.32 (d, J=8.5 Hz, 1H), 8.08 (d, J=9.1 Hz, 2H), 7.87 (dd, J=3.9, 1.5 Hz, 1H), 7.81 (ddd, J=8.3, 6.8, 1.3 Hz, 1H), 7.66 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.41 (dd, J=4.0, 1.8 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.05-6.98 (m, 2H), 6.02 (q, 0.1=6.9 Hz, 1H), 4.65 (d, J=2.1 Hz, 2H), 4.33 (t, J=4.9 Hz, 2H), 3.91 (s, 2H), 3.60-3.55 (m, 2H), 3.35 (s, 2H), 2.96 (s, 6H), 2.28 (d, J=1.5 Hz, 3H), 1.74 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.38, 160.72, 160.36, 155.56, 152.19, 150.82, 147.52, 147.11, 137.20, 133.59, 132.56, 131.72, 130.39, 128.47, 126.95, 125.23, 123.23, 115.82, 113.80, 113.18, 63.58, 61.99, 56.26, 54.07, 51.17, 45.36, 42.48, 19.82, 17.49. LCMS calcd for C32H39N4O3S (M+H+): 559.7410; Found: 559.7.
White solid 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.77 (dd, J=8.3, 4.6 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.32 (d, J=3.5 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.98-6.88 (m, 2H), 6.67 (dd, J=3.5, 1.8 Hz, 1H), 6.00 (q, J=7.0 Hz, 1H), 4.11 (t, J=5.3 Hz, 2H), 2.85 (t, J=5.3 Hz, 2H), 2.40 (s, 6H), 2.28 (s, 3H), 1.71 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.57, 156.44, 153.18, 151.09, 148.80, 147.96, 144.44, 137.11, 131.51, 129.82, 128.71, 127.55, 126.36, 124.98, 123.10, 115.69, 113.38, 112.97, 112.16, 110.28, 64.94, 57.48, 47.42, 47.21, 46.99, 45.10, 44.18, 19.80, 17.40. LCMS calcd for C27H30N3O3 (M+H+): 444.5470; Found: 444.2.
White solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.41 (s, 1H), 8.34-8.24 (m, 1H), 8.09 (dd, J=8.5, 1.2 Hz, 1H), 7.93 (s, 1H), 7.82-7.73 (m, 1H), 7.69-7.55 (m, 2H), 7.19-7.09 (m, 1H), 6.94 (tt, J=4.2, 2.2 Hz, 2H), 6.03 (q, J=7.0 Hz, 1H), 4.12 (td, J=5.2, 2.1 Hz, 2H), 2.89 (t, J=5.3 Hz, 2H), 2.44 (d, J=4.6 Hz, 6H), 2.27 (d, J=3.4 Hz, 3H), 1.73 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 156.35, 151.03, 140.56, 131.54, 129.75, 128.86, 127.61, 126.78, 126.37, 125.70, 125.00, 123.11, 115.67, 115.26, 113.02, 64.53, 57.31, 47.39, 47.18, 46.97, 45.02, 43.93, 19.83, 17.33. LCMS calcd for C27H30F2N5O2 (M+H+): 494.5588; Found: 494.5.
White solid. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 6.98-6.92 (m, 2H), 6.02 (q, J=7.0 Hz, 1H), 4.40 (t, J=5.1 Hz, 2H), 4.13 (t, J=5.3 Hz, 2H), 3.80 (t, J=5.1 Hz, 2H), 3.34 (s, 3H), 2.92 (t, J=5.3 Hz, 2H), 2.46 (s, 6H), 2.27 (s, 3H), 1.73 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.51, 156.36, 151.87, 150.78, 148.15, 137.89, 137.16, 131.53, 130.29, 129.60, 128.40, 127.62, 125.84, 124.66, 123.10, 123.05, 115.70, 115.11, 113.01, 70.56, 64.57, 57.71, 57.32, 51.90, 45.02, 43.96, 19.88, 17.36. LCMS calcd for C29H36N5O3 (M+H+): 501.6310; Found: 501.6.
White solid. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.67 (s, 1H), 8.83 (d, J=7.6 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.15 (s, 1H), 6.95-6.89 (m, 2H), 6.47 (s, 1H), 5.49 (p, J=7.1 Hz, 1H), 4.24 (t, J=4.9 Hz, 4H), 3.45 (q, J=5.1 Hz, 3H), 2.79 (d, J=3.9 Hz, 5H), 2.18 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.51, 158.83, 155.68, 151.07, 138.62, 138.17, 134.03, 132.06, 131.00, 130.68, 128.32, 126.82, 124.71, 124.11, 118.77, 116.08, 115.98, 114.14, 62.84, 55.93, 54.61, 44.98, 43.29, 21.44, 18.78, 6.83. LCMS calcd for C29H34N5O2 (M+H+): 484.6160; Found: 484.6.
White solid 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.95 (d, J=7.5 Hz, 2H), 6.86 (d, J=2.1 Hz, 1H), 6.04 (q, J=7.0 Hz, 1H), 4.34 (s, 3H), 4.12 (t, J=5.3 Hz, 2H), 2.88 (t, J=5.3 Hz, 2H), 2.43 (s, 6H), 2.27 (s, 3H), 1.72 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 174.46, 160.40, 154.97, 153.14, 151.73, 145.44, 141.75, 141.00, 135.48, 133.72, 133.69, 131.42, 130.97, 128.67, 126.94, 120.51, 119.61, 116.92, 110.98, 68.87, 61.40, 49.00, 48.12, 42.58, 23.89, 21.36. LCMS calcd for C27H32N5O2 (M+H+): 458.5780, Found: 458.5.
White solid. 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.04 (d, J=7.6 Hz, 1H), 8.61 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.28 (s, 1H), 8.16-8.02 (m, 2H), 7.88 (p, J=7.1, 6.4 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.00 (d, J=6.8 Hz, 2H), 5.94 (q, J=7.1 Hz, 1H), 4.30 (dt, J=16.6, 5.1 Hz, 4H), 3.82 (t, J=5.3 Hz, 2H), 3.51 (q, J=4.7 Hz, 2H), 2.87 (s, 6H), 2.22 (s, 3H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.54, 158.94, 158.59, 155.70, 138.71, 138.09, 132.06, 131.82, 131.53, 128.35, 127.10, 124.60, 124.26, 116.14, 116.09, 114.13, 62.88, 60.23, 55.90, 55.17, 45.12, 43.27, 21.47, 18.81. LCMS calcd for C28H34N5O3 (M+H+): 487.6040; Found: 487.6.
White solid. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.10 (d, J=7.6 Hz, 1H), 8.54 (s, 2H), 8.43 (d, J=8.5 Hz, 1H), 8.28-8.10 (m, 2H), 7.94 (t, J=7.7 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.05 (d, J=6.8 Hz, 2H), 5.99 (p, J=7.0 Hz, 1H), 4.37 (t, J=4.9 Hz, 2H), 3.57 (q, J=4.6 Hz, 2H), 2.97 (s, 6H), 2.27 (s, 3H), 1.71 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.55, 158.94, 158.60, 155.69, 138.08, 132.05, 128.35, 127.13, 124.62, 124.28, 118.22, 116.40, 116.11, 114.17, 62.88, 55.89, 45.14, 43.27, 21.43, 18.80. LCMS calcd for C26H30N5O2 (M+H+): 444.5510; Found: 444.5.
White solid. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.04 (d, J=7.7 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J=8.5 Hz, 1H), 8.26 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.87 (t, J=7.7 Hz, 1H), 7.74-7.65 (m, 2H), 7.36 (s, 1H), 7.24-7.15 (m, 1H), 7.00 (q, J=3.2, 2.7 Hz, 2H), 5.95 (t, J=7.2 Hz, 1H), 4.93 (s, 4H), 4.31 (t, J=5.0 Hz, 2H), 3.51 (q, J=4.7 Hz, 2H), 2.22 (s, 3H), 1.64 (d, J=6.9 Hz, 3H. 13C NMR (101 MHz, DMSO-d6) δ 168.59, 168.53, 158.93, 158.59, 155.69, 150.79, 138.80, 138.10, 132.78, 132.06, 131.37, 128.35, 127.04, 124.65, 124.21, 121.02, 118.09, 116.17, 116.03, 114.07, 62.86, 55.90, 54.61, 45.02, 43.27, 21.52, 18.81. LCMS calcd for C28H33N6O3 (−M+H+): 501.6030. Found: 501.2.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.10 (d, J=7.4 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.84 (t, J=7.7 Hz, 1H), 7.22 (d, J=9.3 Hz, 2H), 7.05-7.00 (m, 2H), 5.78 (p, J=7.1 Hz, 1H), 4.33 (t, J=5.1 Hz, 2H), 3.74 (s, 6H), 3.52 (s, 2H), 2.24 (s, 3H), 2.08 (s, 2H), 1.56 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.67, 158.68, 158.36, 155.74, 137.94, 132.12, 128.36, 124.91, 119.14, 116.32, 114.13, 109.04, 62.94, 55.91, 45.54, 43.29, 35.41, 25.17, 21.36, 18.94. LCMS calcd for C27H35N4O2 (M+H+): 447.5950; Found: 447.6.
White solid, 1H NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 8.65 (t, J=4.4 Hz, 2H), 8.55-8.39 (m, 2H), 8.14 (t, J=7.8 Hz, 1H), 7.96 (t, J=7.7 Hz, 1H), 7.22 (dd, J=5.6, 2.9 Hz, 2H), 7.06 (dd, J=8.4, 2.5 Hz, 1H), 6.12 (q, J=7.0 Hz, 1H), 4.69 (d, J=6.8 Hz, 2H), 4.44 (t, J=4.8 Hz, 2H), 4.21 (dt, J=27.8, 10.4 Hz, 3H), 3.65 (d, J=4.7 Hz, 2H), 3.03 (s, 6H), 2.29 (s, 3H), 1.84 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 140.31, 134.23, 133.85, 131.84, 128.87, 124.48, 120.61, 116.73, 116.28, 113.66, 62.17, 56.34, 53.08, 49.11, 47.41, 47.20, 46.99, 46.31, 42.68, 42.62, 32.24, 19.77, 17.63. LCMS calcd for C29H35N6O2 (M+H+): 499.6310; Found: 499.6.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.56 (d, J=2.2 Hz, 1H), 9.08 (d, J=7.9 Hz, 1H), 8.84 (dd, J=8.2, 2.2 Hz, 1H), 8.38 (d, J=5.1 Hz, 2H), 8.20 (d, J=8.5 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.05-6.98 (m, 2H), 6.03 (p, J=7.2 Hz, 1H), 4.51 (s, 3H), 4.34 (t, J=5.0 Hz, 2H), 3.54 (d, J=15.0 Hz, 2H), 2.88 (d, J=4.6 Hz, 6H), 2.24 (s, 3H), 1.67 (d, J=6.9 Hz, 3H). 1′C NMR (101 MHz, DMSO-d6) δ 168.50, 164.30, 158.78, 158.44, 155.72, 153.38, 152.47, 149.08, 148.41, 147.26, 138.28, 136.31, 135.61, 132.08, 130.61, 128.31, 127.79, 125.47, 123.93, 122.99, 116.23, 115.41, 114.00, 62.92, 55.96, 44.89, 43.31, 21.94, 18.78. LCMS calcd for C25H30N7O2 (M+H+): 460.5540; Found: 460.6.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.02 (d, J=7.6 Hz, 1H), 8.77 (s, 1H), 8.35 (d, J=9.1 Hz, 2H), 8.22-8.05 (m, 2H), 7.86 (t, J=7.7 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 6.99 (d, J=6.4 Hz, 2H), 5.93 (p, J=7.0 Hz, 1H), 5.51 (s, 2H), 4.32 (d, J=5.0 Hz, 2H), 3.51 (q, J=4.8 Hz, 2H), 2.86 (d, J=3.4 Hz, 6H), 2.21 (s, 3H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.50, 158.96, 158.61, 155.69, 150.85, 139.43, 138.15, 132.04, 131.70, 131.05, 128.36, 126.96, 124.84, 124.15, 117.89, 116.18, 116.10, 114.98, 114.17, 82.03, 62.88, 56.78, 55.93, 45.00, 43.28, 21.41, 18.79. LCMS calcd for C28H34N5O3 (M+H+): 488.6040; Found: 488.2.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.26 (s, 2H), 9.03 (d, J=7.7 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.13 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.85-7.77 (m, 2H), 7.66 (ddd, J=8.3, 6.7, 1.3 Hz, 1H), 7.39 (d, J=3.7 Hz, 1H), 7.24-7.14 (m, 1H), 7.05-6.90 (m, 2H), 5.92 (p, J=7.1 Hz, 1H), 4.46 (t, J=5.3 Hz, 2H), 4.33 (t, J=5.1 Hz, 2H), 3.53 (dt, J=10.1, 5.6 Hz, 3H), 2.87 (s, 6H), 2.21 (s, 3H), 2.00 (td, J=10.0, 8.2, 3.8 Hz, 2H), 1.71 (dt, J=11.2, 4.9 Hz, 4H), 1.65 (d, J=6.9 Hz, 3H), 1.59-1.51 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 168.51, 158.95, 158.62, 155.71, 151.74, 151.61, 148.08, 147.14, 138.28, 136.83, 132.02, 131.94, 130.50, 129.81, 128.27, 127.09, 126.63, 125.37, 116.06, 114.15, 62.93, 58.38, 55.90, 44.99, 44.07, 43.27, 29.62, 24.13, 21.54, 18.76. LCMS calcd for C33H41N4O2S (M+H+): 557.7690; Found: 557.8.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J=7.8 Hz, 1H), 8.89 (d, J=2.6 Hz, 1H), 8.50-8.26 (m, 2H), 8.25-8.04 (m, 2H), 7.90 (q, J=8.6, 7.7 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.28-7.15 (m, 2H), 7.06-6.90 (m, 2H), 5.97 (p, J=7.1 Hz, 1H), 4.32 (t, J=5.1 Hz, 5H), 4.12 (dt, J=13.7, 4.7 Hz, 2H), 3.81 (tt, J=8.3, 4.0 Hz, 1H), 3.37 (ddd, J=13.3, 9.5, 3.3 Hz, 2H), 2.20 (s, 3H), 1.85 (dq, J=13.1, 3.9 Hz, 2H), 1.64 (d, J=7.0 Hz, 3H), 1.46 (dt, J=17.5, 5.4 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 168.54, 162.28, 158.97, 158.61, 155.72, 139.53, 138.17, 132.07, 131.33, 130.79, 128.40, 128.28, 127.33, 124.76, 124.41, 124.10, 122.31, 116.12, 114.95, 114.14, 108.50, 65.97, 62.89, 55.91, 45.13, 43.28, 43.12, 34.12, 21.76, 18.80. LCMS calcd for C33H40N5O3 (M+H+): 554.7070; Found: 554.3.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.03 (d, J=7.2 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.95-7.84 (m, 1H), 7.80-7.67 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 7.06-6.94 (m, 3H), 5.92 (p, J=7.0 Hz, 1H), 4.30 (t, J=5.2 Hz, 2H), 3.61-3.39 (m, 2H), 3.04 (s, 4H), 2.87 (s, 6H), 2.19 (s, 3H), 1.69 (p, J=6.9 Hz, 4H), 1.61 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.48, 162.27, 158.95, 158.60, 156.66, 155.69, 152.23, 144.04, 139.53, 137.90, 132.11, 130.90, 129.43, 128.46, 127.78, 124.84, 124.09, 119.07, 115.94, 114.42, 112.65, 62.91, 62.82, 55.87, 51.07, 45.18, 43.27, 25.40, 21.37, 18.87, 18.85. LCMS calcd for C32H38N5O2 (M+H+): 524.6810; Found: 524.7.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.06 (d, J=7.6 Hz, 1H), 8.54 (s, 1H), 8.35 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.86 (t, J=7.7 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.00 (d, J=7.0 Hz, 2H), 5.93 (p, J=7.0 Hz, 1H), 4.32 (t, J=5.0 Hz, 2H), 4.15 (s, 2H), 3.51 (q, J=4.8 Hz, 2H), 2.21 (s, 3H), 1.64 (d, J=7.0 Hz, 3H), 1.13 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 168.53, 158.91, 158.57, 155.70, 150.97, 138.14, 138.06, 132.06, 131.26, 128.33, 126.94, 124.62, 124.19, 118.22, 116.12, 116.00, 115.29, 114.11, 69.64, 62.92, 62.88, 55.90, 45.08, 43.27, 27.64, 21.50, 18.80.
