NZ615301B2 - Pyrimidine derivatives for the treatment of viral infections - Google Patents

Pyrimidine derivatives for the treatment of viral infections Download PDF

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NZ615301B2
NZ615301B2 NZ615301A NZ61530112A NZ615301B2 NZ 615301 B2 NZ615301 B2 NZ 615301B2 NZ 615301 A NZ615301 A NZ 615301A NZ 61530112 A NZ61530112 A NZ 61530112A NZ 615301 B2 NZ615301 B2 NZ 615301B2
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nmr
mhz
ppm
dmso
amino
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NZ615301A
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NZ615301A (en
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Werner EMBRECHTS
Tim Hugo Maria Jonckers
Stefaan Julien Last
Gowan David Mc
Serge Maria Aloysius Pieters
Pierre Jeanmarie Bernard Raboisson
Jaromir Vlach
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Janssen Sciences Ireland Uc
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Priority claimed from PCT/EP2012/056388 external-priority patent/WO2012136834A1/en
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Publication of NZ615301B2 publication Critical patent/NZ615301B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

Disclosed are 2-amino-5-(alkoxy/phenoxyl)-4-(5-amino)pyrimidine derivatives and analogues as represented by the general formula (I), or a pharmaceutically acceptable salt, tautomer, solvate or polymorph thereof, wherein R1 is hydrogen, alkyl, cyclopropyl, alkoxy, halogen, hydroxyl or trifluoromethyl; R2 is alkyl, alkoxyalkyl, cycloalkyl, heterocycle, aryl, bicyclic heterocycle, alkylaryl, heteroaryl and alkylheteroaryl, each of which is optionally substituted; R3 is alkyl, alkoxy, alkenyl or alkynyl, each of which is optionally substituted; and wherein the remaining substituents are as defined herein. Representative compounds include 2-amino-5-((3,4-dimethoxypyridin-2-yl)methoxy)-4-(hydroxyhexan-3-yl)amino)pyrimidine, 2-amino-5-methoxy-4-(hydroxyheptan-3-yl)amino)pyrimidine, and 2-amino-5-((3,4-dimethoxypyridin-2-yl)methoxy)-4-(butylamino)pyrimidine. Also disclosed is a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt, tautomer, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers, for use in the treatment of a disorder or disease in which the modulation of TLR7 and /or TLR8 is involved, and for the treatment of viral infections, such as hepatitis C virus. ; R2 is alkyl, alkoxyalkyl, cycloalkyl, heterocycle, aryl, bicyclic heterocycle, alkylaryl, heteroaryl and alkylheteroaryl, each of which is optionally substituted; R3 is alkyl, alkoxy, alkenyl or alkynyl, each of which is optionally substituted; and wherein the remaining substituents are as defined herein. Representative compounds include 2-amino-5-((3,4-dimethoxypyridin-2-yl)methoxy)-4-(hydroxyhexan-3-yl)amino)pyrimidine, 2-amino-5-methoxy-4-(hydroxyheptan-3-yl)amino)pyrimidine, and 2-amino-5-((3,4-dimethoxypyridin-2-yl)methoxy)-4-(butylamino)pyrimidine. Also disclosed is a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt, tautomer, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers, for use in the treatment of a disorder or disease in which the modulation of TLR7 and /or TLR8 is involved, and for the treatment of viral infections, such as hepatitis C virus.

Description

/056388 PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS.
This invention relates to pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating viral infections, like HBV or HCV.
The present invention relates to the use of pyrimidine derivatives in the treatment of viral infections, immune or inflammatory disorders, whereby the modulation, or m, of toll-like-receptors (TLRs) is involved. Toll-Like ors are primary transmembrane proteins characterized by an extracellular leucine rich domain and a cytoplasmic extension that ns a conserved region. The innate immune system can recognize pathogen- associated molecular patterns via these TLRs expressed on the cell surface of certain types of immune cells. Recognition of foreign pathogens activates the production of cytokines and upregulation of co-stimulatory molecules on phagocytes. This leads to the modulation of T cell behaviour.
It has been estimated that most mammalian species have between ten and fifteen types of Toll-like ors. Thirteen TLRs (named TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus.
On the other hand, mice s TLRs 11, 12, and 13, none of which are represented in humans. Other s may express TLRs which are not found in humans. Other non—mammalian species may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the s of using experimental animals as models of human innate immunity.
For ed reviews on toll—like ors see the following journal articles. 3O Hoffmann, J.A., Nature, 426, p33-38, 2003; Akira, S., Takeda, K., and , T., Annual Rev. Immunology, 21, p335-376, 2003; Ulevitch, R. J., Nature Reviews: lmmunology, 4, p512—520, 2004.
Compounds indicating activity on Toll—Like receptors have been previously described such as purine derivatives in , e derivatives in WO 98/01448 and WO 99/28321, and pyrimidines in .
However, there exists a strong need for novel ike receptor modulators having preferred selectivity, higher y, higher metabolic stability, and an improved safety profile compared to the compounds of the prior art.
In the treatment of certain viral infections, regular injections of eron (IFNα) ?? can be administered, as is the case for hepatitis C virus (HCV), (Fried et. al.
Peginterferon-alfa plus rin for chronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82). Orally available small molecule IFN inducers offer the potential advantages of reduced immunogenicity and convenience of administration. Thus, novel IFN inducers are potentially effective new class of ??? drugs for treating virus infections. For an example in the literature of a small molecule IFN inducer having antiviral effect see De Clercq, E.; Descamps, J.; De Somer, P. Science 1978, 200, 563-565.
IFNα is also given in combination with other drugs in the treatment of certain ??? types of cancer (Eur. J. Cancer 46, 2849–57, and Cancer Res. 1992, 52, 1056). TLR 7/8 agonists are also of interest as e adjuvants because of their ability to induce pronounced Th1 response (Hum. es 2010, 6, 1????? Hum. Vaccines 2009, 5, 381−394).
??? In accordance with the present invention a compound of formula (I) is ed R2 N N N NH2 R3 (I) or a pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof, wherein R1 is hydrogen, methyl. C1-2alkyl, ropyl, methoxy, halogen, hydroxyl, ??? trifluoromethyl, or difluoromethyl, R2 is C1-8alkyl, (C1-4)alkoxy-(C1-4)alkyl, C3-7cycloalkyl, C4-7heterocycle, aryl, bicyclic heterocycle, alkylaryl, heteroaryl and alkylheteroaryl, each of which is optionally substituted by one or more tuents independently selected from: • halogen; ??? • hydroxyl; • amino; • C1-6alkyl; • di-(C1-6)alkylamino; • C1-6alkylamino; ??? • C1-6 alkoxy; • C3-6 cycloalkyl; • carboxylic acid; • carboxylic ester; • carboxylic amide; ?? • heterocycle optionally substituted by one or more groups independently selected from C1-6 alkyl, C1-6 alkoxy, carboxylic ester and amide; • aryl optionally substituted by one or more groups independently selected from: halogen; C1-6 alkyl optionally substituted by one or more groups independently selected from hydroxyl and aryl; C1-6 alkoxy optionally ??? substituted by one or more halogen; carboxylic acid; ylic ester; amide; and aryl optionally tuted by one or more groups independently selected from halogen, C1-6 alkyl and C1-6 alkoxy; • alkenyl; • alkynyl; ??? • alkylaryl; • heteroaryl optionally substituted by one or more groups independently selected from: halogen; hydroxyl; C1-6 alkyl optionally tuted by one or more groups independently selected from yl, C1-6 alkyl, C1-6 , heterocycle, carboxylic ester, aryl and nitrile; C1-6 alkoxy optionally ??? substituted by one or more groups independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, heterocycle, carboxylic ester and nitrile; carboxylic acid; carboxylic ester; amide; aryl optionally substituted by one or more groups ndently selected from halogen, C1-6 alkyl and C1-6 alkoxy; heterocycle; and nitrile; ??? • alkylheteroaryl; and • nitrile; and R3 is C4-8 alkyl, C4-8 alkoxy, C2-6 alkenyl or C2-6 alkynyl, each of which is optionally tuted by one or more substituents independently selected from n, ??? yl, amino, C1-3 alkyl, C1-3 alkoxy or C3-6 cycloalkyl, nitrile.
In a first embodiment the present invention provides compounds of formula (I) wherein R3 is butyl or pentyl and wherein R2 and R1 are as specified above.
In a further embodiment the invention concerns compounds of formula (I) wherein R3 is C4-8 alkyl substituted with hydroxyl, and wherein R2 and R1 are as ??? specified above.
Another embodiment relates to nds of formula (I) wherein R3, when being C4-8 alkyl substituted with hydroxyl, is one of the following (S) (S) (S) (S) rmore the present invention also provides compounds of formula (I) n R1 is hydrogen or -CH3 and wherein R2 and R3 are as specified above.
In another embodiment the present invention provides compounds of formula ?? (I) wherein wherein R2 is alkylaryl or alkylheteroaryl, substituted with C1-3alkyl, hydroxyl, alkoxy, nitrile, heterocycle or ester and wherein R1 and R3 are as specified above.
In a further ment the current invention concerns compounds of formula (I) n R2 is C1-3alkyl substituted by aryl, cycle, or heteroaryl which is ??? further substituted by kyl, alkoxy, carboxylic ester or carboxylic amide and wherein R1 and R3 are as specified above.
Furthermore the invention relates to compounds of formula (I) wherein R2 is one of the following examples that can be further substituted with C1-3alkyl, hydroxyl, alkoxy, nitrile, heterocycle or ester.
N N N N O O The preferred compounds according to the invention are: The nds of formula (I) and their pharmaceutically acceptable salt, ??? er(s), solvate or polymorph thereof have activity as pharmaceuticals, in particular as modulators of Toll-Like Receptors (especially TLR7 and/or TLR8) activity.
In a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
?? Furthermore a nd of formula (I) or a ceutically acceptable salt, solvate or rph thereof according to the current invention, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used as a medicament.
??? Another aspect of the invention is that a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, or said pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used accordingly in the treatment of a disorder or disease in which the modulation of ??? TLR7 and /or TLR8 is involved.
The term ” refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms.
The term “halogen” refers to fluorine, chlorine, bromine or iodine.
The term “alkenyl” refers to an alkyl as defined above consisting of at least two ??? carbon atoms and at least one carbon-carbon double bond.
The term “alkynyl” refers to an alkyl as defined above ting of at least two carbon atoms and at least one carbon-carbon triple bond.
The term “cycloalkyl” refers to a saturated carbocyclic ring containing the specified number of carbon atoms.