LCMS calcd for C30H38N5O3 (M+H+): 516.2896; Found: 516.2899.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.21 (s, 2H), 8.98 (d, J=7.9 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.21-8.01 (m, 2H), 7.81 (t, J=7.7 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.00 (d, J=6.1 Hz, 2H), 5.96 (p, J=7.0 Hz, 1H), 4.31 (d, J=5.0 Hz, 2H), 3.84 (t, J=4.8 Hz, 4H), 3.71 (t, J=4.8 Hz, 4H), 3.51 (q, J=4.9 Hz, 2H), 2.86 (d, J=4.0 Hz, 6H), 2.22 (s, 3H), 1.63 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.44, 161.70, 158.80, 158.46, 157.23, 155.69, 152.82, 151.94, 148.04, 138.31, 132.05, 130.39, 128.26, 126.86, 124.96, 123.85, 121.20, 116.07, 114.29, 114.14, 66.42, 62.87, 55.91, 44.81, 44.49, 43.28, 21.83, 18.80. LCMS calcd for C31H37N6O3 (M+H+): 541.6680; Found: 541.7.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.10 (d, J=7.8 Hz, 1H), 5.99 (p, J=7.1 Hz, 1H), 4.31 (t, J=5.0 Hz, 2H), 3.51 (s, 3H), 2.85 (d, J=7.3 Hz, 9H), 2.20 (s, 3H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.47, 168.48, 159.04, 158.70, 155.72, 155.42, 152.14, 148.21, 139.62, 138.30, 135.96, 132.05, 130.41, 129.55, 128.23, 126.42, 125.29, 116.10, 115.49, 114.04, 62.85, 55.88, 52.60, 44.94, 43.24, 42.74, 21.81, 18.79. LCMS calcd for C35H42N5O3 (M+H+): 580.7450; Found: 580.3.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.01 (d, J=7.8 Hz, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.23 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.98 (d, J=4.0 Hz, 1H), 7.83 (t, J=7.1 Hz, 2H), 7.70 (t, J=7.7 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 5.95 (p, J=7.2 Hz, 1H), 4.31 (t, J=5.0 Hz, 2H), 2.86 (d, J=3.4 Hz, 6H), 2.21 (s, 3H), 1.65 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.48, 158.81, 158.46, 155.69, 152.22, 150.59, 149.94, 147.91, 138.22, 132.05, 131.68, 130.83, 129.97, 128.28, 127.71, 126.55, 125.73, 124.07, 116.12, 114.39, 114.08, 62.84, 55.91, 44.87, 43.27, 21.58, 18.79. LCMS calcd for C28H29F3N3O2S (M+H+): 528.6062; Found: 528.6.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.99 (d, J=7.3 Hz, 1H), 8.61 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.94-7.75 (m, 2H), 7.66 (t, J=7.6 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.11-6.80 (m, 2H), 5.90 (p, J=7.0 Hz, 1H), 4.39-4.20 (m, 4H), 3.51 (q, J=4.7 Hz, 2H), 2.86 (s, 6H), 2.22 (s, 3H), 1.63 (d, J=7.0 Hz, 3H), 1.48 (t, J=7.2 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.39, 158.92, 158.57, 155.62, 151.07, 150.09, 148.12, 138.08, 133.13, 132.01, 130.20, 130.06, 128.45, 127.05, 124.87, 123.90, 121.76, 117.05, 115.96, 114.25, 62.86, 55.90, 47.83, 44.82, 43.26, 21.26, 18.82, 15.55. LCMS calcd for C29H33F3N5O2 (M+H+): 540.6032; Found: 540.2.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.57 (d, J=2.2 Hz, 1H), 9.01 (d, J=8.0 Hz, 1H), 8.83 (dd, J=8.1, 2.2 Hz, 1H), 8.46-8.35 (m, 2H), 8.28 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.00 (d, J=6.5 Hz, 2H), 6.01 (q, J=7.3 Hz, 1H), 4.31 (t, J=4.9 Hz, 2H), 3.51 (q, J=5.0 Hz, 2H), 2.86 (d, J=4.2 Hz, 6H), 2.21 (s, 3H), 1.66 (d, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.48, 158.82, 158.47, 155.70, 152.57, 152.42, 150.04, 148.35, 138.22, 137.79, 136.31, 133.32, 132.06, 130.79, 129.78, 128.28, 128.23, 125.64, 123.98, 117.99, 116.15, 115.91, 114.09, 62.85, 55.92, 44.87, 43.28, 21.85, 18.79. LCMS calcd for C29H30N5O2 (M+H+): 480.5840; Found: 480.6.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.03 (d, J=7.8 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.04-6.91 (m, 2H), 6.68 (s, 1H), 5.94 (p, J=7.1 Hz, 1H), 4.31 (t, J=4.9 Hz, 2H), 4.25 (s, 3H), 3.51 (q, J=4.7 Hz, 2H), 2.22 (d, J=4.4 Hz, 6H), 1.61 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.45, 158.88, 158.54, 155.70, 151.73, 149.56, 146.45, 141.60, 138.26, 132.05, 130.39, 128.27, 127.45, 124.75, 123.80, 117.26, 116.03, 114.13, 107.27, 62.85, 55.90, 44.67, 43.26, 21.70, 18.81, 13.61. LCMS calcd for C28H34N5O2 (M+H+): 472.6050; Found: 472.2.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.98 (d, J=2.3 Hz, 1H), 8.44 (dd, J=8.9, 2.6 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J=8.5 Hz, 1H), 7.85 (t, J=7.7 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.09 (d, J=9.1 Hz, 1H), 7.03-6.96 (m, 2H), 5.97 (t, J=7.3 Hz, 1H), 4.31 (t, J=5.1 Hz, 2H), 3.74 (t, J=4.8 Hz, 4H), 3.63 (t, J=4.8 Hz, 4H), 3.51 (q, J=4.7 Hz, 3H), 2.21 (s, 3H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.49, 159.59, 158.86, 158.51, 155.71, 154.10, 138.28, 136.96, 132.07, 130.84, 128.39, 128.26, 127.01, 124.79, 123.95, 122.31, 117.99, 117.67, 116.08, 114.80, 114.13, 107.51, 66.34, 62.88, 55.91, 45.37, 44.96, 43.28, 21.84, 18.80. LCMS calcd for C32H38N5O3 (M+H+): 540.6800; Found: 540.2.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.85 (s, 1H), 9.17 (d, J=7.3 Hz, 1H), 8.78 (s, 1H), 8.45 (d, J=8.7 Hz, 2H), 7.96 (t, J=8.0 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.99 (dd, J=8.2, 2.6 Hz, 2H), 5.97 (t, J=7.2 Hz, 1H), 4.66 (d, J=9.5 Hz, 2H), 4.40 (d, J=4.6 Hz, 2H), 3.94 (s, 2H), 3.72-3.67 (m, 2H), 3.49 (d, J=4.7 Hz, 2H), 2.83 (d, J=4.5 Hz, 6H), 2.21 (s, 3H), 1.69 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.54, 164.27, 155.65, 140.31, 139.90, 137.65, 132.07, 128.54, 124.90, 124.54, 116.39, 114.34, 60.65, 59.42, 55.66, 54.24, 44.07, 43.20, 26.75, 21.35, 18.96. LCMS calcd for C31H36N7O2 (M+H+): 538.6680; Found: 538.2.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.18 (d, J=7.4 Hz, 1H), 8.40-8.21 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.99-7.78 (m, 2H), 7.68 (t, J1=7.7 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.13-6.94 (m, 3H), 5.90 (p, J=7.0 Hz, 1H), 4.34 (s, 2H), 3.97 (s, 3H), 3.52 (q, J=4.8 Hz, 2H), 2.87 (s, 6H), 2.23 (s, 3H), 1.61 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.54, 158.89, 158.54, 155.67, 152.70, 151.61, 150.26, 146.86, 138.23, 133.56, 132.05, 130.58, 128.91, 128.50, 127.06, 125.44, 124.02, 116.03, 114.84, 114.25, 105.36, 62.86, 55.91, 45.11, 43.28, 39.48, 21.45, 18.82. LCMS calcd for C27H32N5O2 (M+H+): 458.5780; Found: 458.2.
‘White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.18-9.05 (m, 1H), 8.33 (d, J=8.5 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.83 (dd, J=8.6, 5.2 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.21 (dd, J=8.8, 3.8 Hz, 1H), 7.03-6.99 (m, 2H), 5.94 (p, J=7.1 Hz, 1H), 4.31 (t, J=4.9 Hz, 2H), 3.98 (s, 3H), 2.23 (s, 3H), 1.62 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.50, 162.41, 155.69, 154.42, 152.11, 151.29, 148.13, 146.89, 138.13, 133.16, 132.09, 130.60, 128.37, 127.38, 124.64, 123.88, 116.55, 114.11, 109.20, 62.90, 55.94, 53.56, 44.93, 43.31, 21.58, 18.86. LCMS calcd for C27H31N4O2S (M+H+): 475.623; Found: 475.2.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=2.1 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.50-7.40 (m, 2H), 7.36 (d, J=3.6 Hz, 1H), 7.13-7.05 (m, 2H), 6.99 (t, J=7.7 Hz, 1H), 6.40 (d, J=5.5 Hz, 1H), 6.29-6.22 (m, 2H), 5.32 (q, J=7.0 Hz, 1H), 3.54 (d, J=8.8 Hz, 2H), 3.28 (s, 2H), 2.80 (d, J=4.1 Hz, 2H), 2.17 (s, 6H), 1.52 (s, 3H), 0.97 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.48, 162.51, 155.60, 154.64, 141.73, 137.15, 132.71, 131.77, 130.08, 128.52, 127.69, 126.16, 125.29, 124.28, 123.33, 123.12, 116.08, 115.70, 115.29, 113.17, 112.86, 108.39, 61.95, 61.93, 56.33, 56.29, 45.67, 42.96, 42.51, 20.10, 17.44. LCMS calcd for C30H34N3O4S (M+H+): 532.6170; Found: 532.2.
White solid, 68% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J=7.2 Hz, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.93 (t, J=7.7 Hz, 1H), 7.29-7.24 (m, 1H), 7.17 (d, J=2.3 Hz, 1H), 7.13-6.98 (m, 2H), 5.95 (q, J=7.1 Hz, 1H), 4.38 (t, J=5.1 Hz, 2H), 3.57 (q, J=4.6 Hz, 1H), 2.93 (s, 3H), 2.29 (s, 2H), 1.68 (d, J=6.9 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 168.64, 155.69, 151.18, 149.16, 138.21, 132.25, 132.04, 131.10, 128.48, 128.05, 127.36, 125.42, 124.17, 116.02, 114.92, 114.28, 105.62, 62.87, 55.91, 47.35, 45.41, 43.28, 21.39, 18.80, 15.91. LCMS calcd for C28H34N5O2 (M+H+): 472.2636; Found: 472.2639.
To a solution of methyl 5-bromo-2-methylbenzoate (1.0 equiv) in dry toluene in sealed tube, corresponding amine (1.5 equiv), XPhos (0.04 equiv), tris(dibenzylideneacetone)dipalladium (0.02 equiv) and Cs2CO3 (2.0 equiv) were added. The reaction mixture was degassed and purged with argon, and then the tube was sealed and heated to 110° C. overnight. The mixture was diluted with EtOAc and was then washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (Hexanes/EtOAc=1:1) to provide the desired product.
White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.00 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.54 (q, J=7.6, 6.2 Hz, 1H), 7.47 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.00 (d, J=9.3 Hz, 2H), 5.81 (d, J=7.2 Hz, 1H), 4.32 (t, J=4.9 Hz, 2H), 3.88-3.75 (m, 7H), 3.52 (q, J=4.8 Hz, 2H), 2.87 (d, J=3.7 Hz, 6H), 2.23 (d, J=6.6 Hz, 3H), 1.56 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.56, 159.25, 158.91, 158.56, 158.22, 155.72, 138.06, 132.06, 128.34, 124.96, 124.34, 120.11, 118.14, 116.27, 114.06, 107.78, 65.99, 62.92, 55.92, 46.61, 45.37, 43.29, 21.50, 18.82. LCMS calcd for C27H35N4O3 (M+H+): 463.5940; Found: 463.6.
White solid, 53% yield, 1H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 9.10 (d, J=7.4 Hz, 1H), 8.28 (d, J=9.6 Hz, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.77 (q, J=6.8, 6.2 Hz, 1H), 7.62 (q, J=8.1 Hz, 1H), 7.18-7.10 (m, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.93 (d, J=6.6 Hz, 2H), 5.85 (q, J=7.2 Hz, 1H), 4.25 (d, J=5.4 Hz, 2H), 3.46 (q, J=5.0 Hz, 2H), 2.80 (d, J=3.8 Hz, 6H), 2.16 (d, J=6.2 Hz, 3H), 1.56 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 168.53, 155.66, 151.49, 146.63, 138.19, 132.04, 130.71, 128.75, 128.44, 127.15, 125.47, 124.08, 118.05, 116.10, 115.15, 114.13, 104.69, 93.94, 62.86, 55.89, 45.06, 43.26, 21.42, 18.84. LCMS calcd for C26H30NO2 (M+H+): 444.2321; Found: 444.2323.
White solid, 58% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.26 (d, J=17.0 Hz, 1H), 8.99-8.87 (m, 1H), 8.36 (d, J=17.1 Hz, 1H), 8.18-8.07 (m, 1H), 7.94-7.83 (m, 1H), 7.74 (t, J=10.6 Hz, 1H), 7.23 (d, J=17.6 Hz, 1H), 7.05 (dd, J=21.2, 10.4 Hz, 2H), 5.92 (s, 1H), 4.32 (d, J=16.2 Hz, 2H), 3.50 (d, J=19.2 Hz, 2H), 2.85 (d, J=16.4 Hz, 6H), 2.28 (dd, J=25.8, 11.9 Hz, 3H), 1.74-1.56 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.79, 158.53, 155.71, 152.02, 148.04, 138.46, 132.05, 130.43, 130.33, 128.47, 127.90, 126.40, 124.11, 115.93, 114.92, 114.34, 62.89, 55.91, 45.63, 43.28, 21.48, 18.91. LCMS calcd for C26H29N6O2 (M+H+): 445.2274; Found: 445.2278.
White solid, 55% yield, 1H NMR (400 MHz, DMSO-d6) δ9.92 (s, 2H), 9.04 (d, J=7.7 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.14 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.87 (d, J=3.7 Hz, 1H), 7.81 (t, J=7.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.40 (d, J=3.8 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.03-6.96 (m, 2H), 5.92 (p, J=7.0 Hz, 1H), 4.59 (s, 2H), 3.51 (dt, J=7.6, 4.0 Hz, 2H), 3.44 (d, J=11.8 Hz, 2H), 2.94 (d, J=11.8 Hz, 2H), 2.86 (d, J=3.1 Hz, 5H), 2.50 (s, 3H), 2.20 (s, 3H), 1.85 (d, J=13.7 Hz, 2H), 1.70 (d, J=13.3 Hz, 2H), 1.65 (s, 3H). 13C NMR (101 MHz, DMSO-d6) −168.49, 158.83, 155.71, 151.82, 151.45, 148.23, 148.05, 138.28, 133.90, 132.04, 130.58, 129.81, 128.24, 127.20, 126.77, 125.40, 124.04, 116.05, 114.13, 62.88, 55.89, 53.54, 52.06, 44.98, 43.26, 22.93, 21.59, 18.80. LCMS calcd for C32H40N5O2S (M++): 557.2824; Found: 557.2826.
White solid, 51% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.42 (s, 1H), 9.04 (d, J=4.7 Hz, 2H), 8.38-8.26 (m, 3H), 8.17 (d, J=8.4 Hz, 1H), 7.85 (t, J=7.7 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.25-7.16 (m, 1H), 6.99 (d, J=6.0 Hz, 2H), 6.00 (q, J=7.3 Hz, 1H), 4.31 (t, J=5.0 Hz, 2H), 3.51 (t, J=5.2 Hz, 2H), 2.85 (d, J=4.3 Hz, 6H), 2.22 (s, 3H), 1.67 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.46, 158.45, 155.71, 152.03, 148.91, 138.33, 134.77, 132.06, 130.43, 130.26, 129.13, 128.27, 127.18, 125.07, 123.86, 116.11, 115.55, 115.00, 114.07, 62.84, 55.94, 43.29, 21.89, 18.79. LCMS calcd for C29H31N6O2 (M+H+): 495.2430; Found: 495.2433.