??? The term “heteroaryl” means an ic ring structure as defined for the term “aryl” comprising at least 1 heteroatom selected from N, O and S, in ular from N and O.
The term “aryl” means an aromatic carbocyclic ring structure. Said ic ring structure may have 4, 5, 6 or 7 ring atoms. In particular, said ic ring ??? structure may have 5 or 6 ring atoms.
The term “bicyclic cycle” means an aromatic ring structure comprised of two fused aromatic rings as defined for the term “aryl”, wherein at least one ring comprises at least one atom selected from N, O and S, in particular from N and O. ?????????????????????? -5a- The term “alkylaryl” means an aromatic ring structure as defined for the term “aryl” substituted with an alkyl group.
The term “alkylheteroaryl” means an aromatic ring structure as d for the term “heteroaryl” substituted by an alkyl group.
?? The term “alkoxy” refers to an alkyl (carbon and hydrogen chain) group singular bonded to oxygen like for instance a y group or ethoxy group.
Heterocycle refers to molecules that are saturated or partially saturated and include ethyloxide, tetrahydrofuran, dioxane or other cyclic ethers. Heterocycles containing nitrogen include, for example ine, morpholine, dine, ??? piperazine, idine, and the like. Other heterocycles include, for e, thiomorpholine, dioxolinyl, and cyclic sulfones.
Heteroaryl groups are heterocyclic groups which are aromatic in nature. These are monocyclic, bicyclic, or polycyclic containing one or more heteroatoms selected from N, O or S. Heteroaryl groups can be, for example, imidazolyl, ??? isoxazolyl, furyl, oxazolyl, pyrrolyl, pyridonyl, pyridyl, pyridazinyl, or pyrazinyl. ????????????????????? 2012/056388 Pharmaceutically acceptable salts of the compounds of formula (l) include the acid on and base salts thereof. Suitable acid on salts are formed from acids which form non-toxic salts. Suitable base salts are formed from bases which form non-toxic salts.
The compounds of the invention may also exist in unsolvated and solvated forms. The term “soivate” is used herein to describe a lar x comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, l.
The term “polymorph” refers to the ability of the compound of the invention to exist in more than one form or crystal structure.
The compounds of the present invention may be stered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other compounds of the invention or in ation with one or more other drugs. lly, they will be administered as a formulation in ation with one or more pharmaceutically acceptable excipients. The term ient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically stering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition sait form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral, rectal, or percutaneous administration. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, , elixirs, ons, and solutions; or solid carriers W0 2012/136834 such as starches, sugars, kaolin, ts, lubricants, binders, disintegrating agents and the like in the case of s, pills, capsules, and tablets.
Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid ceutical carriers are obviously employed. Also ed are solid form preparations that can be converted, shortly before use, to liquid forms. In the compositions suitable for percutaneous stration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be stered in s ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations ed in the art for administration via this way. Thus, in general the compounds of the present invention may be stered to the lungs in the form of a solution, a suspension or a dry powder.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of stration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
Those of skill in the treatment of infectious diseases will be able to determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more ses at riate intervals throughout the day. Said sub- doses may be formulated as unit dosage forms, for e, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
W0 2012/136834 2012/056388 The exact dosage and frequency of administration depends on the particular compound of formula (l) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. rmore, it is evident that the effective amount may be lowered or increased depending on the response of the treated subject and/or ing on the tion of the physician prescribing the nds of the instant invention. The effective amount ranges mentioned above are therefore only guidelines and are not intended to limit the scope or use of the ion to any extent.
Pre aration of com ounds.
Compounds of formula (I), where R1 is hydrogen atom are prepared according to scheme 1. j]: 0i 1. THF, NaH + 0/\ --—--—-—-—> H o/\ R2/ 2.EtOH,NaOEt of“!\ J\ Guanidine carbonate HO N NHz A B '32 R \3 NH2 5 R/0 / N POCi3 o 2 / N l R3\ \ )\ l o N N NH \ )\ Et3N,EtOH,8OC 2 Cl N NH2 C D Scheme 1 Compounds of type A, in scheme 1 are made by either (i) Reaction of a heterocyclic alcohol with a halogenated ester and an suitable base, for example potassium carbonate, cesium carbonate, or sodium hydride. Example shown in scheme 2a. (ii) Reaction of an alcohol, or hydroxy ester, for e 2—hydroxy ethyl acetate, with an alkyl halide using an appropriate base, for example sodium hydride. Example shown in scheme 2b.
I 1 ——> , o o modkoA/ N 2 NaH DMF N Scheme 2a Ji 0 HO O/\ , NaH, TBAI, THF O\/U\O/\ Scheme 2b Compounds of formula (i), when R1 is alkyl, lkyl, oromethyl, or alkoxy and where R2 is aryl or heteroaryl, are prepared as in scheme 3 below. The betaketoester (E) can be chlorinated using, for example, thionyl chloride to provide the 2—chloro—beta-ketoester intermediate (F). The phenol or hetero- aromatic alcohol (RZOH) is combined with an lar ratio of aqueous sodium hydroxide. The ts are then removed under reduced pressure to afford the phenol or heteroaromatic alcohol salt of R2. This salt is combined with the 2-chloro-B-ketoester intermediate (F) to afford intermediate G according to literature ure. Intermediate G is then combined, with or without base, with guanidine carbonate in an appropriate solvent, for example, ethanol. Intermediate H is then reacted with phosphorous oxychloride to form the chloropyrimidine intermediate (J). The products are then formed as a result of heating (J) in the presence of excess amine and optionally excess organic base, for example triethylamine, at elevated temperature. This is a general scheme using s known to a skilled person, see for instance Organic Syntheses volume 33, p.43 (1953).
W0 2012!136834 N \N /\ R OH R1 0/\ 1 cool2 RKUHAO“ NaOR2 R1 0 Base o~ CI O‘Rz guanidine carbon ate R2 E F G Pool3 & R3\NH hi \N H / 0\ R2 R2 solvent, heat Compounds Scheme 3 / NHz N k o o R E /> o o N’ r1 A j/ W N y M R MOI-l 0 R2\ R1 1 Cl 0 TiCl4 ,0 1 Guanidine Carbonate /o Bu3N R2 NaOEt R2 -78C A G POCig N/ i“ N/ i“ \ \ H Et3N, acetonitnle ,0 so to 120°C /O R2 R mine 2 Compounds Scheme 4 Compounds of formula (I), when R1 is alkyl, cycloalkyl, oromethyl, or alkoxy and where R2 is ic or aliphatic, can be prepared according scheme 4.
This reaction scheme begins with a crossed-Claisen reaction where an acyl chloride reacts with ester intermediate A ( shown in scheme 1) to form intermediates (G) as in scheme 3. From intermediate G, the reaction scheme follows the same pathway to the products as in scheme 3. This is a general W0 2012/136834 2012/056388 scheme using methods known to a skilled person, see for ce The Journal of American Chemical Society volume 127, page 2854 (2005).
Experimental Section. sis of Intermediate A-1. 0 ©/\Br HQVLLOA o -———-———————> NaH, TBAl, THF O\/U\O/\ To a mixture of ethyl glycolate [6237] 0 9, 2.40 mol), NaH (105.65 g, 2.64 mol), tetrabutylammonium iodide (TBAl) (88.70 9, 240.14 mmol) in anhydrous THF (2 L) was added benzyl bromide (451.80 9, 2.64 mol) dropwise at 0°C. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with saturated, aqueous ammonium chloride (1L), and the aqueous layer was ted with ethyl acetate (3 x 1L). The combined organic layers were washed with brine (1 L), dried over magnesium sulfate, the solids were d via filtration, and the solvents of the filtrate were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain intermediate A-1 (200 g). 1H NMR (CDCl3 400MHz) 6 ppm .27 (m, 5H); 4.62 (s, 2H), 4.24-4.19 (q, J = 6.8 Hz, 2H); 4.07 (s, 2H); 1.29-1.25 (t, J = 6.8 Hz, 3H).
Procedure for preparation of Intermediate B-1.
O 0 O 1. THF, NaH / i0““L P“VO\/U\O/\ _...__.).
H 2.EtOH, NaOEt fNIA HO N NH2 guanidine carbonate B-1 To a stirred suspension of NaH (45.30 g, 1.13 mol) in anhydrous THF (1.2 L) was added ethyl formate 2 g, 1.54 mol). The suspension was cooled in an ice bath, and then compound A-1 (200 g, 1.03 mol) in anhydrous THF (300 mL) was added dropwise via an addition funnel. The white mixture was stirred at 0°C to room temperature for 5 hours. During this time, the reaction was exothermic and turned yellow. In a separate flask, guanidine carbonate [5913—85-1] (111.31 9, 0.618 mol) was treated with a sodium ethoxide solution, freshly prepared by the careful addition of Na (28.41 g, 1.24 mol) to anhydrous ethanol (750 mL) at room temperature. The off-white slurry obtained after stirring for 1 hour, was then added to the yellow solution prepared above. The resulting pale yellow reaction mixture was heated to reflux for 15 hours. The solvent was removed, and then the crude residue was dissolved in water (1.5 L). The e was adjusted to pH=5 with acetic acid. The solid was collected, washed extensively with water and ethanol to give intermediate 3-1 (160 g). 1H NMR (400 MHz, DMSO-de) 5 ppm 4.90 (s, 2 H), 6.33 (br. s., 2 H), 7.25 (s, 1 H), 7.29 — 7.42 (m, 5 H), 1121 (br. s., 1 H) Procedure for preparation of intermediate C-1.
Reaction Scheme: of“. POCI3 O HO N NH2 Cl N NH2 B-1 ‘34 A suspension of intermediate 8-1 (160 g, 0.74 mol) in POCl3 (900 mL) was heated to 100°C under N2 with stirring for 5 hours. The reaction mixture was cooled‘to room temperature. The excess POCI3 was d under d pressure, the oil e was poured into cold, sat. aq. NaHCOa (2 L) that was stirred for 30 minutes. The mixture was extracted with ethyl acetate (3 x 1.5 L).
The ed c layers were separated and washed with brine (1 L), dried over sodium sulfate, the solids were removed via filtration, and the solvents of the filtrate were concentrated to afford intermediate C-1 (70 g) as a yellow solid. The product was used in the next step without further purification.