White solid, 53% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.13 (d, J=7.8 Hz, 1H), 8.86 (s, 1H), 8.37 (d, J=8.5 Hz, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.55 (t, J=8.2 Hz, 2H), 7.34 (t, J=7.7 Hz, 1H), 7.27-7.16 (m, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.00 (q, J=7.2 Hz, 1H), 4.29 (t, J=5.1 Hz, 2H), 3.50 (q, J=4.9 Hz, 2H), 2.85 (d, J=4.4 Hz, 6H), 2.22 (s, 3H), 1.67 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.45, 158.81, 155.71, 151.63, 148.30, 141.39, 140.34, 138.31, 134.86, 133.78, 132.09, 130.32, 128.29, 127.32, 126.33, 125.11, 120.75, 120.62, 116.52, 114.02, 110.54, 62.81, 55.93, 44.83, 43.28, 21.80, 18.81. LCMS calcd for C30H32N5O2 (M+H+): 495.2430; Found: 495.2433.
White solid, 50% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=7.7 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.86 (d, J=3.7 Hz, 1H), 7.80 (t, =7.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.41 (d, J=3.7 Hz, 1H), 7.22-7.17 (m, 1H), 6.99 (dd, J=4.5, 2.1 Hz, 2H), 5.91 (q, J=7.2 Hz, 1H), 4.69-4.64 (m, 2H), 4.32 (t, J=5.0 Hz, 2H), 3.51 (dt, J=15.6, 7.1 Hz, 4H), 3.17 (d, J=9.3 Hz, 2H), 2.87 (s, 6H), 2.21 (s, 3H), 2.04 (q, J=7.8, 6.6 Hz, 2H), 1.96-1.82 (m, 2H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.49, 155.70, 151.79, 151.50, 148.04, 147.73, 138.26, 135.83, 132.86, 132.03, 130.56, 129.81, 128.25, 126.78, 125.39, 124.03, 118.23, 116.04, 114.19, 114.13, 62.88, 55.87, 53.31, 51.48, 44.96, 43.24, 23.08, 21.57, 18.79. LCMS calcd for C32H39N4O2S (M+H+): 543.2715; Found: 543.2718.
White solid, 48% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=7.6 Hz, 1H), 8.68 (s, 1H), 8.32 (s, 2H), 8.05 (d, J=8.5 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.99 (d, J=5.2 Hz, 2H), 5.90 (p, J=7.0 Hz, 1H), 4.69 (t, J=6.4 Hz, 2H), 4.31 (t, J=5.1 Hz, 2H), 3.96-3.76 (m, 2H), 3.72 (t, J=6.6 Hz, 2H), 3.51 (d, J=4.9 Hz, 2H), 3.28 (dd, J=64.9, 30.7 Hz, 4H), 2.87 (s, 6H), 2.50 (s, 2H), 2.20 (s, 3H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.49, 155.69, 151.11, 139.09, 138.19, 132.03, 131.44, 130.70, 128.29, 126.68, 124.83, 124.11, 122.90, 118.09, 116.02, 115.90, 115.17, 114.17, 63.74, 62.87, 55.87, 55.31, 51.90, 46.32, 45.05, 43.24, 21.37, 18.80. LCMS calcd for C32H41N6O3 (M+H+): 557.7110; Found: 557.7113.
White solid, 50% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.01 (d, J=7.7 Hz, 1H), 8.56 (s, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.22 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.98 (s, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 6.99 (d, J=9.3 Hz, 2H), 5.92 (q, J=7.2 Hz, 1H), 2.86 (s, 6H), 2.22 (s, 3H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 169.82, 168.48, 158.82, 158.48, 155.68, 138.66, 138.20, 132.18, 132.05, 130.86, 128.33, 126.76, 124.74, 124.07, 116.09, 115.87, 114.11, 62.84, 55.92, 53.51, 44.89, 43.28, 21.49, 18.80. LCMS calcd for C29H32N5O4 (M+H+): 502.2376; Found: 502.2376.
White solid, 47% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.06 (d, J=8.6 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.28-8.02 (m, 2H), 7.85 (q, J=10.0, 8.8 Hz, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.57 (d, J=7.1 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.12 (d, J=7.9 Hz, 2H), 7.01 (d, J=7.6 Hz, 2H), 6.00 (t, J=8.4 Hz, 1H), 4.41-4.20 (m, 2H), 2.87 (d, J=4.9 Hz, 2H), 2.21 (d, J=7.6 Hz, 3H), 1.60 (d, J=7.5 Hz, 3H). LCMS calcd for C28H31N4O3 (M+H+): 471.2318; Found: 471.2320.
White solid, 51% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=7.7 Hz, 1H), 8.49 (s, 3H), 8.35 (d, J=8.5 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.86 (dd, J=9.5, 5.8 Hz, 2H), 7.71 (t, J=7.6 Hz, 1H), 7.37 (d, J=3.8 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H), 7.06 (dd, J=5.9, 2.9 Hz, 2H), 5.95 (q, J=7.2 Hz, 1H), 4.38 (q, J=5.4 Hz, 4H), 3.57 (d, J=10.3 Hz, 4H), 2.92 (s, 6H), 2.26 (s, 3H), 1.70 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.54, 158.95, 158.62, 155.69, 151.70, 151.67, 148.06, 146.39, 139.17, 138.25, 132.03, 130.52, 129.78, 128.24, 127.06, 125.32, 123.99, 116.04, 114.09, 62.86, 55.88, 44.99, 43.25, 37.76, 21.52, 18.76. LCMS calcd for C28H31N4O3 (M+H+): 489.2246; Found: 489.2248.
White solid, 51% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.02 (d, J=8.0 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.23 (d, J=9.8 Hz, 2H), 8.13 (dd, J=8.3, 6.2 Hz, 2H), 7.83 (t, J=7.6 Hz, 1H), 7.77-7.57 (m, 2H), 7.28-7.13 (m, 1H), 7.07-6.90 (m, 2H), 5.98 (q, J=7.2 Hz, 1H), 4.31 (t, J=4.9 Hz, 2H), 3.51 (q, J=4.7 Hz, 2H), 2.85 (s, 6H), 2.21 (s, 3H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.43, 155.70, 154.69, 152.00, 148.12, 144.26, 144.07, 138.29, 136.34, 132.04, 130.41, 128.26, 127.36, 125.22, 124.09, 123.83, 116.08, 115.41, 114.09, 110.88, 109.08, 62.85, 55.90, 44.78, 43.25, 21.84, 18.78. LCMS calcd for C30H30F2N3O4 (M+H+): 534.2126; Found: 534.2128.
White solid, 56% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 2H), 9.39 (s, 1H), 9.06 (d, J=8.0 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 8.27-8.21 (m, 1H), 7.93 (ddd, J=8.4, 6.7, 1.2 Hz, 1H), 7.80 (ddd, J=8.3, 6.7, 1.3 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.09-7.04 (m, 2H), 6.07 (t, J=7.3 Hz, 1H), 4.37 (d, J=5.1 Hz, 2H), 3.57 (q, J=4.7 Hz, 2H), 2.92 (d, J=3.5 Hz, 6H), 2.27 (s, 3H), 1.72 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 168.48, 159.28, 158.93, 158.58, 155.78, 155.70, 152.49, 151.86, 148.35, 138.23, 132.38, 132.04, 130.66, 130.60, 128.29, 127.92, 125.54, 123.96, 117.86, 116.13, 115.53, 114.13, 62.87, 55.91, 44.86, 43.28, 21.84, 18.78. LCMS calcd for C27H30N5O2 (M+H+): 456.2321; Found: 456.2323.
White solid, 46% yield, 1H NMR (400 MHz, MeOD-d4) δ 8.17 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.51 (q, J=7.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.08 (d, J=6.4 Hz, 1H), 7.06-6.94 (m, 2H), 5.92 (q, J=7.0 Hz, 1H), 4.34 (q, J=5.1 Hz, 2H), 4.07 (d, J=5.7 Hz, 2H), 3.59 (q, J=5.5, 4.8 Hz, 2H), 2.97 (d, J=4.4 Hz, 6H), 2.31 (d, J=8.9 Hz, 3H), 1.64 (d, J=10.6 Hz, 3H). 13C NMR (101 MHz, MeOD-d4) δ 174.19, 166.45, 159.45, 140.02, 142.80, 140.96, 135.60, 133.52, 132.47, 130.82, 128.15, 127.01, 126.79, 65.84, 60.24, 56.77, 54.68, 46.38, 23.52, 21.28. LCMS calcd for C30H29F5N3O3 (M+H+): 574.2051; Found: 574.2055.
White solid, 52% yield, 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J=13.9 Hz, 1H), 8.42 (d, J=11.6 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.95 (t, J=10.3 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.37 (t, J=7.4 Hz, 1H), 7.16 (t, J=8.7 Hz, 1H), 7.03-6.86 (m, 1H), 6.58 (s, 1H), 4.52 (t, J=6.4 Hz, 2H), 3.88-3.75 (m, 2H), 3.18 (t, J=6.2 Hz, 2H), 2.96 (s, 3H), 2.77 (d, J=10.3 Hz, 3H), 2.24 (s, 3H), 2.00 (d, J=7.5 Hz, 1H), 1.90 (s, 1H), 1.83 (d, J=7.4 Hz, 3H). LCMS calcd for C29H33N6O2 (M+H+): 497.2587; Found: 497.2589.
White solid, 50% yield, 1H NMR (400 MHz, MeOD-d4) δ 8.68 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.9 Hz, 3H), 7.53 (d, J=7.9 Hz, 2H), 7.22 (t, J=7.6 Hz, 3H), 7.06-6.98 (m, 2H), 5.92 (q, J=6.9 Hz, 1H), 4.33 (t, J=5.1 Hz, 2H), 3.57 (t, J=5.0 Hz, 2H), 2.97 (d, J=5.6 Hz, 6H), 2.30 (s, 3H), 1.66 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, MeOD-d4) δ 155.53, 148.79, 133.40, 131.71, 130.45, 128.45, 120.63, 120.39, 115.83, 113.00, 111.80, 109.01, 61.93, 56.28, 42.45, 19.84, 17.33. LCMS calcd for C30H32N5O2 (M+H+): 494.2478; Found: 494.2475.
White solid, 53% yield, 1H NMR (400 MHz, MeOD-d4) δ 8.27 (s, 2H), 8.15 (s, 1H), 7.98 (s, 2H), 7.75 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 7.22 (s, 1H), 7.02-6.98 (m, 2H), 5.94 (d, J=6.8 Hz, 1H), 4.34 (d, J=5.0 Hz, 2H), 3.59 (d, J=4.9 Hz, 2H), 2.97 (s, 6H), 2.30 (s, 3H), 1.67 (s, 3H). 13C NMR (101 MHz, MeOD-d4) δ 170.62, 155.55, 154.72, 151.57, 150.97, 149.23, 148.73, 137.32, 134.01, 131.74, 130.49, 129.45, 128.51, 128.47, 115.89, 115.00, 113.04, 112.05, 111.06, 62.01, 56.30, 42.50, 19.93, 17.39. LCMS calcd for C30H32N5O2 (M+H+): 494.2478; Found: 494.2479.
White solid, 51% yield, 1H NMR (400 MHz, MeOD-d4) δ 8.12 (d, J=5.4 Hz, 2H), 7.86 (s, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.06 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 5.91 (q, J=7.0 Hz, 1H), 4.34 (q, J=6.8, 4.9 Hz, 2H), 3.99 (s, 3H), 3.58 (t, J=4.9 Hz, 2H), 2.96 (s, 6H), 2.29 (s, 3H), 1.66 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.57, 159.41, 156.22, 149.95, 146.55, 142.38, 141.54, 135.58, 133.38, 132.68, 131.02, 128.03, 126.95, 124.94, 119.59, 118.42, 117.06, 112.44, 65.84, 60.18, 57.91, 46.37, 23.52, 21.28. LCMS calcd for C28H32N5O3 (M+H+): 486.2427; Found: 486.2429.
White solid, 54% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.92 (d, J=7.8 Hz, 1H), 8.64 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.08 (d, J=9.1 Hz, 2H), 7.81 (t, J=7.7 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.26-7.14 (m, 1H), 6.97 (d, J=6.6 Hz, 2H), 5.93 (p, J=6.9 Hz, 1H), 4.29 (t, J=5.1 Hz, 2H), 3.49 (q, J=4.3 Hz, 2H), 2.85 (s, 6H), 2.21 (s, 3H), 1.67 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.42, 158.94, 155.64, 151.40, 149.78, 148.08, 143.21, 138.13, 132.01, 130.41, 129.82, 128.35, 127.09, 126.44, 125.38, 124.04, 116.45, 116.05, 114.13, 62.79, 55.91, 44.77, 43.24, 21.21, 18.79. LCMS calcd for C27H29F3N5O2 (M+H+): 512.2195; Found: 512.2199.
White solid, 52% yield, 1H NMR (400 MHz, DMSO-d6) δ 5.92 (p, J=7.1 Hz, 1H), 5.00-4.93 (m, 2H), 4.81 (d, J=8.4 Hz, 1H), 4.31 (t, J=5.0 Hz, 2H), 3.51 (q, J=4.9 Hz, 2H), 2.87 (s, 6H), 2.56 (d, J=9.4 Hz, 2H), 2.47-2.41 (m, 2H), 2.22 (s, 3H), 1.85 (tt, J=10.7, 6.6 Hz, 2H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.48, 158.83, 158.49, 155.68, 138.86, 138.50, 138.17, 132.05, 131.11, 128.33, 124.72, 124.17, 116.14, 116.07, 114.18, 105.38, 62.86, 55.93, 55.57, 43.29, 30.65, 30.42, 21.40, 18.81, 14.64. LCMS calcd for C30H36N5O2 (M+H+): 498.2791; Found: 498.2794.
White solid, 53% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=7.6 Hz, 1H), 8.77 (s, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.34 (s, 1H), 8.17 (d, J=9.1 Hz, 2H), 7.92 (t, J=7.7 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.03-6.98 (m, 2H), 5.96-5.91 (m, 1H), 4.32 (t, J=5.0 Hz, 2H), 3.51 (d, J=5.6 Hz, 2H), 2.87 (d, J=3.0 Hz, 6H), 2.21 (s, 3H), 1.67 (s, 3H), 1.62 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 168.58, 158.97, 158.62, 155.70, 150.56, 138.49, 138.03, 132.06, 131.87, 128.36, 127.30, 124.58, 124.41, 116.44, 116.13, 114.19, 62.88, 59.74, 55.91, 45.33, 43.27, 29.73, 21.35, 18.80. LCMS calcd for C30H38N5O2 (M+H+): 500.2947; Found: 500.2949.
White solid, 57% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.00 (d, J=7.6 Hz, 1H), 8.34 (d, J=5.4 Hz, 2H), 8.15 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.18 (d, J=4.7 Hz, 1H), 6.98 (d, J=5.7 Hz, 2H), 5.93 (t, J=7.2 Hz, 1H), 4.28 (s, 2H), 2.85 (s, 6H), 2.50 (s, 3H), 2.19 (s, 3H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.56, 159.01, 158.68, 155.65, 152.12, 147.52, 139.43, 138.01, 132.56, 132.06, 130.78, 130.40, 128.36, 128.09, 125.15, 124.02, 116.93, 116.12, 114.10, 62.79, 55.91, 44.99, 43.25, 37.22, 21.37, 18.80. LCMS calcd for C28H32NO2 (M+H+): 458.2478; Found: 458.2479.
White solid, 56% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J=7.9 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.27-8.18 (m, 2H), 7.91 (d, J=7.5 Hz, 1H), 7.84 (d, J=1.9 Hz, 2H), 7.76 (t, J=7.6 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.30-7.22 (m, 1H), 7.22-7.15 (m, 1H), 7.09-7.01 (m, 2H), 6.04 (q, J=7.2 Hz, 1H), 4.37 (t, J=5.0 Hz, 2H), 3.93 (s, 3H), 3.56 (q, J=4.6 Hz, 2H), 2.92 (s, 6H), 2.27 (s, 3H), 1.69 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.50, 160.26, 158.59, 155.98, 155.71, 152.44, 147.70, 140.32, 138.31, 132.07, 130.53, 130.49, 128.25, 127.33, 125.21, 123.83, 119.98, 115.70, 114.08, 113.23, 62.84, 55.91, 55.76, 44.89, 43.27, 21.89, 18.78. LCMS calcd for C30H34N3O3 (M+H+): 484.2522; Found: 484.2524.