Procedure for preparation of compound 1. /\/\ oI/\N H2N | 0 (Lo? Cl \N/kNHZ Et3N EtOH 80 0 MN\NXNHZH 1 W0 2012/136834 2012/056388 To a suspension of C-1 (70.00 9, 297.03 mmol) in ethanol (1.4 L) was added n- butylamine (217.24 g, 2.97 mol) and triethylamine (60.11 g, 594.05 mmol). The reaction mixture was heated to reflux for 16 hours. The on mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was purified by silica gel flash chromatography using a petroleum ether to ethyl acetate gradient to obtain 1 (26 g) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 0.96 (t, J=7.3 Hz, 3 H), 1.32 — 1.43 (m, 2 H), 1.52 — 1.61 (m, 2 H), 3.38 (1, J=7.2 Hz, 2 H), 5.01 (s, 2 H), 7.28 (s, 1 H), 7.31 — 7.46 (m, 5 H) N Cb) Aczo fl” /\/\N \N N/U\ H H 0% Preparation of intermediate D-1.
Into a 100 mL round bottom flask ed with a magnetic stir bar was placed 1 (1 g, 3.67 mmol) in acetic anhydride (40 mL). The yellow solution was allowed to stir at reflux for 15 hours. The ts were removed under reduced pressure. The crude was purified via silica gel chromatography using a heptane to ethyl acetate gradient. The best fractions were collected and the solvents were removed under reduced pressure to afford a white solid, D-1.
LC—MS: Anal. Calcd. For C19H24N403: 356.19; found 357[M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 0.94 (t, J=7.4 Hz, 3 H), 1.31 — 1.45 (m, 2 H), 1.50 — 1.67 (m, 2 H), 2.31 (s, 6 H), 3.44 (m, J=6.0 Hz, 2 H), 5.12 (s, 2 H), 5.41 ~ 5.52 (m, 1 H), 7.43 (m, J=1.5 Hz, 5 H), 7.79 (s, 1 H) Preparation of intermediate D-2.
WK)“V /H\Ni —————» MK ° \N N/“\ 0;; /\/\N 2,10% Pd/C H 0A D-1 D-2 Method A. Into a 250 mL erlenmeyer flask equipped with a magnetic stir bar was placed intermediate D—1 (1g), and ethanol (100 mL). The flask is sparged with nitrogen, ed by the addition of 10% Pd on carbon (100 mg). The flask was sealed and the here removed and replaced with hydrogen. The on was allowed to stir at room temperature for 15 hours. The heterogeneous mixture was filtered through packed celite and the solvents of the filtrate were removed under reduced pressure to afford D-2 in quantitative yield.
Method B. A 0.1 M solution of starting material in methanol was run h the H-cube, equipped with a 10% Pd/C cartridge, at 0.5 mL/min and 30 bar pressure of en. LC-MS shows te conversion. The solvents were removed under reduced pressure. The crude was purified via silica gel chromatography using a dichloromethane to 10% methanol in dichloromethane gradient. The best fractions were pooled; the solvents were removed under reduced pressure to afford a white solid, D-2.
LC—MS: Anal. Calcd. For C12H18N403: 266.14; found 267[M+H]+ 1H NMR (400 MHz, DMSO-da) 5 ppm 0.87 (t, J=7.4 Hz, 3 H), 1.28 (dd, J=14.9, 7.4 Hz, 2 H), 1.49 (t, J=7.2 Hz, 2 H), 2.15 (s, 6 H), 3.20 — 3.37 (m, 2 H), 7.02 - 7.12 (m, 1 H), 7.58 (s, 1 H), 10.27 (br. s, 1 H) Preparation of intermediate D-3.
O O/U\ ACN, reflux 16h /l< W0 2012/136834 -1 5- Into a 100 mL round bottom flask was placed 1 (1 g, 3.67 mmol), di-tert—butyl dicarbonate (7.5 g), and acetonitrile (50 mL). The yellow solution was stirred at reflux for 16 hours. The solvents were removed under reduced pressure. The residue was purified via silica chromatography using a prepacked 80g silica column and a heptane to ethyl acetate gradient autocollecting at 254nm. The best fractions were pooled to afford a yellow oil, D-3.
LC-MS: Anal. Calcd. For 025H36N405: 472.259; found 473[M+H]+ 1H NMR (400 MHz, FORM-d) 6 ppm 0.94 (t, J=7.4 Hz, 3 H), 1.33 — 1.42 (m, 2 H), 1.45 (s, 18 H), 1.50 - 1.85 (m, 2 H), 3.35 — 3.51 (m, 2 H), 5.09 (s, 2 H), 5.31 — 5.38 (m, 1 H), 7.36 - 7.48 (m, 5 H), 7.75 (s, 1 H) Preparation of intermediate D4.
QC?“ 0 J< ”fr it 2 Mn\ Mk0 0}} ——————>/\/\”\Ni0H2,Pd/C 0—3 D-4 Intermediate D-4 is prepared according to the ure to e intermediate D—2, employing either method A or B.
LC-MS: Anal. Calcd. For C18H30N4052 382.222; found 383[M+H]+ 1H NMR (400 MHz, CHLOROFORM—d) 8 ppm 0.95 (t, J=7.3 Hz, 3 H), 1.39 (s, 18 H), 1.40 - 1.45 (m, 2 H), 1.53 - 1.54 (m, 2 H), 3.42 - 3.51 (m, 2 H), 5.85 (s,1 H), 7.43 (s, 1 H) W0 2012!136834 Preparation of compound 2.
Hof\IN o /\/\H \N N OJ< 212.Elzgsliumcarbonate,DMF O - ft/ N MN\N NH2 Into a 30 mL vial was placed intermediate D—4 (200 mg, 0.52 mmol), DMF (5 mL), 1—(3-bromopropyl)—4—methoxybenzene (130 mg, 0.57 mmol), and cesium ate (508 mg, 1.56 mmol). The reaction was allowed to stir for hours at room temperature. The solids were removed via filtration. The solvents of the filtrate were d under reduced pressure and the crude was reconstituted in methanol and to it was added HCI (6M in isopropanol) and the reaction was allowed to stir 15 hours at room temperature. The solvents were d under reduced pressure and the crude was purified via reverse phase separation to afford 2 as the free base.
Preparation of ediate G-1.
Ckou‘ioa ‘50 TiCl4, BugN,1~methylimidazole @2130“ A-1 6-1 To a stirred solution of A-1 (60 g, 309 mmol, 1eq) and 1—methylimidazole (30.4 g, 370 mmol, 1.2 eq) in CHZClz (1 L) was added acetyl chloride (24.3 g, 309 mmol, 1eq) at -45 °C under N2. After stirring for 20 min, TiCl4 (210 g, 1.08 mol, 3.5 eq) and tributylamine (230 g, 1.24 mol, 4 eq) were added to the mixture at —45°C under N2, and continues to stir for 50 minutes at —45°C under N2. After completion, water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice.
The organic layer was washed with brine and dried over sodium sulfate. The solids were removed by filtration and the ts of the filtrate were removed under reduced pressure. The crude was purified via silica column chromato- graphy using a heptane to ethyl e gradient to afford a pale yellow oil, G-1. 1H NMR (400 MHz, CHLOROFORM—d) 8 ppm 1.30 (t, J=7.2 Hz, 3 H), 2.28 (s, 8 H), 4.27 (q, J=7.2 Hz, 2 H), 4.41 (s, 1 H), 4.58 (d, J=11.8 Hz, 1 H), 4.75 (d, J=11.8 Hz, 1 H), 7.32 - 7.43 (m, 5 H) Preparation of intermediate H-1.
@/ O O O/\ guanidine carbonate. . -——-——————-——-—-—~> l 0-1 EtOH HO N NH2 Into a 20 mL ave vial was placed intermediate 6-1 (500 mg, 2.12 mmol), ethanol (5mL), and guanidine carbonate (200 mg, 2.22 mmol). The vial was sealed and allowed to react at 120°C with stirring for 4 hours. The solvents were removed under reduced pressure. Water (25 mL) was added. The mixture was brought to pH=5 via careful addition of acetic acid. The itate was isolated via filtration to afford a white solid, H-1. 1H NMR (400 MHz, CHLOROFORM—d) 8 ppm 1.88 (s, 3 H), 4.85 (s, 2 H), 6.38 (br. s., 2 H), 7.24 — 7.49 (m, 5 H), 11.16 (s, 1 H) ation of intermediate 6-2. 0 O O O Mo“ NaOPh Mo“ Cl O‘Ph F-1 G-2 Step 1. Sodium phenolate was prepared by evaporating equimolar portions of phenol and sodium hydroxide in a 1L round bottom flask on the rotary evaporator. Toluene is used in the azeotropic removal of water.
Step 2. Sodium phenolate (116 g, 1 mol) prepared in step 1 and toluene (1 L) were placed in a 2L three-necked flask fitted with mechanical stirrer, addition funnel, and reflux condenser with drying tube. The suspension was heated to , then ethyl d-chloroacetoacetate (165 g, 1 mol) was added with stirring through the addition funnel where the reaction continues heating at reflux for 4 hours. The light brown sion is cooled to room temperature, extracted -18— with water (2 x 500 mL), and dried (anhydrous ium sulfate). The solids were removed via filtration and the solvents of the filtrate were d under reduced pressure. The crude is used in the next step without purification.
Preparation of intermediate H-2. 00AM“ Q 0 guanidine carbonate \© ethanol HO N/JNH2 lnto a 100 mL round bottom flask equipped with a magnetic stir bar and reflux condenser was added intermediate G-2 (19, 4.5 mmol), ethanol (50 mL), and guanidine carbonate [5931](203 mg, 2.25 mmol). The reaction mixture is brought to reflux for 15 hours. The solvent was removed under reduced pressure. Water (25 mL) was added. The mixture was brought to pH=5 via l addition of acetic acid. The precipitate was isolated via filtration to afford a white solid, H-2. This is used t further purification in the next step. ation of intermediate J-1.
Into a 50 mL round bottom flask equipped with a magnetic stir bar and reflux condenser was added intermediate H—2 (500 mg, 2.3 mmol) and POCI3 (20 mL). The suspension was heated to reflux with stirring for 6 hours. The solvents were removed under reduced pressure to afford a crude brown oil, J-1. No further purification was done. The compound was used as such in the subsequent step.
W0 2012/136834 -1 9.
Preparation of 3.
A butylamine A Cl N NHz basicAlumina MN N NH2 dioxane H 120°C,15h J-1 3 into a 50 mL sealed tube equipped with a magnetic stir bar was placed intermediate J—1 (150 mg, 0.64 mmol), n-butylamine (70 mg, 0.96 mmol), basic alumina (100 mg), and dioxane (10 mL). The tube was sealed, placed in an oil bath at 120°C, and the reaction was heated with stirring for 15 hours. The vessel was cooled to room temperature and the cap was carefully removed.