White solid, 50% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.08-9.01 (m, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 7.03 (d, J=5.3 Hz, 1H), 6.50 (d, J=4.1 Hz, 1H), 5.91 (t, J=7.2 Hz, 1H), 4.35 (d, J=4.9 Hz, 2H), 4.00 (s, 3H), 3.54 (s, 2H), 2.90 (s, 6H), 2.25 (s, 3H), 1.66 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.62, 168.71, 155.62, 151.44, 147.18, 132.11, 128.40, 127.98, 126.46, 124.76, 123.83, 114.12, 113.96, 105.94, 62.68, 60.64, 55.99, 53.61, 43.27, 21.44, 18.70. LCMS calcd for C28H31N3O3S (M+H+): 490.2086; Found: 490.2089.
White solid, 45% yield, 1H NMR (400 MHz, MeOD-d4) δ 8.73 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.21 (s, 1H), 8.09 (t, =7.8 Hz, 1H), 7.91 (t, J=7.7 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.06 (d, J=7.3 Hz, 2H), 6.11 (d, J=7.0 Hz, 1H), 5.28 (s, 2H), 4.37 (t, J=5.0 Hz, 3H), 3.67 (d, J=6.8 Hz, 2H), 3.62 (d, J=4.9 Hz, 2H), 3.50 (d, J=6.7 Hz, 2H), 3.00 (s, 6H), 2.30 (s, 3H), 2.09 (d, J=6.9 Hz, 2H), 1.96 (d, J=7.1 Hz, 2H), 1.80 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, MeOD-d4) δ 170.52, 165.15, 155.59, 148.97, 139.20, 136.88, 133.87, 133.33, 131.82, 128.60, 128.24, 124.50, 124.19, 122.24, 116.06, 113.14, 61.99, 56.31, 53.73, 45.80, 42.49, 25.60, 23.69, 19.60, 17.41. LCMS calcd for C32H39N6O3 (M+H+): 555.3005; Found: 555.3009.
White solid, 48% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J=7.8 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.5 Hz, 3H), 7.90 (t, J=1.7 Hz, 1H), 7.75 (ddd, J=8.2, 6.8, 1.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.26 (s, 1H), 7.03 (q, J=2.7 Hz, 2H), 6.00 (q, J=7.2 Hz, 1H), 4.35 (d, J=4.9 Hz, 2H), 3.55 (s, 2H), 2.60 (s, 3H), 2.24 (s, 3H), 1.69 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.70, 159.03, 158.69, 155.64, 152.70, 141.58, 138.10, 134.72, 132.12, 130.75, 128.30, 128.11, 127.31, 126.26, 125.03, 123.84, 116.11, 115.27, 113.99, 62.71, 55.97, 45.05, 43.27, 21.66, 18.72, 14.72. LCMS calcd for C30H34N3O2S (M+H+): 500.2293; Found: 500.2298.
White solid, 49% yield, 1H NMR (400 MHz, MeOD) δ 8.80 (d, J=5.3 Hz, 1H), 8.59 (d, J=8.6 Hz, 1H), 8.27 (d, J=5.9 Hz, 2H), 8.12-8.06 (m, 1H), 7.95-7.88 (m, 1H), 7.24-7.18 (m, 1H), 7.07 (d, J=2.7 Hz, 1H), 7.02 (dd, J=8.4, 2.8 Hz, 1H), 6.12-6.06 (m, 1H), 5.37 (d, J=6.9 Hz, 2H), 4.36 (s, 2H), 3.60 (s, 2H), 3.02 (d, J=9.8 Hz, 6H), 2.98 (d, J=4.4 Hz, 6H), 2.27 (d, J=7.7 Hz, 3H), 1.78 (d, J=7.3 Hz, 3H). 13C NMR (101 MHz, MeOD) δ 170.57, 166.75, 155.59, 148.27, 139.44, 136.60, 134.67, 134.11, 131.83, 128.73, 124.41, 120.79, 116.28, 116.11, 115.30, 113.23, 62.03, 56.28, 53.23, 47.40, 47.18, 46.97, 42.51, 35.45, 34.81, 19.56, 17.47. LCMS calcd for C30H37N6O3 (M+H+): 529.2849; Found: 529.2853.
White solid, 48% yield, 1H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.86 (d, J=3.7 Hz, 1H), 7.80 (dd, J=8.4, 6.9 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.38 (d, J=5.4 Hz, 1H), 7.20 (dd, J=8.8, 4.6 Hz, 2H), 7.01-6.97 (m, 2H), 5.90 (q, J=7.2 Hz, 1H), 4.64 (s, 2H), 4.31 (t, J=4.9 Hz, 2H), 3.89-3.74 (m, 4H), 3.40 (d, J=4.1 Hz, 2H), 3.25 (dd, J=21.0, 8.9 Hz, 4H), 2.86 (s, 6H), 2.20 (s, 3H), 1.64 (d, J=6.9 Hz, 3H). LCMS calcd for C32H39N4O4 (M+H+): 543.2893; Found: 543.2898.
White solid, 62% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J=7.5 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.13 (d, J=11.0 Hz, 2H), 8.02 (d, J=1.7 Hz, 1H), 7.87 (t, J=7.7 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.07 (dd, J=8.1, 2.7 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 6.82 (dd, J=3.5, 1.8 Hz, 1H), 5.96 (d, J=7.1 Hz, 1H), 3.95-3.82 (m, 2H), 3.61 (d, J=12.0 Hz, 2H), 3.23 (s, 2H), 3.02 (t, J=12.6 Hz, 2H), 2.93 (s, 3H), 2.25 (s, 3H), 1.67 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.03, 153.30, 152.66, 148.39, 147.74, 145.63, 137.74, 131.69, 130.61, 129.47, 127.14, 127.04, 125.09, 124.00, 117.84, 115.26, 113.67, 113.28, 111.24, 52.77, 46.35, 45.07, 42.58, 21.54, 18.73. LCMS calcd for C28H31N4O2 (M+H1): 455.2369; Found: 455.2372.
To a solution of methyl 5-bromo-2-methylbenzoate (1.0 equiv) in dry toluene in sealed tube, corresponding amine (1.5 equiv), XPhos (0.04 equiv), tris(dibenzylideneacetone)dipalladium (0.02 equiv) and Cs2CO3 (2.0 equiv) were added. The reaction mixture was degassed and purged with argon, and then the tube was sealed and heated to 110° C. overnight. The mixture was diluted with EtOAc and was then washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (Hexanes/EtOAc=1:1) to provide the desired intermediate. The intermediate was dissolved in DCM and HCl (4M in dioxane, 10.0 equiv) was added. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with DCM, adjusted to pH=10, and then washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by Prep-HPLC to give the final product A-8 as a white solid.
A solution of (A-8, 1.0 equiv) in HCl (2 M aqueous, 8 mL/gm) was stirred at 110° C. for 16 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature, basified to pH 6 using NaOH (2 M aqueous) the mixture was concentrated under vacuum to give the desired product A-9, 90% yield as a white solid.
To a solution of compound methyl 5-hydroxy-2-methylbenzoate (1.0 equiv) in dry toluene in a sealed tube corresponding alcohol (1.5 equiv) and cyanomethylene trimethylphosphorane (CMMP) (2.0 equiv) were added. The reaction mixture was degassed and purged with argon, and then the tube was sealed and heated to 110° C. overnight. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=20:1) to provide the desired product A-10 as a white solid.
A solution of (A-10, 1.0 equiv) in HCl (2 M aqueous, 8 mL/gm) was stirred at 110° C. for 16 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature, basified to pH 6 using NaOH (2 M aqueous) the mixture was concentrated under vacuum to give the desired product A-11, 90% yield as a white solid.
White solid, 89% yield. 1H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.54 (s, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.16 (s, 1H), 3.91 (d, J=18.0 Hz, 2H), 3.56 (d, J=11.6 Hz, 2H), 3.01 (s, 3H), 2.90 (s, 2H), 2.56 (s, 3H). 13C NMR (101 MHz, CD3OD) δ 171.61, 140.60, 137.39, 135.72, 132.95, 129.09, 127.92, 116.85, 55.85, 53.42, 42.96, 35.38, 25.58, 21.37. LCMS calcd for C14H18NO2 (M+H+): 232.1259; Found: 232.1259.
White solid, 89% yield. 1H NMR (400 MHz, CD3OD) δ 7.38 (d, J=2.7 Hz, 1H), 7.12 (d, J1=8.4 Hz, 1H), 7.01 (dd, J=8.4, 2.8 Hz, 1H), 3.80 (dp, J=12.7, 2.1 Hz, 2H), 3.28-3.17 (m, 1H), 2.87 (s, 6H), 2.80-2.62 (m, 2H), 2.15 (dt, J=12.5, 2.9 Hz, 2H), 1.82 (qd, J=12.2, 4.1 Hz, 2H). 13C NMR (101 MHz, CD3OD) δ 174.64, 150.70, 136.31, 133.99, 131.56, 121.53, 119.64, 65.68, 50.36, 41.32, 28.25, 21.48. LCMS calcd for C15H23N2O2 (M+H+): 262.1681; Found: 262.1685.
White solid, 89% yield. 1H NMR (400 MHz, CD3OD) δ 7.76 (d, J=2.8 Hz, 1H), 7.34 (dd, J=8.5, 2.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 4.22 (d, J=10.6 Hz, 2H), 3.95 (d, J=10.7 Hz, 2H), 3.38-3.32 (m, 2H), 3.27 (t, J=5.5 Hz, 2H), 2.98 (s, 3H), 2.52 (s, 3H), 2.20 (t, J=5.7 Hz, 2H), 2.17-2.07 (m, 2H). 13C NMR (101 MHz, CD3OD) δ 170.48, 147.20, 136.26, 133.88, 132.37, 123.21, 121.44, 65.67, 49.95, 42.68, 35.30, 34.34, 21.07. LCMS calcd for C16H23N2O2 (M+H+): 275.1681; Found: 275.1684.
White solid, 86% yield. 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 6.98 (d, J=12.3 Hz, 2H), 6.74 (d, J=8.3 Hz, 1H), 3.86-3.76 (m, 2H), 3.52-3.41 (m, 2H), 3.18-2.99 (m, 2H), 2.69 (s, 3H), 2.34 (d, J=16.6 Hz, 3H), 2.21-2.16 (m, 1H), 2.05-1.99 (m, 1H), 1.92-1.83 (m, 2H). 13C NMR (101 MHz, CD3OD) δ 148.88, 141.94, 132.13, 127.52, 116.42, 115.35, 63.62, 53.33, 39.19, 25.35, 24.10, 19.78. LCMS calcd for C15H21N2O2 (M+H+): 261.1525; Found: 260.1527.
White solid, 86% yield. 1H NMR (400 MHz, CD3OD) δ 6.99 (d, J=8.2 Hz, 1H), 6.79-6.68 (m, 1H), 6.50 (dd, J=8.3, 2.5 Hz, 1H), 4.41 (s, 1H), 4.10 (s, 1H), 3.54 (d, J=10.6 Hz, 1H), 3.44 (d, J=10.9 Hz, 1H), 3.04 (d, J=11.1 Hz, 1H), 2.69 (s, 3H), 2.30 (s, 3H), 2.21 (d, J=11.1 Hz, 1H), 2.10 (d, J=11.3 Hz, 1H), 1.88 (s, 1H). 13C NMR (101 MHz, CD3OD) δ 178.07, 144.97, 141.73, 132.54, 125.46, 114.59, 113.50, 66.81, 60.96, 57.73, 52.51, 41.25, 23.92, 19.81. LCMS calcd for C14H19N2O2 (M+H+): 247.1368; Found: 247.1369.
White solid, 91% yield. 1H NMR (400 MHz, CD3OD) δ 7.17 (t, J=4.4 Hz, 1H), 7.12-6.98 (m, 1H), 6.92 (dq, J=9.5, 3.0 Hz, 1H), 3.26 (q, J=3.7 Hz, 4H), 3.10 (t, J=5.1 Hz, 4H), 2.72 (s, 3H), 2.40 (d, J=4.5 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 177.20, 149.26, 140.47, 132.53, 129.34, 118.90, 117.30, 54.69, 48.36, 44.09, 20.05. LCMS calcd for C13H19N2O2 (M+H+): 235.1368; Found: 235.1369.
White solid, 76% yield. 1H NMR (400 MHz, CD3OD) δ 7.11 (d, J=2.7 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.85 (dd, J=8.3, 2.7 Hz, 1H), 3.57-3.47 (m, 2H), 3.32-3.20 (m, 1H), 3.03 (ddd, J=12.3, 6.1, 2.6 Hz, 1H), 2.99-2.88 (m, 2H), 2.71 (s, 3H), 2.70-2.64 (m, 1H), 2.35 (s, 3H), 1.29 (d, J=6.4 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 177.12, 149.11, 140.35, 132.56, 129.44, 118.98, 117.32, 60.29, 55.40, 55.01, 48.49, 40.93, 20.07, 14.84. LCMS calcd for C14H21N2O2 (M+H+): 249.1525; Found: 249.1528.
White solid, 70% yield. 1H NMR (400 MHz, CD3OD) δ 7.12 (q, J=3.6 Hz, 1H), 7.04 (dd, J=8.6, 2.6 Hz, 1H), 6.86-6.81 (m, 1H), 3.41 (t, J=5.8 Hz, 1H), 3.35 (d, J=3.3 Hz, 1H), 3.19 (d, J=3.1 Hz, 1H), 3.13-3.10 (m, 1H), 2.48 (d, J=3.8 Hz, 1H), 2.43 (s, 1H), 2.37 (d, J=2.8 Hz, 3H), 1.91 (d, J=2.7 Hz, 3H), 0.82 (d, J=6.4 Hz, 2H), 0.67-0.54 (m, 2H). 13C NMR (101 MHz, CD3OD) δ 178.37, 150.26, 141.57, 132.05, 128.06, 117.60, 116.56, 52.74, 44.29, 42.97, 36.95, 23.91, 19.88, 11.91. LCMS calcd for C15H21N2O2 (M+H+): 261.1525; Found: 260.1528.
White solid, 80% yield. 1H NMR (400 MHz, CD3OD) δ 6.99 (s, 1H), 6.93 (s, 1H), 6.68-6.57 (m, 1H), 3.56-3.46 (m, 2H), 3.37 (d, J=10.0 Hz, 2H), 3.18-3.10 (m, 2H), 3.04 (d, J=9.7 Hz, 4H), 2.76 (s, 3H), 2.33 (s, 3H). 13C NMR (101 MHz, CD3OD) δ 177.63, 147.84, 140.33, 132.21, 126.65, 116.69, 115.53, 62.14, 54.73, 42.35, 40.61, 19.98. LCMS calcd for C14H19N2O2 (M+H+): 246.1368; Found: 246.1368.
White solid, 48% yield. 1H NMR (400 MHz, CD3OD) δ 7.34 (s, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.55 (dd, J=8.3, 2.6 Hz, 1H), 4.05 (t, J=7.4 Hz, 2H), 3.76 (dd, J=8.0, 5.5 Hz, 2H), 3.65 (p, J=6.2 Hz, 1H), 2.52 (s, 6H), 2.40 (s, 3H). 13C NMR (101 MHz, CD3OD) δ 173.91, 150.29, 132.79, 129.58, 129.46, 115.42, 113.94, 57.49, 56.00, 41.36, 20.53. LCMS calcd for C13H19N2O2 (M+H+): 235.1368; Found: 250.1369.
White solid, 87% yield. 1H NMR (400 MHz, CD3OD) δ 7.29 (d, J=3.5 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.85 (dd, J=8.5, 2.7 Hz, 1H), 3.07 (dt, J=13.2, 3.1 Hz, 2H), 2.53 (ddd, J=14.4, 12.6, 2.2 Hz, 2H), 2.46 (s, 3H), 2.25 (d, J=1.4 Hz, 6H), 1.84-1.80 (m, 1H), 1.36 (qd, J=12.2, 4.1 Hz, 2H). 13C NMR (101 MHz, CD3OD) δ 169.55, 156.84, 133.64, 131.40, 120.51, 118.06, 63.34, 52.21, 46.31, 41.40, 29.71, 20.80. LCMS calcd for C14H21N2O2 (M+H+): 249.1525; Found: 249.1529.
White solid, 75% yield. 1H NMR (400 MHz, CD3OD) δ 7.30 (d, J=2.9 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.4, 2.8 Hz, 1H), 4.69 (dd, J=9.1, 4.9 Hz, 1H), 4.36-4.30 (m, 2H), 4.18 (td, J=9.5, 5.5 Hz, 1H), 3.97 (q, J=9.4 Hz, 1H), 2.95 (s, 3H), 2.58 (dd, J=7.3, 4.9 Hz, 1H), 2.44 (s, 3H), 2.40-2.35 (m, 1H). 13C NMR (101 MHz, CD3OD) δ 174.90, 156.85, 138.63, 133.04, 131.26, 117.22, 115.77, 69.49, 67.42, 54.17, 41.38, 20.29, 19.58. LCMS calcd for C13H18NO3 (M+H+): 236.1208; Found: 236.1209.
White solid, 89% yield. 1H NMR (400 MHz, CD3OD) δ 6.88 (dq, J=6.5, 2.5 Hz, 2H), 6.59 (dt, J=7.7, 3.6 Hz, 1H), 4.85 (t, J=5.4 Hz, 1H), 4.78-4.69 (m, 2H), 3.24 (dt, J=12.5, 5.2 Hz, 1H), 3.10-3.00 (m, 1H), 2.70-2.63 (m, 3H), 2.26 (dt, J=14.2, 7.1 Hz, 1H), 2.20-2.16 (m, 3H), 2.00 (dt, J=13.9, 7.0 Hz, 1H). 13C NMR (101 MHz, CD3OD) δ 177.06, 155.52, 141.74, 132.78, 129.92, 116.95, 116.30, 61.47, 55.15, 41.86, 32.03, 19.95. LCMS calcd for C13H18NO3 (M+H+): 236.1208; Found: 236.1209.
White solid, 85% yield. 1H NMR (400 MHz, CD3OD) δ 6.73 (d, J=8.4 Hz, 1H), 6.52 (td, J=8.5, 7.2, 2.7 Hz, 1H), 3.89 (t, J=5.5 Hz, 1H), 3.43-3.33 (m, 1H), 3.31 (td, J=7.0, 3.6 Hz, 1H), 2.96-2.68 (m, 2H), 2.60 (s, 3H), 2.02 (d, J=4.2 Hz, 3H), 1.98-1.79 (m, 1H), 1.73 (dq, J=14.4, 7.2 Hz, 2H), 1.66 (d, J=6.6 Hz, 1H). 13C NMR (101 MHz, CD3OD) δ 176.33, 156.93, 155.38, 132.76, 130.35, 116.48, 115.16, 68.58, 67.42, 58.14, 41.34, 27.75, 23.36, 20.05. LCMS calcd for C14H20NO3 (M+H+): 250.1365; Found: 250.1369.
White solid, 87% yield. 1H NMR (400 MHz, CD3OD) δ 6.78-6.72 (m, 1H), 6.66 (s, 1H), 6.48 (td, J=8.1, 2.6 Hz, 1H), 3.83 (d, J=6.5 Hz, 1H), 3.37-3.29 (m, 1H), 3.25 (dt, J=11.9, 6.1 Hz, 1H), 2.96-2.78 (m, 1H), 2.79-2.64 (m, 1H), 2.54 (s, 3H), 1.97 (d, J=4.5 Hz, 3H), 1.88 (dt, J=15.1, 7.3 Hz, 1H), 1.66 (dp, J=14.0, 7.0 Hz, 2H), 1.52 (dd, J=13.3, 7.1 Hz, 1H). 13C NMR (101 MHz, CD3OD) δ 175.81, 156.92, 155.36, 132.86, 130.67, 116.72, 115.38, 68.57, 67.36, 58.13, 41.30, 27.72, 23.34, 20.15. LCMS calcd for C14H20NO3 (M+H+): 250.1365; Found: 250.1366.
White solid, 80% yield. 1H NMR (400 MHz, CD3OD) δ 7.09 (d, J=8.4 Hz, 1H), 6.96 (d, J=2.8 Hz, 1H), 6.71 (dd, J=8.3, 2.8 Hz, 1H), 4.35 (dd, J=10.7, 6.2 Hz, 1H), 2.80 (s, 3H), 2.41 (s, 3H), 1.77 (td, J=11.6, 7.6 Hz, 2H), 1.56-1.52 (m, 1H), 1.46 (d, J=7.3 Hz, 1H). 13C NMR (101 MHz, CD3OD) δ 177.36, 155.27, 142.38, 132.72, 129.96, 116.08, 114.92, 63.42, 27.53, 25.07, 13.93. LCMS calcd for C12H13NO3 (M+H+): 222.1052; Found: 222.1053.
White solid, 72% yield. 1H NMR (400 MHz, CD3OD) δ 7.21 (s, 1H), 6.91 (d, J=18.9 Hz, 1H), 6.85-6.73 (m, 1H), 5.38-5.17 (m, 1H), 5.12 (d, J=19.3 Hz, 1H), 4.15 (d, J=11.0 Hz, 1H), 4.04 (s, 2H), 3.85 (d, J=47.6 Hz, 2H), 2.82 (s, 3H), 2.29 (d, J=17.0 Hz, 1H), 2.15 (s, 3H). 13C NMR (101 MHz, CD3OD) δ 170.48, 156.79, 134.29, 133.88, 132.36, 119.57, 117.43, 66.40, 63.47, 63.23, 35.90, 35.68, 20.92. LCMS calcd for C14H19FNO3 (M+H7): 268.1271; Found: 268.1275.
To a solution of (S)—N—((R)-1-(2-chloroquinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (A-6) (1.0 equiv) in dioxane/H2O (4:1) in a microwave reaction vial was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 equiv) and tripotassium phosphate (1.8 equiv). The mixture was purged with nitrogen for 5 min, then XPhosPdG2 (0.1 equiv) was added. The resulting mixture was heated in the biotage microwave reactor at 140° C. for 90 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was diluted with EtOAc and extracted with water and brine. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue for the next step without purification. The crude was dissolved in 1,4-dioxane (0.1 M) and then concentrated HCl was added. The reactions were stirred at room temperature. When the starting material was consumed entirely as monitored by LCMS, solvent was removed under vacuum to give 100, which was used in the next step without purification. Yellow solid, 67% yield. 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 8.16 (s, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.84 (s, 1H), 7.71-7.61 (m, 1H), 7.48 (t, J=7.7 Hz, 1H), 3.93 (s, 3H), 1.51 (d, J=6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 154.15, 153.22, 149.22, 139.25, 131.74, 130.74, 129.71, 127.05, 125.64, 124.69, 123.91, 115.55, 47.10, 39.24, 24.40. LCMS calcd for C15H17N4 (M+H+): 253.1375; Found: 253.1376.
The corresponding acid (A-9) or (A-11) (1.1 equiv), HATU (1.1 equiv) and DIPEA (3.0 equiv) were dissolved in DMF (0.2 M) and stirred for 15 min. After that (R)-1-(2-(1-methyl-1H-pyrazol-4-yl)quinolin-4-yl)ethan-1-amine (100) (1.0 equiv) was added and stirred at room temperature overnight. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with EtOAc and was then washed with saturated aq. NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by Prep-HPLC to give the final product.
White solid, 67% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=7.4 Hz, 1H), 8.62 (s, 1H), 8.39 (d, J=8.5 Hz, 1H), 8.27 (s, 1H), 8.12 (d, J=8.5 Hz, 1H), 8.07 (s, 1H), 7.91 (t, J=7.7 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.01 (d, J=7.9 Hz, 2H), 5.92 (q, J=7.1 Hz, 1H), 4.67 (dt, J=9.4, 5.0 Hz, 1H), 4.35-4.27 (m, 2H), 4.10-4.02 (m, 2H), 3.98 (s, 3H), 3.93 (s, 1H), 2.89 (d, J=4.1 Hz, 3H), 2.45-2.33 (m, 2H), 2.21 (s, 3H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.57, 155.78, 150.34, 138.86, 138.01, 132.17, 132.09, 131.91, 128.35, 127.37, 124.59, 124.36, 116.17, 116.06, 114.21, 68.29, 67.06, 53.12, 45.26, 41.48, 21.38, 18.82. LCMS calcd for C28H32N5O2 (M+H+): 470.2478; Found: 470.2479.
White solid, 64% yield. 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J=4.1 Hz, 1H), 8.57 (d, J=8.5 Hz, 1H), 8.40 (s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.20 (d, J=3.1 Hz, 1H), 8.07 (ddd, J=8.5, 7.0, 1.1 Hz, 1H), 7.89 (dd, J=8.6, 7.3 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 6.97 (d, J=8.0 Hz, 2H), 6.04 (q, J=7.1 Hz, 1H), 4.05 (s, 5H), 3.73 (dd, J=13.5, 2.7 Hz, 2H), 3.22-3.10 (m, 2H), 2.88 (s, 3H), 2.37-2.27 (m, 2H), 2.21 (s, 3H), 2.19-2.13 (m, 2H), 1.77 (d, J=7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.18, 150.60, 147.68, 138.71, 137.60, 131.97, 131.58, 127.12, 126.11, 124.61, 124.31, 116.16, 116.12, 114.03, 62.57, 52.02, 51.94, 45.27, 38.75, 23.83, 21.45, 18.67. LCMS calcd for C30H3N6O (M+H+): 495.2794; Found: 495.2798.
White solid, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=7.2 Hz, 1H), 8.72 (d, J=5.7 Hz, 1H), 8.47 (d, J=8.5 Hz, 1H), 8.36 (d, J=4.6 Hz, 1H), 8.26-8.15 (m, 2H), 7.98 (t, J=7.7 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.13 (d, J=3.4 Hz, 1H), 6.77-6.66 (m, 2H), 5.97 (p, J=7.0 Hz, 1H), 4.67 (d, J=20.7 Hz, 1H), 4.41 (s, 1H), 4.04 (s, 3H), 3.75-3.59 (m, 2H), 3.36 (d, J=10.8 Hz, 1H), 3.20-3.06 (m, 1H), 2.93 (d, J=4.8 Hz, 3H), 2.80 (s, 1H), 2.43 (d, J=11.3 Hz, 1H), 2.21 (d, J=6.0 Hz, 4H), 1.70 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.30, 158.76, 150.19, 144.15, 138.96, 137.77, 132.33, 132.04, 131.80, 127.43, 124.57, 124.44, 123.73, 118.06, 116.35, 115.14, 114.58, 112.12, 66.26, 61.28, 56.37, 52.99, 45.40, 42.35, 33.37, 21.37, 18.68. LCMS calcd for C29H19N6O (M+H+): 481.2638; Found: 481.2639.
White solid, 64% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=7.7 Hz, 1H), 8.56 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.89-7.77 (m, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.99-6.95 (m, 2H), 5.96-5.80 (m, 1H), 3.94 (s, 3H), 3.79 (d, J=13.6 Hz, 2H), 3.50 (d, J=11.6 Hz, 2H), 3.21-3.13 (m, 2H), 2.99-2.92 (m, 2H), 2.86 (d, J=17.0 Hz, 3H), 2.15 (s, 3H), 1.61 (d, J=7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.06, 150.75, 147.73, 145.21, 138.66, 137.60, 131.86, 131.70, 131.39, 127.12, 127.01, 124.64, 124.26, 120.85, 118.27, 117.75, 116.10, 115.36, 52.77, 46.33, 45.22, 42.58, 39.47, 21.43, 18.77. LCMS calcd for C28H33N6O (M+H+): 469.2638; Found: 469.2639.
White solid, 62% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=7.2 Hz, 1H), 8.72 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.36 (s, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.18 (s, 1H), 7.97 (t, J=7.7 Hz, 1H), 7.79 (t, J=7.7 Hz, 1H), 7.19 (d, J=9.1 Hz, 1H), 7.09-7.02 (m, 2H), 5.98 (p, J=7.0 Hz, 1H), 4.04 (s, 3H), 3.92 (dd, J=17.3, 13.6 Hz, 2H), 3.63 (d, J=12.4 Hz, 1H), 3.41 (s, 1H), 3.29 (d, J=18.4 Hz, 1H), 3.01 (td, J=13.0, 2.6 Hz, 1H), 2.94 (s, 3H), 2.87-2.75 (m, 1H), 2.23 (s, 3H), 1.70 (d, J=6.9 Hz, 3H), 1.39 (t, J=5.7 Hz, 3H). 1C NMR (101 MHz, DMSO-d6) δ 169.13, 158.77, 150.27, 147.56, 138.94, 137.57, 132.30, 131.96, 131.67, 127.38, 127.02, 125.99, 124.57, 124.42, 117.69, 116.27, 115.21, 59.30, 53.66, 52.98, 46.46, 45.37, 21.43, 18.76, 14.47. LCMS calcd for C29H5N60 (M+H+): 483.2794; Found: 483.2798.
White solid, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J=7.4 Hz, 1H), 8.58 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.21 (s, 1H), 8.10-8.00 (m, 2H), 7.83 (t, J=7.7 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.06 (d, J=9.1 Hz, 1H), 6.99-6.87 (m, 2H), 5.86 (p, J=7.0 Hz, 1H), 3.91 (s, 3H), 3.52 (d, J=43.8 Hz, 2H), 3.44-3.21 (m, 3H), 3.12-3.00 (m, 1H), 2.84 (s, 3H), 2.11 (s, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.18 (d, J=25.1 Hz, 2H), 0.96-0.73 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 169.14, 150.42, 147.98, 138.86, 137.60, 132.18, 131.80, 131.54, 127.27, 126.83, 124.58, 124.38, 118.08, 117.60, 116.24, 115.18, 51.74, 49.96, 45.26, 44.40, 42.12, 36.25, 21.48, 18.78. LCMS calcd for C30H35N6O (M+H+): 494.2794; Found: 494.2798.
White solid, 63% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (dd, J=7.7, 3.4 Hz, 1H), 8.50 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.96 (s, 1H), 7.79 (t, J=7.7 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.02-6.98 (m, 1H), 6.69-6.53 (m, 2H), 5.85 (p, J=7.0 Hz, 1H), 3.90 (s, 3H), 3.88 (t, J=3.7 Hz, 1H), 3.81 (s, 1H), 3.40 (t, J=9.1 Hz, 2H), 3.25 (d, J=17.6 Hz, 2H), 3.17 (d, J=6.2 Hz, 2H), 3.04-2.93 (m, 2H), 2.77 (dd, J=20.9, 4.4 Hz, 3H), 2.10 (d, J=1.9 Hz, 2H), 1.56 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.29, 158.58, 146.76, 138.55, 137.64, 131.68, 131.49, 126.91, 124.67, 124.23, 124.18, 116.00, 61.12, 60.40, 54.15, 52.78, 45.05, 40.96, 21.48, 18.73. LCMS calcd for C30H35N6O (M+H+): 495.2794; Found: 495.2797.
White solid, 59% yield. 1H NMR (400 MHz, CD3OD) δ 9.03-8.96 (m, 1H), 8.87 (d, J=8.6 Hz, 1H), 8.70 (dt, J=7.8, 3.5 Hz, 1H), 8.57 (d, J=8.6 Hz, 1H), 8.49 (dt, J=9.7, 4.2 Hz, 1H), 8.39 (t, J=8.3 Hz, 1H), 8.26-8.13 (m, 11H), 7.53 (d, J=8.2 Hz, 11H), 7.30 (d, J=8.1 Hz, 2H), 6.37 (q, J=7.0 Hz, 1H), 5.50 (d, J=14.7 Hz, 1H), 4.37 (s, 3H), 4.16 (s, 2H), 3.78-3.65 (m, 1H), 3.62 (t, J=1.8 Hz, 3H), 3.51 (d, J=16.4 Hz, 1H), 2.91 (d, J=20.2 Hz, 1H), 2.67 (s, 1H), 2.56 (s, 3H), 2.09 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.47, 158.60, 154.38, 150.82, 138.64, 138.25, 132.18, 131.82, 131.38, 127.02, 124.64, 124.22, 116.07, 115.22, 75.99, 60.22, 53.98, 45.10, 40.96, 30.62, 21.41, 18.78. LCMS calcd for C28H32N5O2 (M+H+): 470.2478; Found: 470.2479.
White solid, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (t, J=6.9 Hz, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.52-8.43 (m, 1H), 8.36 (s, 1H), 8.25-8.14 (m, 2H), 7.97 (ddd, J=8.3, 6.9, 1.2 Hz, 1H), 7.79 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.25 (dd, J=8.4, 3.4 Hz, 1H), 7.16-7.09 (m, 1H), 6.00 (t, J=7.2 Hz, 1H), 4.40 (dd, J=11.1, 3.5 Hz, 1H), 4.36-4.24 (m, 1H), 3.86 (td, J=7.5, 3.4 Hz, 1H), 3.75-3.62 (m, 1H), 3.27-3.13 (m, 1H), 3.03 (d, J=3.9 Hz, 3H), 2.37-2.30 (m, 1H), 2.27 (s, 3H), 2.17-2.08 (m, 1H), 1.98 (qd, J=7.5, 5.2 Hz, 1H), 1.88 (dt, J=11.4, 3.9 Hz, 1H), 1.70 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.58, 159.06, 155.78, 150.28, 138.95, 137.96, 132.32, 132.06, 128.38, 127.42, 124.58, 124.40, 116.25, 116.01, 114.15, 67.22, 66.73, 57.07, 45.27, 41.14, 26.75, 22.49, 21.37, 18.82. LCMS calcd for C29H34N5O2 (M+H+): 484.2634; Found: 484.2636.