The contents were poured into a round bottom flask where the solvents were removed under reduced pressure. The crude was purified via silica gel column chromatography using a dichloromethane to 5% methanol in dichloromethane gradient. The best fractions were pooled, and the solvents were removed under reduced pressure to afford 3.
LC-MS: Anal. Calcd. For C15H20N4O: 272.16; found 273 [M+H]* 1H NMR (300 MHz, FORM—d) 8 ppm 0.80 (t, J=7.3 Hz, 3 H), 1.20 (dq, J=15.0, 7.3 Hz, 2 H), 1.83 — 1.47 (m, 2 H), 1.98 (s, 3 H), 8.20 - 3.34 (m, 2 H), 4.74 (br. s., 2 H), 4.79 (br. s., 1 H), 6.78 - 6.84 (m, 2 H), 8.91 ~ 7.01 (m, 1 H), 7.18 — 7.28 (m, 2 H) Preparation of 4 /O \ /O /O \ \N l i ' 2 / f“ A Cl N Cl n-butylamine /\/\N N Cl NH3 aq. MN N NHZ ethanol H pressure vessel H 120°C CuO microwave ammonium onate Step 1.
Into a 20 mL microwave vial was added commercially available chl0ro methoxy dine (300 mg, 1.68 mmol), ethanol (5 mL), and n—butylamine (0166 mL, 1.68 mmol). The vial is sealed then heated in the microwave for W0 2012/136834 minutes at 120°C. LC—MS shows complete conversion. The solvents were d under reduced pressure. The crude is used as such in step 2.
Step 2.
Compound from step 1 was placed into a 20 mL pressure vessel with aqueous ammonia (10 mL) and to this was added ammonium bicarbonate (200 mg, 2.6 mmol), and CuO (24 mg, 0.17 mmol, 0.1eq). The vessel was sealed and the mixture was heated to 120°C with stirring for 24 hours. The reaction mixture was extracted 3 times with 5mL dichloromethanezmethanol 9:1 and the les were removed under reduced pressure. The compound was filtered through silica eluting with romethanezmethanol 9:1 and the volatiles were removed under d pressure. The e was purified by reversed phase chromatography.
LC/MS: Anal. Calcd. For CgH16N4O: 196.13; found 197[M+H]+ 1H NMR (400 MHz, CHLOROFORM—d) 6 ppm 0.97 (t, J=7.3 Hz, 3 H), 1.35 — 1.48 (m, 2 H), 1.56 — 1.68 (m, 2 H), 3.44 - 3.52 (m, 2 H), 3.80 (s, 3 H), 5.86 (s, 1 H), 5.97 (s, 2 H), 7.07 — 7.14 (m, 1 H) Preparation of 5.
HOHi /\/| ”OfN O I —> \ NorNI 0% 2 EMF H 0% Ethanol H 175°C D-2 5 Step 1.
Into a 16 x 100 test tube was placed ediate D2 (180 mg, 0.66 mmol), DMF (5 mL), propyl iodide (111 mg, 0.656 mmol), and cesium carbonate (320 mg, 0.98 mmol). The on was allowed to stir at room temperature for hours. The solids were removed by filtration, and the solvents of the filtrate were removed under reduced pressure. The crude was purified via silica gel chromatography using a dichloromethane to 10% methanol in dichloromethane gradient. The best fractions were pooled, the solvents were removed under reduced pressure to afford a white solid.
Step 2.
Into a 10 mL microwave vial was placed the above white solid (100 mg), ammonium hydroxide (1 mL) and ethanol (1 mL). The vial was sealed and heated with stirring to 175°C for 10 minutes. LC-MS shows complete conversion to product. The solvents were removed under reduced pressure.
The crude was purified via silica gel chromatography using a dichloromethane to 10% methanol in dichloromethane gradient. The best fractions were , the solvents were removed under reduced pressure to afford a colorless oil.
Addition of one equivalent of HO! (using 5 to GM HCl in isopropanol) s a white solid, 5.
LC/MS: Anal. Calcd. For 011H20N4O: 224.16; found H]+ 1H NMR (400 MHz, DMSO—ds) 6 ppm 0.90 (t, J=7.3 Hz, 3 H), 0.98 (t, J=7.4 Hz, 3 H), 1.20 - 1.35 (m, 2 H), 1.54 (t, J=7.2 Hz, 2 H), 1.69 - 1.75 (m, 2 H), 3.40 (d, J=7.0 Hz, 2 H), 3.87 (t, J=6.5 Hz, 2 H), 7.39 (d, J=5.5 Hz, 1 H), 7.48 (br. s., 2 H), 8.28 — 8.37 (m, 1 H) Synthetic Scheme for the preparation of AA-9 Ph/P\;1\n/0/ 7< AA-2 THF, 15h. I1 n--BuLi, THF, 78°C ><OJJ\W (S) LAH/THF 10% Pd!C,50psi, (S) 75k© N (S) —-> HO/\\x“ —---*----—-D' MeOH, 50°C, 24h How"?WWWEtOACBoczo, EtaN \N HCl/EtOAc “”2 HC' AA-9 W0 2012/136834 Synthesis of intermediate AA-3 \n/0/ Ph 0 74 0 o/ o THF, 16h, n AA-1 AA-3 To a solution of ldehyde (43 g, 500 mmol) in THF (1 L) was added AA-2 (200 g, 532 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvents were evaporated and the residue was diluted in petroleum ether and ed. The solvents of the filtrate were removed under reduced pressure and the residue was ed by silica chromatography using a petroleum ether to 3% ethyl acetate in petroleum ether gradient to give AA-3 (90 g) as a colorless oil. 1H NMR (400 MHz, CDClg): 6 ppm 6.81-6.77 (m, 1H), 5.68-5.64 (td, J=1.2Hz, .6 Hz, 1H), 2.11-2.09 (m, 2H), 1.406 (s, 9H), 1.38—1.26(m, 4H), O.85—O.81(t, J=7.2Hz, 3H).
Synthesis of compound AA-5 SHx/Q X01 (311(3) ><O/U\/\/\/—'—“‘:'—""“"_"> n-BuLi THF, -78°C AA-3 AA—5 n—butyl lithium (290mL, 725mmol, 1.5eq.) was added to a stirred solution of AA—4 (165 g, 781 mmol) in THF (800 mL) at -78°C. The reaction mixture was stirred for 30 minutes then AA—B (90 g, 488.4 mmol) in THF (400 mL) was added and the reaction was stirred for 2 hours at -78°C. The mixture was ed with sat, aq. NH4C| on and warmed to room temperature. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by column chromatography eluting with 5% ethyl acetate in petroleum ether to afford a colorless oil, AA-5 (132 g). 1H NMR (400 MHz, CDCI3): 8 ppm 7.36-7.16 (m, 10H), 3.75-3.70 (m, 2H), 3.43- 3.39 (d, J=15.2Hz, 1H), 3.33-3.15 (m, 1H), 1.86-1.80 (m, 2H), 1.47-1.37 (m, 2H), 1.32 (s, 9H), 1.26-1.17 (m, 7H), 0.83-0.79 (t, J=7.2Hz, 3H).
Synthesis of AA-6 X /U\ .(S) LiAlH \\‘ ()S 4 O (S) (f ~——T—H—F—-——> HO/\\‘‘. N (s) AA'5 cfi AA_6 AA—5 (130 g, 328 mmol) was dissolved in THF (1.5 L) and LAH (20 g, 526 mmol) was added at 0°C in small portions. The resulting mixture was stirred at the same ature for 2 hours and then allowed to warm to room temperature. The mixture was quenched with a sat. aq. NH4C| solution. The t was partitioned between ethyl e and water. The organic phase was washed with brine, dried and evaporated. The ed organic layers were dried over sodium sulfate, the solids were removed via filtration and concentrated to afford crude AA-6 (100 g), which was used in the next step without further purification. 1H NMR (400 MHz, 00013): 8 ppm 7.33-7.14 (m, 10H), 3.91-3.86 (m, 1H), 3.80- 3.77 (d, J=13.6Hz, 1H), .60 (d, J=13.6Hz, 1H), 3.43-3.42 (m, 1 H), 3.15- 3.10 (m, 1H), 2.70-2.63 (m, 2H), 1.65-1.28 (m, 10H), 0.89-0.81 (m, 3H).
Synthesis of AA-9 HO/\ N63) “—4.. ___—;. ©2AA-6 10% Pd/C 50psi (Boc)20 Et3N,DCM 50°C, 24h AA-7 AA-8 HCl/EtOAC EtOAC HOWNH2 HCI AA-9 A solution of AA—6 (38 g, 116.75 mmol) and 10% Pd/C in methanol (200 mL) was hydrogenated under 50 PSI hydrogen at 50°C for 24 hours. The reaction mixture was filtered and the solvent was evaporated to give crude product AA-7 (17 g).
The crude product was dissolved in dichloromethane (200 mL), triethylamine (26.17 g, 259.1 mmol) and t—butyl dicarbonate (84.7 9, 194.4 mmol) was added at 0°C. The ing mixture was stirred at room temperature for 16 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in petroleum ether to give AA-8 (13 g) as colorless oil. 1H NMR (400 MHz, 00013): 5 ppm 4.08-4.03 (br, 1H), 3.68 (m, 1H), 3.58-3.55 (m, 2H), 8.20-2.90(br, 1H), .73 (m, 1H), 1.42-1.17 (m, 15 H), O.85—O.82(t, J=6.8Hz, 3H).
AA—8 (42 g, 0.182 mol) was dissolved in dioxane (200 mL) and dioxane/HCI (4M, 200 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 2h. The solvent was evaporated to afford the crude product. A romethane/petroleum ether mixture (50 mL, 1:1, v/v) was added to the crude t, and the atant was decanted. This procedure was repeated two times to obtain an oil, AA-9 (26.6 g). 1H NMR (400 MHz, DlVlSO—de): 8 ppm 8.04 (s, 3H), 3.60-3.49 (m, 2H), 3.16- 3.15 (m, 1H), 1.71—1.67 (m, 2H), 1.60-1.55(m, 2H), 1.33-1.26 (m, 4H), 0.90— 0.87 (t, J=6.8Hz, 3H). ation of AA-10 HO%NH2 HCI AA-10 AA-tO was prepared according to the preparation of AA-9, using butyraldehyde instead of valeraldehyde. 1H NMR (400 MHz, DMSO-de):8 ppm 8.07 (s, 3H), 4.85 (br, 1H), 3.57—3.45 (m, 2H), 3.14—3.12 (m, 1H), 1.70—1.64 (m, 2H), 1.56-1.49 (m, 2H), 1.38-1.30 (m, 2H), 0.90-0.80 (t, J=6.8Hz, 3H). ation of 74 HO OH (3on/ \ Raney Ni, H2, THF oQflo 0 O / \ Step 1. methoxycinnamic acid (5 g, 24 mmol) was dissolved in THF (100 mL). Raney Nickel was added to this solution under a N2 atmosphere.