White solid, 66% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J=7.4 Hz, 1H), 8.74 (s, 1H), 8.55-8.40 (m, 1H), 8.38 (s, 1H), 8.26-8.12 (m, 2H), 7.99 (ddd, J=8.4, 6.9, 1.2 Hz, 1H), 7.80 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15-7.01 (m, 2H), 6.01 (d, J=7.1 Hz, 1H), 4.40 (dd, J=11.2, 3.5 Hz, 1H), 4.34-4.24 (m, 1H), 4.04 (s, 3H), 3.93-3.80 (m, 1H), 3.67 (td, J=13.6, 12.7, 7.7 Hz, 1H), 3.21 (dd, =11.2, 7.2 Hz, 1H), 3.03 (d, J=4.3 Hz, 3H), 2.35-2.29 (m, 1H), 2.27 (s, 3H), 2.13 (qq, J=7.6, 4.6 Hz, 1H), 2.06-1.95 (m, 1H), 1.89 (dtd, J=14.1, 8.3, 5.8 Hz, 1H), 1.71 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.58, 158.73, 155.78, 150.14, 139.04, 137.91, 132.45, 132.15, 132.07, 128.40, 127.52, 124.57, 124.45, 116.30, 116.02, 114.17, 67.22, 66.74, 57.07, 45.32, 41.13, 26.75, 22.49, 21.35, 18.84. LCMS calcd for C29H34N5O2 (M+H+): 484.2634; Found: 484.2638.
White solid, 56% yield, 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=7.4 Hz, 1H), 8.69 (s, 1H), 8.42 (d, J=8.5 Hz, 1H), 8.33 (s, 1H), 8.17 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 7.01 (dd, J=8.4, 2.8 Hz, 1H), 5.94 (d, J=7.1 Hz, 1H), 4.42 (d, J=11.0 Hz, 1H), 4.28 (dd, J=11.1, 6.7 Hz, 1H), 4.10 (s, 1H), 3.99 (s, 3H), 3.55 (dd, J=23.0, 14.0 Hz, 1H), 3.05 (s, 3H), 2.58 (d, J=5.8 Hz, 1H), 2.32 (d, J=33.4 Hz, 1H), 2.21 (s, 3H), 1.65 (d, J=7.0 Hz, 3H). HC NMR (101 MHz, DMSO-d6) δ 168.57, 159.13, 155.69, 150.07, 139.07, 137.94, 132.51, 132.23, 132.05, 128.48, 127.57, 124.56, 124.47, 117.84, 116.34, 116.01, 114.93, 114.26, 67.16, 66.01, 45.34, 43.70, 34.81, 21.34, 18.82. LCMS calcd for C29H33FN5O2 (M+H+): 502.2540; Found: 502.2544.
White solid, 73% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=7.4 Hz, 1H), 8.67 (s, 1H), 8.41 (d, J=8.5 Hz, 1H), 8.30 (s, 1H), 8.25-8.04 (m, 2H), 7.92 (t, J=7.6 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.07 (d, =8.3 Hz, 1H), 6.84-6.61 (m, 2H), 5.93 (p, J=7.0 Hz, 1H), 3.64 (t, J=7.4 Hz, 2H), 3.29-3.15 (m, 2H), 2.90 (s, 3H), 2.50 (d, J=3.2 Hz, 2H), 2.15 (s, 3H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.43, 158.74, 150.14, 146.89, 138.97, 137.68, 132.36, 132.09, 131.68, 127.45, 124.59, 124.46, 123.67, 116.34, 114.48, 112.06, 53.07, 47.27, 45.31, 43.05, 38.55, 21.40, 18.56, 14.39. LCMS calcd for C29H32N5O (M+H+): 466.2529; Found: 466.2528.
White solid, 71% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.04 (d, J=7.2 Hz, 1H), 8.74 (s, 1H), 8.47 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 8.25-8.13 (m, 2H), 7.98 (t, J=7.8 Hz, 2H), 7.79 (t, J=7.8 Hz, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.99 (d, J=7.1 Hz, 2H), 5.94 (p, J=7.1 Hz, 1H), 4.00 (s, 3H), 3.82 (d, J=12.3 Hz, 2H), 3.33 (d, J=10.4 Hz, 1H), 2.79 (d, J=4.6 Hz, 6H), 2.72 (d, J=12.5 Hz, 2H), 2.50 (d, J=3.0 Hz, 2H), 2.17 (s, 3H), 2.11-2.03 (m, 2H), 1.72 (td, J=13.3, 10.8, 4.8 Hz, 2H), 1.65 (d, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.26, 158.74, 149.59, 148.21, 139.31, 137.31, 132.87, 131.67, 127.88, 126.53, 124.65, 124.53, 118.07, 117.65, 116.52, 115.65, 114.75, 62.82, 48.23, 48.16, 45.56, 25.93, 21.32, 18.76. LCMS calcd for C30H7N6O (M+H+): 497.2951; Found: 497.2956.
White solid, 55% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.07-8.96 (m, 1H), 8.64 (s, 1H), 8.39 (d, J=8.5 Hz, 1H), 8.28 (s, 1H), 8.18-8.04 (m, 2H), 7.90 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 6.79 (d, J=4.4 Hz, 2H), 5.92 (p, J=7.2 Hz, 1H), 4.69 (t, J=7.3 Hz, 1H), 4.42 (s, 2H), 4.34-4.20 (m, 1H), 4.15-4.03 (m, 1H), 3.98 (d, J=2.0 Hz, 3H), 2.87 (s, 3H), 2.85 (s, 3H), 2.16 (s, 3H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ169.11, 158.76, 150.42, 147.25, 138.83, 137.74, 132.15, 131.78, 131.65, 127.26, 126.27, 124.60, 124.36, 117.20, 116.24, 115.41, 115.17, 60.32, 59.20, 48.93, 45.28, 42.14, 35.81, 21.40, 18.69.
LCMS calcd for C28H33N6O (M+H+): 469.2638; Found: 469.2639.
White solid, 56% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=7.4 Hz, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.19-8.11 (m, 2H), 7.93 (t, J=7.8 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.81 (ddd, J=13.6, 8.4, 2.7 Hz, 1H), 6.72 (dd, J=4.8, 2.7 Hz, 1H), 5.92 (p, J=7.0 Hz, 1H), 4.16-4.06 (m, 1H), 3.99 (s, 3H), 3.85 (dd, J=42.1, 7.0 Hz, 2H), 3.58 (dd, J=15.3, 7.2 Hz, 2H), 2.87 (d, J=9.3 Hz, 3H), 2.82 (d, J=5.3 Hz, 1H), 2.78 (d, J=4.8 Hz, 1H), 2.14 (s, 3H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.51, 159.11, 150.11, 147.34, 147.13, 138.97, 137.74, 132.36, 132.10, 131.58, 127.45, 124.57, 124.46, 123.31, 116.36, 114.51, 111.92, 59.74, 58.56, 53.99, 45.35, 41.64, 28.19, 27.36, 21.44, 18.52. LCMS calcd for C29H35N6O (M+H+): 483.2794; Found: 483.2795.
White solid, 59% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=7.4 Hz, 1H), 8.58 (s, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.22 (s, 1H), 8.07 (d, J=8.5 Hz, 1H), 8.00 (s, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.74-7.57 (m, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.87-6.71 (m, 2H), 5.84 (d, J=7.2 Hz, 1H), 5.11 (d, J=17.5 Hz, 1H), 4.95 (t, J=13.1 Hz, 1H), 4.66 (t, J=13.7 Hz, 1H), 4.31 (s, 1H), 4.26-4.01 (m, 1H), 3.91 (s, 3H), 2.86 (s, 3H), 2.14 (s, 3H), 1.58 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.36, 158.79, 153.94, 150.45, 138.86, 138.29, 132.32, 132.17, 131.78, 127.28, 126.36, 124.60, 124.32, 118.05, 116.25, 115.13, 65.53, 62.25, 61.74, 45.26, 21.35, 18.77. LCMS calcd for C27H30N5O2 (M+H+): 456.2321; Found: 456.2324.
White solid, 63% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.13-8.96 (m, 1H), 8.63 (s, 1H), 8.37 (d, J=8.6 Hz, 1H), 8.27 (s, 1H), 8.17-7.99 (m, 2H), 7.89 (d, J=7.3 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.03-6.96 (m, 2H), 5.92 (p, J=6.9 Hz, 1H), 4.31 (t, J=8.4 Hz, 1H), 4.21-4.03 (m, 4H), 3.97 (d, J=8.6 Hz, 3H), 3.85 (t, J=8.1 Hz, 1H), 3.18 (dd, J=14.5, 7.5 Hz, 1H), 2.91-2.81 (m, 3H), 2.21 (d, J=12.9 Hz, 3H), 1.63 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.64, 158.75, 156.44, 156.33, 150.45, 138.84, 137.97, 132.14, 132.04, 131.76, 127.99, 127.26, 124.61, 124.34, 116.19, 115.84, 114.22, 114.09, 67.56, 57.95, 45.20, 41.80, 28.81, 28.53, 21.39, 18.80. LCMS calcd for C28H32N5O2 (M+H+): 470.2478; Found: 470.2478.
White solid, 62% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J=7.3 Hz, 1H), 8.70 (s, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=9.5 Hz, 2H), 5.93 (p, J=7.0 Hz, 1H), 4.04 (dd, J=10.5, 6.6 Hz, 2H), 3.99 (s, 3H), 3.81 (dd, J=10.5, 6.4 Hz, 2H), 3.20 (t, J=5.4 Hz, 2H), 3.11 (t, J=5.3 Hz, 2H), 2.87 (d, J=4.8 Hz, 3H), 2.18 (s, 3H), 1.93 (d, J=5.9 Hz, 4H), 1.65 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.11, 158.78, 149.97, 147.92, 139.09, 137.41, 132.55, 132.28, 131.66, 127.58, 124.57, 124.52, 118.47, 116.38, 116.12, 64.33, 46.82, 45.43, 42.06, 34.46, 33.60, 32.89, 21.34, 18.81. LCMS calcd for C31H37N6O (M+H+): 509.2951; Found: 509.2952.
White solid, 50% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=8.7 Hz, 1H), 7.93 (d, J=12.3 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 6.91-6.74 (m, 2H), 3.96 (s, 3H), 3.77 (s, 8H), 3.33 (d, J=34.5 Hz, 4H), 2.83 (s, 3H), 2.50 (s, 3H), 2.23-2.08 (m, 3H), 1.62 (d, J=7.1 Hz, 3H), 1.22 (s, 3H). 13C NMR (101 MHz, CD3OD) δ 172.57, 172.48, 149.11, 143.92, 139.82, 137.55, 135.49, 135.45, 132.88, 130.35, 129.28, 126.51, 125.68, 122.67, 119.83, 116.89, 116.67, 108.87, 61.39, 55.44, 54.92, 47.91, 40.90, 40.22, 21.01, 18.95, 14.68. LCMS calcd for C29H35N6O (M+H+): 483.2794; Found: 483.2797.
White solid, 49% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=7.2 Hz, 1H), 8.52 (s, 1H), 8.30 (d, J=8.7 Hz, 1H), 8.17 (d, J=3.7 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.93 (d, J=12.3 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.91-6.74 (m, 2H), 5.91 (t, J=7.9 Hz, 1H), 3.96 (s, 3H), 3.38-3.25 (m, 4H), 2.83 (s, 3H), 2.22-2.08 (m, 3H), 1.62 (d, J=7.1 Hz, 3H), 1.22 (s, 3H). 13C NMR (101 MHz, CD3OD) δ 172.60, 163.05, 161.81, 161.45, 149.61, 148.86, 140.82, 139.65, 137.58, 135.56, 134.84, 132.83, 130.11, 128.35, 125.86, 125.76, 121.97, 118.93, 118.39, 117.72, 116.11, 115.27, 64.68, 53.68, 47.80, 39.93, 39.58, 26.78, 24.73, 20.89, 18.76. LCMS calcd for C28H33N6O (M+H+): 469.2638; Found: 469.2638.
White solid, 48% yield. 1H NMR (400 MHz, CD3OD) δ 8.74 (d, J=2.6 Hz, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.23 (d, J=5.5 Hz, 2H), 8.17-8.07 (m, 1H), 7.92 (ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.86-6.74 (m, 2H), 6.06 (q, J=7.0 Hz, 1H), 4.07 (s, 3H), 3.98 (tt, J=5.8, 3.2 Hz, 1H), 3.66 (ddd, J=11.2, 3.3, 1.5 Hz, 1H), 3.62-3.54 (m, 1H), 3.35 (d, J=2.8 Hz, 1H), 3.23 (dq, J=7.4, 2.6, 1.9 Hz, 1H), 2.97 (s, 3H), 2.90 (s, 3H), 2.20 (d, J=2.9 Hz, 3H), 1.78 (dd, J=7.1, 1.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.85, 149.88, 146.04, 140.70, 137.86, 135.33, 134.60, 132.95, 129.99, 126.19, 125.81, 122.47, 119.26, 117.60, 117.09, 117.01, 114.06, 113.96, 62.11, 60.38, 51.68, 47.67, 39.91, 20.92, 18.70. LCMS calcd for C28H33N6O (M+H+): 469.2638; Found: 469.2638.
White solid, 68% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J=7.7 Hz, 1H), 8.62 (t, J=4.5 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.31-8.21 (m, 1H), 8.21-8.03 (m, 3H), 7.90 (t, J=7.8 Hz, 2H), 7.72 (t, J=7.9 Hz, 1H), 7.14-7.02 (m, 1H), 6.63 (dd, J=7.1, 3.0 Hz, 2H), 5.92 (q, J=7.4 Hz, 1H), 3.97 (t, =4.6 Hz, 4H), 3.58 (d, J=8.6 Hz, 1H), 3.53-3.42 (m, 2H), 3.24 (t, J=8.3 Hz, 1H), 2.86 (s, 6H), 2.46-2.36 (m, 1H), 2.26-2.17 (m, 1H), 2.16 (d, J=3.5 Hz, 3H), 1.64 (t, J=5.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.43, 150.37, 145.41, 138.83, 137.70, 132.14, 131.80, 131.55, 127.26, 124.59, 124.39, 123.06, 118.03, 116.23, 115.11, 113.86, 111.46, 64.59, 49.46, 46.89, 45.27, 41.74, 41.53, 27.05, 21.47, 18.63. LCMS calcd for C29H35N6O (M+H+): 483.2794; Found: 483.2796.
To a solution of (S)—N—((R)-1-(2-chloroquinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (A-6) (1.0 equiv) in dioxane/H2O (4:1) in a microwave reaction vial was added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 equiv) and tripotassium phosphate (1.8 equiv). The mixture was purged with nitrogen for 5 min, then XPhosPdG2 (0.1 equiv) was added. The resulting mixture was heated in the biotage microwave reactor at 140° C. for 90 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was diluted with EtOAc and extracted with water and brine. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue for the next step without purification. The crude was dissolved in 1,4-dioxane (0.1 M) and then concentrated HCl was added. The reactions were stirred at room temperature. When the starting material was consumed entirely as monitored by LCMS, solvent was removed under vacuum to give 101, which was used in the next step without purification. Yellow solid, 65% yield. 1H NMR (400 MHz, CD30) δ 8.86 (s, 1H), 8.55 (dd, J=12.9, 8.4 Hz, 2H), 8.18 (t, J=7.7 Hz, 1H), 8.04-7.95 (m, 2H), 7.64 (d, J=2.1 Hz, 1H), 5.69 (q, J=6.6 Hz, 1H), 4.16 (s, 3H), 1.90 (d, J=6.4 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 157.09, 149.16, 143.28, 139.43, 136.27, 135.71, 131.24, 125.90, 125.57, 122.52, 117.71, 110.22, 48.33, 40.46, 25.74. LCMS calcd for C15H17N4 (M+H+): 253.1375; Found: 253.1378.
The corresponding acid (A-9) or (A-11) (1.1 equiv), HATU (1.1 equiv) and DIPEA (3.0 equiv) were dissolved in DMF (0.2 M) and stirred for 15 min. After that (R)-1-(2-(1-methyl-1H-pyrazol-3-yl)quinolin-4-yl)ethan-1-amine (101, 1.0 equiv) was added and stirred at room temperature overnight. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with EtOAc and was then washed with saturated aq. NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by Prep-HPLC to give the final product.
White solid, 69% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J=7.3 Hz, 1H), 8.29 (dd, J=8.6, 1.3 Hz, 1H), 8.24 (s, 1H), 8.09 (dd, J=8.5, 1.3 Hz, 1H), 7.83 (d, J=2.3 Hz, 1H), 7.78 (ddd, J=8.3, 6.8, 1.3 Hz, 1H), 7.68-7.61 (m, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 6.99-6.87 (m, 2H), 5.83 (p, J=7.0 Hz, 1H), 3.91 (s, 3H), 3.81-3.71 (m, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.08 (d, J=14.7 Hz, 2H), 2.92 (d, J=12.6 Hz, 2H), 2.80 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.07, 151.26, 149.67, 147.72, 137.66, 133.68, 131.71, 130.91, 128.34, 127.28, 127.24, 125.42, 124.13, 117.81, 115.35, 114.88, 105.61, 52.74, 46.35, 45.30, 42.57, 21.49, 18.80. LCMS calcd for C28H33N60 (M+H1): 469.2638; Found: 469.2639.
White solid, 67% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J=7.4 Hz, 1H), 8.36 (dt, J=8.7, 1.9 Hz, 1H), 8.31 (d, J=6.9 Hz, 1H), 8.16 (dd, J=8.5, 1.3 Hz, 1H), 7.95-7.80 (m, 2H), 7.70 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.21 (dd, J=9.1, 2.7 Hz, 1H), 7.07-7.00 (m, 2H), 5.91 (td, J=7.1, 2.8 Hz, 1H), 4.41-4.32 (m, 1H), 4.24 (dt, J=11.1, 6.9 Hz, 1H), 3.98 (d, J=2.0 Hz, 3H), 3.80 (tt, J=11.0, 5.4 Hz, 1H), 3.74-3.51 (m, 1H), 3.48-3.27 (m, 1H), 3.15 (dq, J=11.2, 7.9 Hz, 1H), 3.08-2.81 (m, 3H), 2.79 (d, J=4.7 Hz, 1H), 2.23 (d, J=5.8 Hz, 3H), 2.10-1.97 (m, 1H), 1.96-1.85 (m, 1H), 1.62 (d, J=7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.53, 158.67, 155.78, 151.34, 138.20, 133.66, 132.04, 130.86, 128.47, 127.22, 125.43, 124.10, 117.94, 115.94, 115.02, 114.95, 114.18, 105.57, 67.19, 66.70, 57.05, 53.79, 45.20, 41.07, 26.77, 22.46, 21.45, 18.86. LCMS calcd for C29H34N5O2 (M+H+): 484.2634; Found: 484.2638.
White solid, 67% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J=7.3 Hz, 1H), 8.35-8.26 (m, 1H), 8.24 (s, 1H), 8.09 (dd, J=8.5, 1.2 Hz, 1H), 7.86-7.74 (m, 2H), 7.63 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.09-6.99 (m, 2H), 6.99-6.88 (m, 2H), 5.82 (p, J=7.0 Hz, 1H), 3.90 (s, 3H), 3.85-3.69 (m, 2H), 3.50 (d, J=12.4 Hz, 1H), 3.31-3.24 (m, 1H), 3.14 (d, J=11.1 Hz, 1H), 2.89 (td, J=12.8, 2.7 Hz, 1H), 2.79 (d, J=3.3 Hz, 3H), 2.73-2.61 (m, 1H), 2.11 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 1.24 (dd, J=6.4, 4.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.14, 159.06, 158.56, 133.80, 131.67, 131.22, 127.83, 127.43, 127.14, 125.40, 124.20, 115.21, 115.06, 105.85, 63.24, 59.30, 53.63, 53.06, 46.44, 45.37, 21.47, 18.76, 14.47. LCMS calcd for C29H35N6O (M+H+): 483.2794; Found: 483.2796.
White solid, 65% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (dd, J=7.4, 3.1 Hz, 1H), 8.31-8.23 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.83 (d, J=2.3 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.63 (ddd, J=8.3, 6.7, 1.2 Hz, 1H), 7.02 (t, J=2.2 Hz, 1H), 6.61-6.55 (m, 2H), 5.84 (q, J=7.1 Hz, 1H), 3.95 (d, J=6.4 Hz, 1H), 3.91 (s, 3H), 3.53 (td, J=7.6, 3.7 Hz, 1H), 3.46-3.37 (m, 2H), 3.24-3.15 (m, 1H), 2.79 (s, 6H), 2.37 (ddt, J=15.5, 7.6, 3.7 Hz, 1H), 2.15 (dd, J=8.4, 4.5 Hz, 1H), 2.11 (d, J=1.9 Hz, 3H), 1.54 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.41, 151.29, 145.39, 137.81, 133.66, 131.55, 130.88, 128.36, 127.21, 125.43, 124.14, 123.28, 123.21, 117.97, 115.05, 114.92, 113.88, 111.62, 105.60, 64.60, 49.49, 46.93, 45.25, 41.75, 41.47, 39.52, 27.02, 21.54, 18.67. LCMS calcd for C29H35N6O (M+H+): 483.2794; Found: 483.2796.
White solid, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J=7.3 Hz, 1H), 8.33-8.21 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 7.86-7.76 (m, 2H), 7.63 (t, J=7.7 Hz, 1H), 7.11-6.99 (m, 2H), 6.95-6.88 (m, 2H), 5.84 (p, J=7.1 Hz, 1H), 3.91 (s, 3H), 3.58-3.45 (m, 2H), 3.45-3.20 (m, 3H), 3.05 (d, J=18.7 Hz, 1H), 2.84 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.18 (d, J=26.8 Hz, 2H), 0.89 (d, J=15.9 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 169.11, 151.31, 149.75, 147.94, 137.75, 133.65, 131.54, 130.85, 128.42, 127.20, 126.97, 125.42, 124.12, 118.00, 117.64, 115.20, 115.08, 115.00, 105.58, 51.74, 50.02, 45.23, 44.41, 42.15, 39.52, 36.26, 21.53, 18.82. LCMS calcd for C30H35N60 (M+H+): 495.2794; Found: 495.2795.
White solid, 71% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J=7.3 Hz, 1H), 8.35-8.28 (m, 1H), 8.24 (s, 1H), 8.09 (dd, J=8.5, 1.3 Hz, 1H), 7.89-7.81 (m, 1H), 7.81-7.73 (m, 1H), 7.63 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.08-6.98 (m, 2H), 6.87-6.80 (m, 2H), 5.83 (q, J=7.0 Hz, 1H), 4.00 (t, J=3.5 Hz, 2H), 3.91 (s, 3H), 3.64 (dt, J=13.5, 3.5 Hz, 2H), 3.05 (d, J=12.4 Hz, 2H), 2.72 (d, J=4.8 Hz, 3H), 2.17-2.12 (m, 2H), 2.11 (s, 3H), 1.96-1.86 (m, 2H), 1.54 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.17, 151.24, 147.66, 137.68, 133.68, 131.58, 130.91, 128.32, 127.23, 126.28, 125.42, 124.14, 117.96, 116.20, 115.04, 114.92, 113.99, 105.62, 68.71, 62.92, 62.54, 53.31, 51.96, 45.30, 39.53, 38.74, 23.86, 21.51, 18.71. LCMS calcd for C30H35N6O (M+H+): 495.2794; Found: 495.2798.
White solid, 63% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J=7.3 Hz, 1H), 8.47-8.37 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.02-7.89 (m, 2H), 7.77 (ddd, J=8.3, 6.8, 1.2 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.81-6.71 (m, 2H), 5.97 (p, J=7.0 Hz, 1H), 4.04 (s, 3H), 3.97-3.88 (m, 1H), 3.54 (dd, J=13.6, 9.2 Hz, 2H), 3.33 (dd, J=18.0, 9.5 Hz, 2H), 3.12 (td, J=11.3, 9.7, 5.0 Hz, 2H), 2.91-2.86 (m, 3H), 2.24 (s, 3H), 1.66 (d, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.36, 151.01, 146.75, 137.63, 133.76, 131.50, 131.12, 127.93, 127.37, 125.43, 124.37, 124.20, 117.88, 115.92, 114.96, 113.45, 105.86, 60.83, 60.26, 53.97, 52.78, 45.29, 40.99, 21.50, 18.77. LCMS calcd for C30H35N6O (M+H+): 495.2794; Found: 495.2798.
To a solution of (S)—N—((R)-1-(2-chloroquinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (A-6) (1.0 equiv) in dioxane/H2O (4:1) in a microwave reaction vial was added 1-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 equiv) and tripotassium phosphate (1.8 equiv). The mixture was purged with nitrogen for 5 min, then XPhosPdG2 (0.1 equiv) was added. The resulting mixture was heated in the biotage microwave reactor at 140° C. for 90 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was diluted with EtOAc and extracted with water and brine. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue for the next step without purification. The crude was dissolved in 1,4-dioxane (0.1 M) and then concentrated HCl was added. The reactions were stirred at room temperature. When the starting material was consumed entirely as monitored by LCMS, solvent was removed under vacuum to give 102, which was used in the next step without purification. Yellow solid, 63% yield. 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.55-8.48 (m, 2H), 8.18 (d, J=8.7 Hz, 1H), 8.02 (d, J=10.1 Hz, 2H), 7.55 (d, J=13.6 Hz, 1H), 5.71-5.61 (m, 1H), 4.45 (d, J=8.6 Hz, 2H), 1.91-1.84 (m, 3H), 1.60 (t, J=7.6 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 156.88, 149.40, 143.38, 139.63, 136.18, 134.24, 131.17, 125.91, 125.52, 122.68, 117.59, 109.93, 48.28, 25.75, 21.07, 15.87. LCMS calcd for C15H19N4 (M+H+): 267.1531; Found: 267.1533.
The corresponding acid (A-11) or (A-9) (1.1 equiv), HATU (1.1 equiv) and DIPEA (3.0 equiv) were dissolved in DMF (0.2 M) and stirred for 15 min. After that (R)-1-(2-(1-ethyl-1H-pyrazol-3-yl)quinolin-4-yl)ethan-1-amine (102, 1.0 equiv) was added and stirred at room temperature overnight. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with EtOAc and was then washed with saturated aq. NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by Prep-HPLC to give the final product.
White solid. 63% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (t, J=4.5 Hz, 1H), 8.34 (dd, J=19.9, 5.3 Hz, 2H), 8.17 (d, J=8.3 Hz, 1H), 7.95 (q, J=2.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.25-7.09 (m, 2H), 7.01 (dt, J=13.1, 3.1 Hz, 2H), 5.92-5.85 (m, 1H), 4.26 (tp, J=6.5, 3.3, 2.7 Hz, 2H), 3.86 (t, J=16.0 Hz, 2H), 3.58 (d, J=12.7 Hz, 1H), 3.37 (d, J=20.1 Hz, 1H), 3.20 (t, J=10.7 Hz, 1H), 2.98 (t, J=12.6 Hz, 1H), 2.78 (dd, J=15.7, 8.2 Hz, 1H), 2.50 (d, J=3.4 Hz, 1H), 2.20 (t, J=2.8 Hz, 3H), 1.62 (dt, J=5.8, 2.8 Hz, 3H), 1.45 (tt, J=6.0, 2.7 Hz, 3H), 1.34 (dt, J=6.2, 2.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.15, 151.29, 149.40, 147.54, 146.03, 137.85, 132.17, 131.64, 130.94, 128.24, 127.24, 127.10, 125.41, 124.15, 117.69, 115.21, 114.94, 105.53, 59.28, 53.63, 53.04, 47.32, 46.46, 45.45, 21.46, 18.78, 15.94, 14.47. LCMS calcd for C3H37N6O (M+H+): 497.2951; Found: 497.2956.
White solid, 63% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J=7.2 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.81-7.73 (m, 1H), 7.67-7.55 (m, 1H), 7.20-7.05 (m, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.95 (d, J=7.0 Hz, 2H), 5.83 (p, J=7.0 Hz, 1H), 4.61 (t, J=6.2 Hz, 1H), 4.27 (t, J=5.1 Hz, 2H), 4.20 (q, J=7.3 Hz, 2H), 4.02 (tt, J=10.2, 5.6 Hz, 1H), 3.85 (tt, J=9.5, 4.5 Hz, 1H), 2.82 (d, J=4.1 Hz, 3H), 2.33 (qd, J=8.4, 7.7, 3.6 Hz, 2H), 2.17 (s, 3H), 1.55 (d, J=6.9 Hz, 3H), 1.39 (t, J=7.2 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.59, 155.80, 151.42, 138.24, 132.15, 132.02, 130.83, 128.44, 127.20, 125.42, 124.11, 116.00, 114.86, 114.25, 105.44, 68.21, 67.09, 53.04, 47.29, 45.37, 41.40, 21.41, 18.93, 18.85, 15.93. LCMS calcd for C29H34N5O2 (M+H+): 484.2634; Found: 484.2638.
White solid, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=7.0 Hz, 1H), 8.80 (dd, J=8.7, 4.2 Hz, 1H), 8.31 (d, J=18.4 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.84 (q, J=7.6, 5.9 Hz, 1H), 7.69 (t, J=5.9 Hz, 1H), 7.15-7.06 (m, 2H), 6.96-6.85 (m, 2H), 5.87 (p, J=6.3 Hz, 1H), 4.27 (dd, J=9.7, 5.3 Hz, 2H), 4.06 (s, 2H), 3.70 (d, J=12.6 Hz, 2H), 3.11 (d, J=12.5 Hz, 2H), 2.78 (d, J=4.5 Hz, 2H), 2.50 (s, 3H), 2.26-2.12 (m, 4H), 2.00-1.95 (m, 1H), 1.69 (d, J=6.3 Hz, 1H), 1.61 (d, J=6.6 Hz, 3H), 1.50-1.36 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.21, 152.91, 151.52, 147.66, 145.31, 140.68, 137.77, 132.06, 131.90, 131.55, 130.69, 130.33, 128.64, 127.48, 127.08, 126.26, 125.41, 124.26, 124.09, 122.09, 117.94, 116.18, 115.02, 114.82, 114.00, 105.75, 105.33, 62.57, 52.00, 47.28, 46.13, 45.39, 38.75, 23.85, 21.47, 20.99, 18.70, 15.95. LCMS calcd for C31H37N6O (M+H+): 509.2951; Found: 509.2953.
White solid. 61% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J=7.1 Hz, 1H), 8.43-8.27 (m, 2H), 8.18 (d, J=8.4 Hz, 1H), 7.99 (d, J=2.3 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.13 (dt, J=11.9, 3.4 Hz, 2H), 6.77-6.62 (m, 2H), 5.93 (p, J=7.1 Hz, 1H), 4.31 (q, J=7.3 Hz, 2H), 3.64 (s, 2H), 3.35 (dd, J=10.9, 7.0 Hz, 1H), 3.13 (d, J=10.8 Hz, 1H), 2.93 (d, J=4.9 Hz, 3H), 2.43 (t, J=5.9 Hz, 1H), 2.25 (d, J=7.2 Hz, 3H), 2.14 (d, J=12.3 Hz, 1H), 1.67 (d, J=7.0 Hz, 3H), 1.51 (t, J=7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.53, 151.70, 144.14, 132.01, 131.72, 130.55, 128.89, 127.01, 125.42, 124.03, 114.88, 112.21, 105.23, 66.28, 56.38, 47.26, 45.33, 42.37, 33.37, 21.46, 18.68, 15.94. LCMS calcd for C30H35N6O (M+H+): 495.2794; Found: 495.2797.
White solid, 64% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J=7.0 Hz, 1H), 8.44 (d, J=8.5 Hz, 1H), 8.36 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.95 (t, J=7.7 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.22-7.12 (m, 2H), 7.05-6.95 (m, 2H), 5.91 (p, J=7.0 Hz, 1H), 4.30 (q, J=7.3 Hz, 2H), 3.84 (s, 2H), 3.53 (d, J=12.3 Hz, 2H), 3.17 (dt, J=18.3, 9.7 Hz, 2H), 2.94 (t, J=12.5 Hz, 2H), 2.88 (s, 3H), 2.19 (s, 3H), 1.63 (d, J=7.0 Hz, 3H), 1.46 (t, J=7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.24, 150.27, 147.72, 137.61, 132.62, 132.01, 131.73, 127.91, 127.27, 126.64, 125.38, 124.42, 117.87, 115.39, 115.17, 106.29, 52.84, 47.53, 46.40, 45.72, 42.61, 21.40, 18.77, 15.91. LCMS calcd for C29H35N6O (M+H+): 483.2794; Found: 483.2795.