The on mixture was exposed to a hydrogen atmosphere and stirred 15 hours at room temperature. The reaction mixture was filtered over a cartridge packed with diatomateous earth and the solvent of the filtrate was removed under reduced pressure. The residue was used as such in the next step.
LC-MS: Anal. Calcd. For C11H14O4: 210.09; found 209[M—H] O O 3' BORANE, THF W0 2012/136834 Step 2. 3-(3,4-dimethoxyphenyl)propanoic acid was dissolved in THF (100 mL). Borane—dimethyl sulfide x (2M in diethyl ether, 20 mL, 40 mmol) was added. The reaction mixture was stirred overnight at room temperature.
Methanol was added slowly to quench the on mixture, then silica was added and the volatiles were removed under reduced pressure. The residue was purified on silica using a heptane to ethyl acetate gradient yielding the product as an oil. This was used as such in the next step.
LC-MS: Anal. Calcd. For : 196.11; found 195[M-H] O ——————————> O ’S\ o ~O MsCl, TEA, ACN 0 o:©/\/\ Step 3. —dimethoxyphenyl)propanol (3.8 g, 19.5 mmol) and triethylamine (3.8 mL, 27.3 mmol) were dissolved in acetonitrile (15 mL) and then methanesulfonyl de (1.5 mL, 195 mmol) was added. The reaction mixture was shaken overnight at room temperature. The volatiles were removed under reduced re and the residue was purified via silica gel chromatography using a heptane to ethyl acetate gradient yielding the product as a clear oil. 1H NMR (400 MHz, DlVlSO-de) 6 ppm 1.91 - 2.01 (m, 2 H), 2.58 - 2.64 (m, 2 H), 3.17 (s, 3 H), 3.72 (s, 3 H), 3.75 (s, 3 H), 4.19 (t, J=6.4 Hz, 2 H), 6.71 — 6.76 (m, 1 H), 6.81 -6.89 (m, 2 H) / O\\S/ \NANAMo o)5 ° / 0% M\ it i k N N N O CS CO2 3 H acetone, 50°C,15h A o /(‘)< D-4 0-5 Step 4. A solution of D-4 (400 mg, 1 mmol), cesium carbonate (511 mg, 1.6 mmol) and 3—(3,4-dimethoxyphenyl)propyl methanesulfonate (430 mg, W0 2012/136834 1.6 mmol) in acetone (50 mL) was heated to 50°C for 15 hours. The reaction mixture was placed in the centrifuge and the supernatant was decanted then evaporated to dryness. The residue was purified via silica column chromato- graphy using a gradient from heptane to ethyl e. The ons containing the product were pooled and the ts were removed under reduced“ pressure to afford D-5.
LC—MS: Anal. Calcd. For 029H44N407: 560.32; found 561 [M+H]+ /\/\N:Ei\l\j:NJLO/l<0 / O H A HCI/lsopropanol DCM' /\/\ fj: 15h,rt E N NHZ 0-5 74 Step 5. The boc-protected compound was dissolved in dichloromethane (5 mL) and 6M HCL in isopropanol (3 mL) was added. The reaction mixture was stirred 15 hours at room temperature. The volatiles were removed under reduced pressure. Ether (5 mL) was added and a precipitate formed, 74 was isolated by filtration then dried in the vacuum oven for 15 hours. ation of 75 O \ \N Orin W \N A DBU, BOP, ACN OfN HN NANHZ W'IIIAOH B-2 AA-9 75 Step 1. Intermediate 3-2 was ed according to the method described for the preparation of intermediate B-1.
Step 2. To a solution of 3-2 (1 g, 3.62 mmol) and DBU (5.4 mL, 36 mmol) in acetonitrile (20 mL) was added BOP (2.08 g, 4.71 mmol) and the reaction mixture became transparent and was stirred for 15 minutes at room W0 20121136834 temperature. AA-9 (910 mg, 5.43 mmol) was added and the on mixture was stirred for 2 days at 50°C. The volatiles were removed under reduced pressure and the residue was purified on silica using a dichloromethane to 10% methanol in dichloromethane gradient. The best fractions were pooled and the ts were removed under d pressure. The crude was reconstituted in dichloromethane (2 mL) then HCl in diethylether was added to form the HCl salt. The precipitate was isolated by filtration and dried in the vacuum oven to afford compound 75.
Preparation of 76 Q 0H Q 0 _—”" fl HO 0 \N \N DIPEA,ACN /\/\L 11:; Cl N NH2 (3):); N NHZ 0-1 D-6 Step 1. C-1 (2 g, 8.49 mmol), L-norvalinol (1.75 g, 17 mmol) and diisopropylethylamine (5.85 mL, 34 mmol) were dissolved in acetonitrile (200 mL) in a 500 mL teflon coated pressure vessel and heated to 130°C for 15 hours. The mixture was d to cool to room temperature, the volatiles were removed under reduced pressure and the crude was purified via silica gel column tography using a gradient from dichloromethane to 10% methanol in dichloromethane. The best fractions were pooled and the solvents were removed under reduced pressure to afford intermediate D-6.
LC—MS: Anal. Calcd. For C15H22N402: 302.17; found 303 [M+H]+ —““——'————> HO 0 \N o o I A /\J\ \N I o Acetic an hydride / / (5)” N NH2 (3m N N D-6 D-7 W0 2012/136834 —29- ‘ Step 2. D-6 (2 g, 6.61 mmol) was heated to reflux in acetic anhydride (100 mL) in a 250 mL round bottom flask for 4 hours. The volatiles were removed under d pressure and the residue was purified via silica gel column chromatography using a heptane to ethyl acetate gradient yielding a yellow oil, D-7.
LC-MS: Anal. Calcd. For C22H23N405: 428.21; found 429 [M+H]" (Slfi Pd/C H2 MeOH (3)” N N 0 o Step 3. D-8 was ed according to the method to prepare intermediate D-2.
LC—MS: Anal. Calcd. For C15H22N405: 338.16; found 339 [M+H]+ A%:f/1NJL (ilk/q QC; O 052003 Acetone Mn/\lN (3) N NJK H A0 0—8 0-9 Step 4. intermediate D-9 was prepared according to the method described in e 75 from intermediate D-4.
LC-MS: Anal. Calcd. For C15H22N4O5: 338.16; found 339 [M+H]+ W0 2012/136834 \ \ / / l l \N \ ——-——> Ho 01A“ lN/kA? NH3(aq) ethanol N NANH (s) N (3} 2 0-9 76 Step 5. Deprotection of DE) was performed according to the method described in step 2 of compound 5 to afford 76.
Preparation of nd 77 HoIiN 1% :J o_ (DH/Q k MH 1008’ O O MNf:,rJi/io oszcos, DMF D-4 D-10 Step 1. D-10 was prepared from D—4 according to the method to prepare example 5, purification via silica column with heptane to ethyl acetate gradient.
LC-lVlS: Anal. Calcd. For N4O7: 530.27; found 531 [M+H]+ 1H NMR (400 MHz, CHLOROFORM—d) 5 ppm 0.93 (t, J=7.3 Hz, 3 H), 1.37 (dd, J=14.9, 7.4 Hz, 2 H), 1.53 — 1.62 (m, 2 H), 3.40 — 3.50 (m, 2 H), 3.92 - 3.95 (m, 3 H), 5.13 (s, 2 H), 5.33 (s, 1 H), 7.45 - 7.52 (m, 1 H), 7.55 - 7.62 (m, 1 H), 7.73 (s, 1 H), 8.05 (dt, 1:7.7, 1.4 Hz, 1 H), 8.09 (d, J=1.5 Hz, 1 H) OM / ’/l\ H N I]: O M LiAlH4,THF,rt n N NH O O 0’gO >‘\ >\ 0-10 D-11 Step 2. D-1O (2.14 g, 3.91 mmol) was dissolved in ous THF (250 mL).
Lithium aluminum hydride (1M in THF, 5.87 mL, 5.87 mmol) was added WC 2012/136834 -31 _ dropwise and the reaction mixture was stirred for 3 hours at room ature.
NH4Cl (sat, aq.) was added drop wise to the reaction mixture and the precipitated salts were removed by filtration and washed with THF. The filtrate was evaporated to dryness and crude D-11 was used as such in the next step.
LC-MS: Anal. Calcd. For C21H30N4O4: ; found 403 [M+H]+ HO\/©\/O HO\/©\/O \N \ /\/\N N NH HCI, 2-propanol, rt N N NH2 H f0 D—11 77 Step 3. D-11 (1.57 g, 3.91 mmol) was dissolved in dichloromethane (20 mL) and to it was added HCI (6 M in isopropanol, 50 mL). The reaction mixture stirred for 16 hours at room temperature. The volatiles were d under reduced pressure and the crude was purified via silica column using a dichloromethane to 10% dichloromethane in methanol gradient ng 77 as an oil which solidified on standing.
Preparation of 78 OH / H A N=N N N N O DIAD PPh3’ THF H Ofi< ' A 0 2'2 D4 042 Step 1. A solution of D-4 (0.5 g, 1.31 mmol), 3-pyridazinylmethanol (158 mg, 1.44 mmol) and triphenylphosphine (377 mg, 1.44 mmol) in anhydrous THF (4 mL) was cooled to 0°C and a solution of DIAD (0.28 mL, 1.44 mmol) was added dropwise at 0°C. After addition, the reaction mixture was stirred for 3 hours at t temperature. The solvent was quenched with water (10 mL), stirred for 1 0 minutes and the volatiles were removed under reduced pressure.
The water layer was extracted with dichloromethane, the organic layers were combined, and the solvent was removed under reduced pressure. The crude W0 2012/136834 2012/056388 was purified via silica gel column chromatography using a heptane to ethyl acetate nt. The best fractions were combined, the solvents were removed under reduced pressure to afford D-12.
LC—MS: Anal. Calcd. For 023H34N505: 474.26; found 475 [M+H]+ / / l l N¢N N¢N Mgfi333% ______, Miffl D-12 78 Step 2. D-11 (620 mg, 1.31 mmol) was dissolved in dichloromethane (10 mL) and to it was added HCI (6 M in isopropanol, 10 mL). The reaction mixture stirred for 15 hours at room temperature. The volatiles were removed under reduced pressure and the residue was purified by reversed phase chromatography to afford 78.
Preparation of 79 @/orgH N/J\NH 1 A020, H2804 NANJK 8—1 3-5 Step 1. in a 500 mL flask a mixture of 8—1 (30 g, 138 mmol) and sulfuric acid (3 mL) in acetic ide (300 mL) was heated to 90°C for 3 hours. The reaction cooled to room temperature and the precipitate was isolated by filtration, washed with diisopropylether and dried in vacuo at 50°C to obtain a white solid, B-5.
Q(KEEN“ Q o 0%N' o NANJK POCl3, DIPEA, ACN NAN/1k H H B-5 0-2 Step 2. In a 400 mL multimax reactor a mixture of 8-5 (21.8 g, 84 mmol) in acetonitrile (244 mL) was stirred at 30°C under a gentle stream of nitrogen.
Phosphoryi chloride (18.14 mL, 195 mmol) was added dropwise over a period of 5 minutes. After addition, the reaction mixture was heated to 45°C and the mixture was stirred for 15 minutes, then DIPEA (33 mL, 195 mmol) was added slowly over a period of 1.5 hours. The reaction was stirred at 45°C until completion ored by LC—MS). A on of sodium ethanoate (65 g ) in water (732 mL) was heated in a 2 L flask to 35°C and the on mixture was portioned into this solution over a period of 5 minutes. The temperature is kept n 35-40°C via an external cooling bath. The mixture was allowed to reach ambient temperature and stirring was continued for 1 hour. The precipitate was ed by filtration, washed with water and dried in vacuo at 50°C to obtain C-2 as a solid.
LC-MS: Anal. CalCd. For C13H12C|N3Ogi 277.06; found 278 [M+H]+ 1H NMR (400 MHz, DMSO—de) 5 ppm 2.11 (s, 3 H), 5.31 (s, 2 H), 7.33 — 7.39 (m, 1 H), 7.43 (t, J=7.2 Hz, 2 H), 7.46 — 7.51 (m, 2 H), 8.59 (s, 1 H), 10.65 (s, 1 H) (S) 0 O OIll j:\ \N O _________> I NH2 HN N/J\N/U\ or N u Et3N, ACN 0W c-2 0-13 Step 3. A solution of intermediate C—2 (5.9 g, 21.2 mmol), methyl (2S)—2— aminohexanoate (5.79 g, 31.9 mmol) and ylamine (14.8 mL, 106 mmol) in acetonitrile (100 mL) was heated to reflux for 4 days. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with W0 2012l136834 brine. The organic layer was dried (magnesium sulfate) then purified directly via silica column using a gradient of dichloromethane to 10% methanol in dichloromethane. The best fractions were pooled and the solvents were removed under reduced pressure to afford D-13.
LC-MS: Anal. Calcd. For C20H25N4O4: 386.20; found 387 [M+H]+ O \ \ N O l ,3: 0 ‘ A Jl\ OW , THF- W (S) 01518) D-13 D-14 Step 2. D-13 (3.7 g, 9.57 mmol) was dissolved in anhydrous THF (100 mL).
Lithium um hydride (1M in THF, 9.6 mL, 9.6 mmol) was added dropwise and the reaction mixture stirred for 3 hours at room temperature. NH4Cl (sat, aq.) was added drop wise to the on mixture and the precipitated salts were removed via filtration and washed with THF. The filtrate was evaporated to dryness and the residue was purified via silica gel column chromatography using a dichloromethane to 10% methanol in dichloromethane nt. The best fractions were combined and the solvents were removed under reduced pressure to afford D-14.
LC-MS: Anal. Calcd. For C19H26N403: 358.20; found 359 [M+H]+ 3: O HO \ I l N o Wk’ A ______.______, HN N N)K (S) Pd/C. methanol W OH 0i?) 0-14 0-15 Step 3. D-15 was prepared according to the method described for intermediate D-2. Used t purification in the next step.
LC—MS: Anal. Calcd. For N403: 268.15; found 269 [M+H]+ W0 2012/136834 N~N/ / I N _% HN N NJK f; j: M HN N N (5) C52003,DMF w ' OH D-15 045 Step 4. A mixture of D—15 (210 mg, 0.78 mmol) and cesium carbonate (765 mg, 2.35 mmol) in DMF (25 mL) was heated to 60°C with stirring then a solution of oromethyl)—1,3—dimethyl-1H—pyrazole (113 mg, 0.78 mmol) in DMF(1O mL) was added drop wise. The reaction mixture was stirred for 1 hour at 60°C. The solids were removed by filtration and the solvent was removed under d pressure. Crude D-16 was used as such in the next step.
LC-MS: Anal. Calcd. For C18H28N603: 376.22; found 377 [M+H]+ / - ‘N N m it I A HN N N NaOCH3 HN N NH2 M methanol WV OH OH D-16 79 Step 5. Into a 30 mL glass tube was placed D—16 (295 mg, 0.78 mmol) and NaOCHa (30% in methanol, 2 mL) and methanol (20 mL) and the mixture was stirred at 60°C overnight. The reaction mixture was purified via reverse phase liquid chromatography (Sunfire Prep C18 OBD 10mm, 30 x 150 mm. Mobile phase 0.25% NH4OAc solution in water, methanol) to afford 79 as the free base.
W0 2012f136834 —36- Preparation of 80 N ll \ Cl HO? 01Q N o N o HN NANJK 052003,DMF,60°C HN N ”k M M OH OH 0-15 0-17 Step 1. Intermediate D-17 was prepared according to the method used for 0-16 via alkylation of 0—15.
LC—MS: Anal. Calcd. For N503: 384.19; found 385 [M+H]+ H HZN o :i' :l“ niN —-———> I A NaOMe, MeOH Step 2. In a 30 mL glass tube D-17 (301 mg, 0.78 mmol) and NaOCH3 (30% in methanol, 2 mL) were dissolved in methanol (20 mL) and stirred at 60°C overnight. 10 mL of water was added to the reaction mixture and it was stirred for 2 hours at 60°C. The reaction mixture was purified via reverse phase liquid chromatography re Prep 018 OBD 10mm, 30 x 150 mm. Mobile phase 0.25% NH4OAc solution in water, methanol) yielding 80 as a powder.
W0 2012/136834 Preparation of 81 N O \N fi/[k I O AA-9, Et N, ACN3 NA k C-2 ' D-18 A solution of intermediate (3-2 (2 g, 7.2 mmol), AA—Q (3.02 g, 18 mmol) and triethylamine (5 mL, 86 mmol) in acetonitrile (75 mL) was heated to reflux for 6 hours. The reaction mixture was cooled down and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with brine. The organic layer was loaded on a silica dge and a gradient of dichloromethane to 10% methanol in dichloromethane was applied.
The fractions containing the t were ated to dryness ng a white powder, D-18.
LC-lVlS: Anal. Calcd. For C20H28N403: 372.22; found 373 [M+H]+ 1H NMR (400 MHz, DMSO-da) 6 ppm 0.77 — 0.92 (m, 3 H) 1.15 - 1.36 (m, 4 H) 1.42 — 1.72 (m, 4 H) 2.12 (s, 3 H) 3.35 — 3.42 (m, 2 H) 4.11 — 4.24 (m, 1 H) 4.35 — 4.52 (m, 1 H) 6.42 (d, J=8.80 Hz, 1 H) 7.42 (s, 1 H) 9.63 (br. s., 1 H) H H Hm) Hrs; ——————-—~> Ho [hr/A591 H2, Pd/C, methanol IN):1;ij D-18 D-19 D-19 was prepared from D-18 according to the method employed for intermediate D-2.
LC-MSI Anal. CBICd. For C13H22N40sI 282.1; found 283 [M+H]+ W0 2012;136834 -38— O Q \‘z: (S) 9” ‘ll/V HN /N‘N HOfi O —> \N | o fI A N/unk cszcoleMF w 0-19 0-20 0-20 was prepared from D49 according to the method to prepare D-17.
LC—MS: Anal. CaiCd. For C19H30N603: 390.24; found 391 [M+H]+ wNaOMB’ meOH wHZ HO HO (3) (8) 0-20 81 was prepared from D-20 according to the method to prepare nd 79.
Preparation of 82 o 1.THF,NaH ©\/\/0 /U\ /\ O\/fi\ /\ / 2.EtOH,NaOEt [\l H O O guanidine carbonate \ * Ho N NH2 Step 1. ediate 8-3 was prepared according to the method described for LC-MS: Anal. CaICd. For C13H15N3021 245.12; found 246 [M+H]+ 1H NMR (400 MHz, DMSO-ds) 5 ppm 1.79 - 1.93 (m, 2 H), 2.66 (t, J=7.8 Hz, 2 H), 3.76 (t, J=6.4 Hz, 2 H), 6.54 (br. s., 2 H), 7.11 - 7.21 (m, 3 H), 7.22 — 7.29 (m, 3 H), 11.46 (br. s, 1 H) my _> m:nPool3\ )K H2 H0 N NH2 B-3 C-3 Step 2. In a 250 mL round bottom flask a mixture of B—3 (15 g, 61.15 mmol) in POCl3 (150 mL) was heated to reflux and stirred for 2 hours. The reaction was allowed to cool and the solvent was removed under reduced re. The residual fraction was ated with ropylether. The formed precipitate isolated by filtration, washed with diisopropylether and dried under vacuo at 50°C to obtain a solid, C-3, used as such in the next step.
LC-MS: Anal. Calcd. For C13H14C|N30: 263.08; found 264 [M+H]+ CI N NH2 0\ DIPEA, CH30N - NH2 MO(3) C-3 82 Step 3. Into a 20 mL tube was placed C—3 (0.45 g, 1.05 mmol), L-2—aminohexanoic acid—methyl ester HCl (0.48 g, 2.62 mmol), DIPEA (1.18 mL, 682 mmol), and acetonitrile (5 mL). The tube was sealed and heated in the microwave for 1.5 hours at 120°C. The reaction was allowed to cool and the t was removed under reduced pressure.