White solid, 64% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=7.2 Hz, 1H), 8.31-8.21 (m, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.77 (ddd, J=8.4, 6.8, 1.2 Hz, 1H), 7.62 (td, J=7.5, 6.9, 1.2 Hz, 1H), 7.17-7.10 (m, 1H), 7.01 (d, J=2.3 Hz, 1H), 6.95 (dt, J=5.1, 2.1 Hz, 1H), 5.82 (dd, J=8.5, 5.6 Hz, 1H), 4.29-4.12 (m, 4H), 3.76-3.69 (m, 1H), 3.58-3.48 (m, 1H), 3.39-3.21 (m, 1H), 3.08 (dq, J=11.2, 7.8 Hz, 1H), 2.89 (d, J=4.3 Hz, 2H), 2.72 (d, J=4.7 Hz, 1H), 2.16 (d, J=5.7 Hz, 3H), 2.03-1.94 (m, 1H), 1.86 (tt, J=12.5, 6.3 Hz, 1H), 1.55 (d, J=7.0 Hz, 3H), 1.39 (t, J=7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.58, 158.67, 155.79, 151.55, 138.28, 132.09, 132.01, 130.69, 128.66, 128.44, 127.11, 125.43, 124.07, 118.04, 115.92, 115.12, 114.84, 114.18, 105.33, 67.19, 66.72, 57.04, 47.27, 45.33, 41.06, 26.79, 22.45, 21.41, 18.85, 15.94. LCMS calcd for C30H6N5O2 (M+H+): 498.2791; Found: 498.2795.
White solid, 69% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J=7.2 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.25 (d, J=3.7 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.80 (dd, J=8.4, 6.9 Hz, 1H), 7.64 (ddd, J=8.3, 6.8, 1.4 Hz, 1H), 7.17-7.11 (m, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.99-6.92 (m, 2H), 5.83 (p, J=7.0 Hz, 1H), 4.25-4.14 (m, 4H), 3.74 (dq, J=7.8, 5.2, 3.6 Hz, 1H), 3.62-3.47 (m, 1H), 3.28 (dt, J=30.8, 12.0 Hz, 1H), 3.08 (dq, J=11.3, 7.9 Hz, 1H), 2.90 (s, 3H), 2.72 (d, J=4.7 Hz, 1H), 2.17 (d, J=2.5 Hz, 3H), 2.00 (qd, J=7.6, 2.7 Hz, 1H), 1.84 (ddt, J=18.8, 12.2, 7.4 Hz, 2H), 1.55 (d, J 7.5 Hz, 3H), 1.38 (d, J=7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.61, 155.79, 154.07, 151.27, 138.26, 132.21, 132.02, 130.99, 128.43, 127.29, 125.41, 124.15, 117.87, 115.86, 114.92, 114.26, 105.55, 67.20, 66.72, 57.05, 47.32, 45.40, 41.08, 26.76, 22.45, 21.41, 18.83, 15.93. LCMS calcd for C30H36NO2 (M+H+): 498.2791; Found: 498.2794.
To a solution of 2-chloro-4-methylquinoline (1.0 g, 6.984 mmol) in THF (30 mL) under N2 was added LDA (6.0 mL, 2 M, 12 mmol) at −78° C. The reaction mixture was stirred at −78° C. under N2 for 30 min, followed by the addition of dimethyl carbonate (1.27 g, 14.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. under N2 for 1 h, then quenched with 3 mL sat. NH4Cl at 0° C. The reaction mixture was partitioned between ethyl acetate and H2O (200/50 mL), the organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography using a Biotage (20 g silica gel column, PE:EA=1:0 to 0:1) to afford B-1(744 mg) as a yellow oil.
Yellow oil, 56% yield. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.78-7.70 (m, 1H), 7.63-7.55 (m, 1H), 7.34 (s, 1H), 4.04 (s, 2H), 3.72 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.84, 150.35, 147.97, 143.17, 130.49, 129.28, 127.27, 126.12, 123.56, 123.43, 52.53, 37.79. LCMS calcd for C12H11ClNO2 (M+H+): 236.0400; Found: 236.0400.
To a solution of methyl 2-(2-chloroquinolin-4-yl)acetate (3.0 g, 12.73 mmol) in DMF (60.0 mL) were added 1,2-dibromoethane (3.59 g, 19.1 mmol), Cs2CO3 (8.3 g, 25.5 mmol), tetra-n-butylammonium fluoride (13 mL, 1 M, 13 mmol), and NaOH (1.020 g, 25.5 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then partitioned between ethyl acetate and H2O (250/100 mL). The organic layer was separated, and the aqueous layer was reextracted with ethyl acetate (150 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel chromatography using a Biotage (80 g silica gel column, PE:EA=1:0 to 0:1) to afford B-2.
Yellow solid, 87% yield. 1H NMR (400 MHz, CDCl3) δ 8.04 (t, J=9.1 Hz, 2H), 7.73 (t, J=7.7 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.35 (s, 1H), 3.58 (s, 3H), 1.97-1.77 (m, 3H), 1.32 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 173.20, 150.37, 148.64, 148.06, 130.24, 129.23, 127.30, 127.06, 124.46, 123.40, 52.66, 26.31, 17.01. LCMS calcd for C14H12ClNO2 (M+H+): 262.0557; Found: 262.0559.
To a solution of methyl 1-(2-chloroquinolin-4-yl)cyclopropane-1-carboxylate (2.88 g, 11.02 mmol) in MeOH (60 mL) was added 10% aq. NaOH (15 mL) at 20° C. The reaction mixture was stirred at 20° C. for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then acidified with 1N HCl to pH=1 at 0° C. and partitioned between ethyl acetate and H2O (250/50 mL). The organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (150 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and evaporated in vacuo to afford B-3 (2.68 g) as a yellow solid.
Yellow solid, 99% yield. 1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=7.9 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 7.58 (t, J=7.3 Hz, 1H), 7.45 (s, 1H), 1.81-1.75 (m, 2H), 1.29 (s, 2H). 13C NMR (101 MHz, CD3OD) δ 175.84, 151.95, 151.38, 148.53, 131.80, 128.88, 128.67, 128.36, 126.19, 124.47, 27.24, 17.45. LCMS calcd for C13H11ClNO2 (M+H+): 248.0400; Found: 247.0403.
To a solution of 1-(2-chloroquinolin-4-yl)cyclopropane-1-carboxylic acid (2.50 g, 10.09 mmol) in toluene (60.0 mL) under N2, was added diphenylphosphoryl azide (3060 mg, 11.1 mmol) and TEA (2.25 g, 22.2 mmol) at 20° C. The reaction mixture was stirred at 90° C. under N2 for 2 hours, then evaporated in vacuo to afford a crude. The crude was dissolved in 1,4-dioxane (40 mL), followed by adding aq. NaOH (10%, 20 mL) at 20° C. under N2. The reaction mixture was stirred at 90° C. for 15 hours. LCMS showed a mass peak of the desired product. The reaction mixture was then partitioned between ethyl acetate and H2O (250/150 mL). The organic layer was separated, and the aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in 30 mL MeOH, then 10 mL 1 N HCl was added to the solution at 20° C. The reaction mixture was stirred at 20° C. for 1 h, then partitioned between ethyl acetate and H2O (250/150 mL). The organic layer was discarded, and the aqueous layer was basified with NH3·H2O to pH=9 at 0° C., followed by extraction with DCM (200 mL). The organic layer was washed with brine, dried with anhydrous Na2SO4 and concentrated in vacuo to afford B-4 (1.44 mg, 65%) as a white solid.
To a solution of 1-(2-chloroquinolin-4-yl)cyclopropan-1-amine (1.0 g, 4.573 mmol) in 1,4-dioxane (40.0 mL) under N2 were added sat. aq. Na2CO3 (8.0 mL), Pd(dppf)Cl2 (335 mg, 0.457 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.90 mg, 9.15 mmol) at 20° C. The reaction mixture was stirred at 100° C. under N2 for 15 h. LCMS showed a mass peak of the desired product. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography using a Biotage (20 g silica gel column, PE:EA=1:0 to 0:1) to afford 103. Yellow oil, 87% yield. 1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.61-8.57 (m, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.08 (ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.93 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 4.05 (s, 3H), 1.86-1.73 (m, 2H), 1.63-1.50 (m, 2H). 13C NMR (101 MHz, CD3OD) δ 150.81, 150.71, 141.68, 140.92, 135.13, 135.03, 130.17, 126.57, 126.14, 124.41, 123.52, 117.30, 39.82, 35.34, 12.64. LCMS calcd for C16H17N4 (M+H+): 265.1375; Found: 265.1377.
The corresponding acid (A-11) or (A-9) (1.1 equiv), HATU (1.1 equiv) and DIPEA (3.0 equiv) were dissolved in DMF (0.2 M) and stirred for 15 min. After that (R)-1-(2-(1-ethyl-1H-pyrazol-3-yl)quinolin-4-yl)ethan-1-amine (PDJ-G-10, 1.0 equiv) was added and stirred at room temperature overnight. When the starting material was consumed entirely as monitored by LCMS, the mixture was diluted with EtOAc and was then washed with saturated aq. NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by Prep-HPLC to give the final product.
White solid, 62% yield. 1H NMR (400 MHz, CD3OD) δ 8.83 (s, 1H), 8.75 (d, J=8.3 Hz, 1H), 8.53 (s, 1H), 8.44 (d, J=1.9 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.15-7.99 (m, 1H), 7.88 (t, J=7.6 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.98 (dd, J=8.5, 2.7 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 4.08 (s, 3H), 3.73 (d, J=13.4 Hz, 2H), 3.57 (d, J=11.8 Hz, 2H), 3.27-3.13 (m, 2H), 2.94 (s, 5H), 1.99 (s, 3H), 1.61 (d, J=3.7 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) δ 170.41, 149.99, 147.64, 139.27, 137.55, 132.90, 131.77, 131.57, 129.34, 128.65, 126.98, 126.83, 126.16, 125.89, 120.80, 119.35, 117.75, 115.10, 52.70, 46.26, 42.54, 34.60, 18.37, 14.28. CMS calcd for C29H33N6O (M+H+): 481.2638; Found: 481.2639.
White solid, 58% yield. 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.04 (t, J=7.8 Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4, 2.7 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H), 4.08 (s, 3H), 4.06-3.93 (m, 2H), 3.64 (d, J=12.8 Hz, 2H), 3.09 (d, J=12.9 Hz, 2H), 2.87 (s, 3H), 2.37-2.21 (m, 2H), 2.14 (t, J=6.7 Hz, 2H), 1.98 (s, 3H), 1.59 (d, J=4.7 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) δ 170.52, 159.06, 150.07, 147.57, 139.23, 137.61, 132.83, 131.67, 131.42, 126.90, 126.16, 125.90, 120.75, 118.12, 116.12, 115.20, 113.70, 62.48, 51.87, 39.50, 38.70, 34.59, 23.80, 18.24, 14.25. LCMS calcd for C31H35N6O (M+H+): 507.2794; Found: 507.2796.
White solid, 60% yield. 1H NMR (400 MHz, CD3OD) δ 8.80 (q, J=4.7, 3.5 Hz, 1H), 8.74 (d, J=8.4 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.42 (q, J=3.8, 2.7 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.05 (t, J=7.5 Hz, 1H), 7.87 (t, J=7.2 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.76 (dd, J=8.3, 2.6 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 4.08 (s, 3H), 3.93 (s, 1H), 3.58 (d, J=11.6 Hz, 1H), 3.43 (dt, J=21.2, 10.4 Hz, 3H), 3.13 (s, 2H), 2.90 (d, J=20.4 Hz, 4H), 1.96 (s, 3H), 1.60 (s, 4H). 13C NMR (101 MHz, DMSO-d6) δ 170.68, 149.96, 146.65, 146.46, 139.30, 137.54, 132.94, 131.82, 131.35, 127.02, 126.20, 125.90, 123.90, 120.81, 118.07, 115.81, 115.15, 113.29, 61.02, 60.34, 54.01, 52.66, 40.91, 34.60, 18.36, 14.30. LCMS calcd for C31H35N6O (M+H+): 507.6540; Found: 507.6543.
White solid, 64% yield. 1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.74 (d, J=8.5 Hz, 1H), 8.52 (s, 1H), 8.42 (d, J=1.7 Hz, 1H), 8.25 (d, J=8.6 Hz, 1H), 8.02 (t, J=7.8 Hz, 1H), 7.85 (t, J=7.7 Hz, 1H), 7.04 (d, J=7.3 Hz, 1H), 6.84 (d, J=2.6 Hz, 1H), 5.49 (s, 1H), 5.36 (s, 1H), 4.39 (d, J=9.9 Hz, 1H), 4.26-4.10 (m, 2H), 4.06 (s, 3H), 3.66-3.47 (m, 1H), 3.07 (s, 3H), 2.59 (d, J=27.3 Hz, 1H), 2.43-2.18 (m, 1H), 2.03 (s, 3H), 1.59 (d, J=5.4 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) δ 169.81, 155.57, 152.64, 150.46, 139.06, 132.43, 131.91, 131.18, 129.82, 128.16, 126.65, 126.03, 125.91, 123.95, 120.73, 120.41, 115.89, 114.02, 67.00, 65.99, 62.14, 61.95, 43.60, 34.44, 18.49, 14.25. LCMS calcd for C30H33FN5O2 (M+H+): 514.2540; Found: 514.2544.
White solid, 64% yield. 1H NMR (400 MHz, CD3OD) δ 8.80 (s, 1H), 8.74 (d, J=8.4 Hz, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 8.25 (d, J=8.6 Hz, 1H), 8.05 (dd, J=8.6, 7.0 Hz, 1H), 7.90-7.83 (m, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.98 (dd, J=8.4, 2.5 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.69 (d, J=8.3 Hz, 1H), 4.30 (dd, J=11.5, 3.2 Hz, 1H), 4.26-4.16 (m, 2H), 4.08 (s, 3H), 3.96 (q, J=9.6 Hz, 1H), 2.95 (s, 3H), 2.56 (q, J=8.9 Hz, 2H), 2.02 (s, 3H), 1.61 (d, J=4.2 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) δ 169.42, 158.61, 155.25, 149.72, 138.73, 137.63, 132.30, 131.47, 131.16, 127.56, 126.47, 125.65, 125.45, 120.41, 119.25, 117.67, 115.48, 114.74, 113.52, 67.71, 66.59, 52.54, 40.93, 34.05, 18.40, 18.01, 13.84. LCMS calcd for C29H32N5O2 (M+H+): 482.2478; Found: 482.2479.
The SARS-CoV-2 PLpro enzymatic assays were carried out as follows. The assay was assembled in 96-well plates with 100 μl of 200 nM PLPro protein in PLPro reaction buffer [50 mM Hepes (pH 7.5), 0.01% Triton X-100, and 5 mM DTT]. Then, 1 μl of testing compound at various concentrations was added to each well and incubated at 30° C. for 30 minutes. The enzymatic reaction was initiated by adding 1 μl of 1 mM FRET substrate (the final substrate concentration is 10 μM). The reaction was monitored in a Cytation 5 image reader with filters for excitation at 360/40 nm and emission at 460/40 nm at 30° C. for 1 hour. The initial velocity of the enzymatic reaction with and without testing compounds was calculated by linear regression for the first 15 minutes of the kinetic progress curve. The IC50 values were calculated by plotting the initial velocity against various concentrations of testing compounds with a dose-response function in Prism 8 software. Data for representative compounds is provided in the following table.
Evaluation of the cytotoxicity of compounds was carried out using the neutral red uptake assay (Repetto, G., et al., Nat Protoc 2008, 3, 1125-31). Briefly, 80.000 cells/ml of the tested cell lines were dispensed into 96-well cell culture plates at 100 μl per well Twenty-four hours later, the growth medium was removed and washed with 150 μl of PBS buffer. Two hundred microliters of fresh serum-free medium containing serial diluted compounds was added to each well. After incubating for 2 days at 37° C., the medium was removed and replaced with 100 μl of DMEM medium containing neutral red (40 μg/ml) and incubated for 2 to 4 hours at 37° C. The amount of neutral red taken up was determined by measuring the absorbance at 540 nm using a Multiskan FC Microplate Photometer (Thermo Fisher Scientific) The CC50 values were calculated from best-fit dose-response curves with variable slope in Prism 8. Data for representative compounds is provided in the following table.
Example 124. The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I (‘Compound X’), for therapeutic or prophylactic use in humans
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
This application claims priority from U.S. Provisional Patent Application No. 63/462,847 that was filed on 28 Apr. 2023. The entire content of U.S. Provisional Patent Application No. 63/462,847 is hereby incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 63462847 | Apr 2023 | US |