The crude mixture was purified by Prep HPLC on (RP Vydac Denali C18 - pm, 250 g, 5 cm). Mobile phase (0.25% NH4OAc solution in water, methanol), the desired fractions were collected and evaporated to dryness. The residual fraction was dissolved in a mixture of dichloromethane/methanol and poured over a acid modified solid phase extraction cartridge (SCX). The product was released using with NH3 7N in ol. The collected solution was concentrated under reduced pressure to obtain the desired solid, 82. 2012/056388 Preparation of 83 1. THF, NaH /U\ /\ /\/O / O\/\/o / O 0 H o 2.EtOH,NaOEt ll guanidine carbonate HO N NH2 Step 1. Intermediate B-4 was prepared according to the method to prepare B-1.
LC—MS: Anal. Calcd. For C14H17N303: 275.13; found 276 [M+H]+ 1H NMR (400 MHz, DMSO-da) 6 ppm 3.63 (dd, J=5.4, 3.9 Hz, 2 H), 3.95 (dd, J=5.4, 3.6 Hz, 2 H), 4.50 (s, 2 H), 6.33 (br. s., 2 H), 7.22 — 7.29 (m, 2 H), 7.30 - 7.36 (m, 4 H), 10.71 — 11.58 (m, 1 H) HO N NH; POCI3 Cl N NH 3-4 c-4 Step 2. Into a 250 mL round bottom flask was placed B-4 (10 g, 38.27 mmol) and POCI3 (75 mL). The mixture was heated to reflux and stirred for 5 hours.
The reaction mixture was allowed to reach room temperature and stirred for 15 hours. The solvent was removed under reduced pressure. Crude C-4 was used as such in the next step.
LC-MS: Anal. CalCd. For C12H12CIN302I 265.06; found 266 [M+H]+ 0°NZIN1NNW@OZZJCINNDlPEA,CH3CN C-4 83 Step 3. Into a 50 mL tubes was placed C—4 (10 g, 35.75 mmol), n-butylamine (10.6 mL, 107.25 mmol) and DIPEA (30.8 mL, 178.75 mmol) in acetonitrile (40 mL). The mixture was heated to 120°C under ave irradiation for 3 hours. The combined reaction es were concentrated under reduced WO 36834 pressure and the residual oil was dissolved in dichloromethane and washed with 1N HCI and water. The organic layer was dried (magnesium sulfate), the solids were d by filtration and the solvent of the filtrate were removed under reduced pressure to obtain an red-brown foam, 83.
Preparation of 84 ”no *WQA”if/lgn< M” N/ NH2 BOCZO CH3CN 83 D-20 Step 1. Into a 500 mL round bottom flask was placed 83 (13.5 g, 25.6 mmol), Boc—anhydride (27.94 g, 128 mmol) and acetonitrile (150 mL). The yellow solution was stirred at reflux for 16 hours. The solvent was d under reduced pressure. The residual fraction was dissolved in dichloromethane and washed with a saturated aqueous NaHCO3 solution and water. The organic layer was dried (magnesium sulfate), the solids were removed via filtration, and the solvents of the filtrate were removed under d pressure to obtain an oil, D-20.
LC-MS: Anal. Calcd. For C22H32N4O4: 416.24; found 417 [M+H]+ if”MLfip‘to WH‘JXNIlNiOkPd/C H2, CH30H D-20 D-21 Step 2. Into a 1L erlenmeyer was suspended 10% Pd/C (4 g) in methanol (350 mL) under N2 gas flow, then D-20 (14.3 g, 34.33 mmol) was added. The e was stirred at 50°C under a hydrogen atmosphere until 1 equivalent of hydrogen was absorbed. The catalyst was removed by filtration over packed decalite. The solvent of the filtrate was removed under reduced pressure to obtain an oil, D-21. The e was used as such in the next step.
LC-MS: Anal. Calcd. For N4O4: 326.20; found 327 [M+H]+ 9 t? ! /§‘CI /駑o/\/Ofrv Mm flick Eth, CH30N Mu mick D-21 D-22 Step 3. Into a 1L round bottom flask a solution of D—21 (8.7 g, 26.66 mmol) and triethylamine (7.41 mL, 53.31 mmol) in acetonitrile (300 mL) was stirred at ambient temperature and methanesulfonyl chloride (3.1 mL, 40 mmol) was added. After addition, the reaction mixture was stirred for 1.5 hours at room temperature. The solvent was removed under reduced pressure. The crude was dissolved in ethyl acetate and washed with saturated aqueous NaH003.
The organic layers were combined, dried (magnesium sulfate), the solids were removed by filtration and the solvent of the filtrate were evaporated to dryness to obtain D-22 as an oil.
LC—MS: Anal. Calcd. For C16H23N4OGS: 404.17; found 405 [M+H]+ o at?) N o l 0 OH I o M” N mic M” N CSZCO3, C H30N SJLO D-22 D-23 Step 4. Into a 30 mL glass tube was placed a e of oxypiridine (94 mg, 0.99 mmol) and 052C03 (0.8 g, 2.47 mmol) in acetonitrile (10 mL). The vial was sealed and shaken at ambient temperature for 1 hour. D—22 (400 mg, 0.99 mmol) as a solution in acetonitrile (10 mL) was added to the reaction mixture and shaken for an additional 18 hours at room temperature. Cesium carbonate (320 mg, 1 mmol) was added and the mixture was shaken for 1 day at room temperature. The solvent was removed under reduced pressure and the crude was treated with a mixture of dichloromethane/methanol, 95/5 and shaken for 1 h, then ed over 2 g of packed silica. The te was concentrated under reduced pressure and D-23 was used as such in the next step.
LC-MS: Anal. Calcd. For C20H29N504I 403.22; found 404 [M+H]+ / O/\/ fr“O / /\/O A 0 O M” J< HCl, rt N ”i0 M D-23 34 Step 5. D—23 was deprotected to afford 84 using the method applied to deprotect 78.
Preparation of 85 NH 5N“: \ 0 O_ HO N‘N NH \ \ ' AN it: $ M1%]: iio N N o Cs co A CHngNa:rt o’N, t o- N/ /}\ o o £1: X 0 j< D-4 0-24 Step 1. Into a 250 mL round bottem flask equipped with a magnetic stir bar was placed D—4 (0.35 g, 5.23 mmol) and cesium carbonate (0.89 g, 2.75 mmol) in acetonitrile (20 mL). The mixture was d at ambient temperature for 30 minutes. A solution of the alkyl halide (0.19 g, 1 mmol) in acetonitrile (5mL) was added and the on mixture was stirred for 1 day at room temperature. The reaction was completed and the salts were removed by filtration. The filtrate was concentrated under reduced re and the crude was purified by silica column chromatography using a heptane to ethyl acetate gradient to afford intermediate D-24.
LC—MS: Anal. Calcd. For C24H37N7O7: 535.28; found 536 [M+H]+ W0 2012/136834 NH NH \ N‘lfl “of!“Nb-+ Pt/C 5°/,Thio hene 4W, , j\ ., .. “of!“NH. 0’ NAN 0t p CH30H GAO ”)1 t/ fl O O )< )< D-24 D-25 Step 2. Into a 100 mL erlenmeyer flask was suspended Pt/C, 5% (100 mg) in thiophene (0.25 mL ) and ol (20 mL) under a blanket of nitrogen gas, then D-24 (130 mg, 0.24 mmol) was added. The reaction mixture was d at 50°C under a hydrogen atmosphere. The catalyst was removed by filtration over packed decalite. The solvents of the filtrate were removed under reduce pressure to obtain D-25 as an oil, that was used as such in the next step.
LC-MS: Anal. Calcd. For C24H39N705: 505.30; found 506 [M+H]+ \ kL N‘N NH \ I “O \ NHZ NANiO HCI I i A 2 N NH2 0 j< D-25 Step 3. Intermediate D—25 is deprotected to afford 85 according to the method used to prepare 78.
Preparation of 86 ><fi\O/\Cl O __.____).. /\ 0 N3 H20, NaN3 90°C, 16h Step 1. Into a 100 mL round bottom flask was placed sodium azide (6.85 g, 103.76 mmol) in water (12.5 mL) then methyl pivalate (10.6 g, WO 36834 70.38 mmol) and stirred vigorously at 90°C for 16 hours. The reaction mixture was allowed to cool to room temperature and dichloromethane (20 mL) was added. The organic layer was ted, dried over anhydrous sodium sulfate, the solids were removed by tion and the solvent of the filtrate was removed under reduced re to obtain A-2 as an oil.
LC-MS: Anal. Calcd. For C5H11N3022 157.09; found 158 [M+H]+ NOfN\ N'N:N NH o 780/“ \A/ojL/KN 0 NA tot —————————» N N/ N 04L %\ CuSO4, L~Ascorbic acid Na salt, A t-butanol, H20, rt 0 0 O 3< D-26 D-27 Step 2. lnto a 25 mL tube was placed of D-26 (100 mg, 0.238 mmol), A-2 (37.9 mg, 0.238 mmol), t—butanol (2.5 mL) and water (2.5 mL). The tube was sealed and the mixture was stirred at ambient temperature. Copper(ll) sulfate pentahydrate (3 mg, 0.012 mmol) and rbic acid sodium salt (15.5 mg, 0.079 mmol) were added. The reaction mixture was stirred for 18 hours at room temperature, then water (2.5 mL) was added. The precipitate was isolated by filtration, washed with water and dried in vacuo at 60°C to obtain a white powder, D-27.
LC—MS: Anal. Calcd. For C27H43N7O7: 577.32; found 578 [M+H]+ o 0/— \ék/OfNN , ‘N NH wHNvK/O A i \N N N o HCl N NH2 0 j< D-27 86 Step 3. In a 100 mL round bottom flask a mixture of D—27 (0.1 g, 0.17 mmol) in HCl (5 mL BM in isopropanol) and dichloromethane (5 mL) was stirred at ambient temperature for 16 hours. The reaction was heated to 65°C and stirred for an additional 16 hours. The t was removed under reduced pressure.
The crude product was purified by reverse phase liquid chromatography (RP Vydac Denali C18 - 10pm, 250 g, 5 cm). Mobile phase (0.25% NH4HCO3 solution in water, methanol), the desired fractions were collected, evaporated, dissolved in methanol and treated with 2M HCl in ether. The solid was ed by filtration to afford 86 as the HCl salt.
Preparation of 87 Ho NH2 (8 (8) I'l/\ Cl HN AA-1o o o A k Et3N,ACN,80°C,16h A /U\ N N N N H H (3-2 D-28 Step 1. Into a 100 mL round bottom flask was placed a solution of C-2 (500 mg, 1.8 mmol), AA—iO (692 mg, 4.5 mmol) and triethylamine (0.75 mL, .4 mmol) in acetonitrile (30 mL). The mixture was heated to 80°C for 16 hours with stirring. The on was allowed to cool and the solvent was removed under d pressure. The crude was dissolved in dichloromethane and washed with brine. The organic layer was dried (magnesium sulfate), the solids were d by filtration and the solvent of the filtrate was removed to obtain an oil, D-28.
LC—MS: Anal. CaICd. For C19H26N403: 358.20; found 359 [M+H]+ 1H NMR (380 MHz, DMSO-ds) 5 ppm 0.85 (t, J=7.32 Hz, 3 H) 1.19 — 1.37 (m, 2 H) 1.38 - 1.53 (m, 1 H) 1.53 - 1.75 (m, 3 H) 2.13 (s, 3 H) 3.38 — 3.48 (m, 2 H) 4.19 - 4.31 (m, 1 H) 5.18 (s, 2 H) 8.89 (d, J=9.15 Hz, 1 H) 7.29 — 7.41 (m, 3 H) 7.45 — 7.53 (m, 2 H) 7.88 (s, 1 H) 9.77 (s, 1 H) OH OH 3' (£9 ©V "A ll’/\ HN HN A H2, Pd/C A k N N N N D-28 D-29 Step2. D-29 was prepared according to the method used to e D—21. THF was added to increase the solubility of D-29.
LC—MS: Anal. Calcd. For N4O3: 268.15; found 269 [M+H]+ OH H I / HCI N__\ o \o H'js) -,,/\ Cl /0 0 \ H13 ) "1/\ HO O I N N \N / 052003, DMF, 50°C N/ NH 0-29 D~30 Step 3. In a 250 mL round bottom flask a mixture of D29 (5 g, 18.6 mmol) and cesium carbonate (18.2 g, 55.9 mmol) in DMF (80 mL) was stirred at ambient temperature for 30 minutes. The e was heated to 60°C and a solution of 2—chloromethyl—3,4-dimethoxy pyridine hydrochloride (3.97 g, 17.7 mmol) in DMF (60 mL) was added dropwise. The reaction mixture was stirred for 2 hours at 60°C. The reaction was allowed to cool and the salts were removed by filtration. The reaction mixture was concentrated under reduced pressure and D-30 was used as such in the next step.
LC-MS: Anal. Calcd. For C20H29N505: 419.22; found 420 [M+H]+ 1H NMR (400 MHz, DMSO—de) 5 ppm 0.83 (t, J=7.4 Hz, 3 H), 1.18 - 1.32 (m, 2 H), 1.41 - 1.71 (m, 4 H), 2.14 (s, 3 H), 3.34 - 3.40 (m, 2 H), 3.78 (s, 3 H), 3.91 (s, 3 H), 4.17 - 4.29 (m, 1 H), 4.41 (t, J=5.3 Hz, 1 H), 5.09 (s, 2 H), 6.79 (d, WO 36834 —48- J=8.8 Hz, 1 H), 7.15 (d, J=5.7 Hz, 1 H), 7.75 (s, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 9.75 (s, 1 H) H H O \ (I) O ., /\ c', (s; \ , I I HN \ ’x/\ / O I x/K NaOCHS, CH3OH A HCI N NH N NH2 D-30 37 Step 4. 87 was prepared according to the same method used to prepare 79 ‘ from ediate D-16. 87 was purified by e phase chromatography (Hyperprep C18 HS 808. Mobile phase (Gradient from 90% ammonium bicarbonate in water 0.25%, 10% acetonitrile to 0% ammonium bicarbonate in water 0.25%, 100% acetonitrile). The best fractions were pooled, the solvents were removed under reduced pressure, reconstituted in methanol and d with 2M HCI in ether and then concentrated under reduced pressure to obtain a white solid, the HCI salt of 87.
Isolation of the HCI salt of 87 via reverse phase liquid chromatography led to the concomitant isolation of 88 in low yield. The best fractions were pooled, and the solvents were removed under reduced pressure to afford a white solid, 88.
W0 2012/136834 Preparation of 89 ;< NCO O l OL< N—< fl 0 HO N—< o HN—\< o (s o DMAP, CHZClZ AA-8 AA-12 Step 1. Into a 100 mL round bottom flask was placed AA—8 (2 g, 8.65 mmol), dichloromethane (6 mL), ethyl isocyanate (1.6 mL, 10.38 mmol), and DMAP (21 mg, 0.173 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature. The solvent was removed under reduced pressure and AA-12 was used in the subsequent step without further cation.
LC-MS: Anal. Calcd. For C15H30N204: 302.22; found 303 [M+H]+ -—\ o HN —\ 0 NH2 HN—< «o —‘——" (S ““4W o HCI 0 AA-1 3 AA-1 2 Step 2. Into a 100 mL round bottom flask was placed crude AA—12 (2.61 g, 8.65 mmol), and dichloromethane (30 mL). To this solution was added HCl (20 mL, 4M in dioxane). The reation was allowed to stir 3 hours at room temperature.
LC—MS: Anal. Calcd. For Og: 202.17; found 203 [M+H]+ WOTNV | OH NH 0 HN_<O NH2 0 \N /O (s l l O N/ A NH2 N NHZ BOP, DBU,DMF, 50°C AA-13 47633 39 W0 2012/136834 -50.
Step 3. into a 100 mL round bottom flask equipped with a magnetic stir bar was placed 2-Amino-4ohydroxy~5-methoxy-pyrimidine (500 mg, 3.54 mmol), anhydrous DMF (30 ,mL), AA-13 (1.27 g, 5.31 mmol), DBU (2.12 mL, 14.17 mmol), and BOP (1.96 g, 4.43 mmol). The reaction mixture was allowed to stir at room ature for 30 minutes then at 5090 for 16 hours. The solvent was removed under reduced re and the residue was partitioned n brine and ethyl acetate. The organic layers were combined, dried (magnesium sulfate), the solids were removed via filtration, and the solvents of the filtrate were removed under reduced pressure. The crude was ed via reverse phase liquid chromatography (FiP Vydac Denali 018 - 10pm, 250 g, cm. Mobile phase 0.25% NH4HCOa on in water, methanol), the best fractions were pooled, the solvents were removed under reduced pressure to afford 89.
Preparation of 261 H2N,- OH Art-14 Step 1. AA-14 was prepared according to the procedure to prepare AA-to, employing the appropriate starting aldehyde.
LC-MS: Anal. Calcd. For C7H17NO: 131.13; found 132 [M+H]" 1H NMFI (400 MHZ, CHLOROFORM-d) 6 ppm 0.81 - 0.89 (m, 6 H), 1.15 - 1.25 (m, 2 H), 1.33 - 1.47 (m, 1 H), 1.54 « 1.69 (m, 2 H), 2.71 (br. 8., 3 H), 2.88 - 2.98 (m. 1 H), 3.69 - 3.30 (m, 2 H) \EH ‘ 0 /° \ / \ N N l l NANHZ NAN”, P0613, CH3CN . C-5 47633 Step 2. C-‘S was prepared ing to the method used to prepare C-2 (from the available starting material. The crude was used without further purification.
LC-MS: Anal. Calcd. For CSHBCIN30: 159.02; found 160 [M+H]+ RECTlFiED SHEET (RULE 91) lSA/EP AA-14 / (KN E) A HN 'I NANH o / \ 2 CH CN,EtN N 3 3 m N NH2 0-5 261 Step 3. (3-5 was combined with AA-14 according to the method used to e compound 1, except that acetonitrile was used as a t, to afford261.
Preparation of 275 HO \NH2 (3) AA-15 Step 1. AA-15 was prepared according to the procedure to prepare AA-10, employing the appropriate starting aldehyde.
LC-MS: Anal. Calcd. For C7H17NO: 131.13; found 132 [M+H]* 1H NMR (400 MHZ, DMSO-da) 8 ppm 0.81 - 0.89 (m, 6 H), 1.05 - 1.20 (m, 1 H), 1.27 - 1.40 (m, 1 H), 1.43 - 1.77 (m, 3 H), 3.05 - 3.19 (m, 1 H), 3.44 - 3.57 (m, 2 H), 4.82 (br. 8., 1 H), 7.94 (d, J=18.6 HZ, 2 H) o All-15 (S) / \ I HN ---——-----> N NH2 CH3CN, EtaN / N as N NH2 Step 2. C-5 was combined with AA-15 according to the method used to prepare compound 1, except that acetonitrile was used as a solvent, to 275.
RECTlFlED SHEET (RULE 91) lSA/EP W0 2012/136834 .52- Preparation of 292 I é§ ’ é“ """‘F ' . . - o- O ........ ., Hg 0 EH2 H 3 Wk allyl-MgBr \ b M H (S) rs; _ valeraldehyde Alt-16 11 0—62-13 3) M9804 (5 equiv), PPTS (0.05 equ'N). CHZCIZ, rt b) HCt in ether, tilter oft byproduct Step 1. Alt-16 was prepared according to the procedures outlined in Chem.
Fiev., 2010, Vol. 110, No. 6, 740.
LC-MS: Anal. Calcd. For C3H17N: 127.14; found 128 [M+H]” AA-16 (5) /o \N HN \ I A -—--—-—--—-> ‘ N NHz CH3CN. Et3N / N N NHg c-s 292 Step 2. C-5 was combined with AA—16 according to the method used to prepare nd 1, except that acetonitrile was used as a solvent, to afford292.
Preparation of 300 (”Ase /s=o \/\/R\ "" V\)”\ 0 \A/IIL/Q: W2 9H $.50? #3736 W (5’ (a 1.LiBHEtg.THF.-78°C 5917313 . _ g r2.- 2. HoI, me1h8"01 3.0H30H0n78’0 AA-17 RECTIFIED SHEET (RULE 91) lSA/EP Step 1. AA-17 was prepared according to the procedures outlined in Chem.
Rev., 2010, Vol. 110, No. 6, 3600—3740.
LC-MS: Anal. Calcd. For CsH1gNOI ; found 146 [M+H]+ Cl 8203) ”3ka “‘47 HN OH I A /O \ N N NHz CHgCN, Et3N I A N NH2 Step 2. 0-5 was combined with AA—1 7 according to the method used to prepare compound 1, except that acetonitrile was used as a solvent, to afford 304.
Table I: Compounds of formula (I).
LCMS Mass Ret Exam 1H NMR STRUCTURE Found Time, Mass [M+H] Metho 1H NMR (400 MHz, METHANOL— >7. d4) 5 ppm 0.96 (t, J=7.3 Hz, 3 H), HQ: 1.32 - 1.43 (m, 2 H), 1.52 - 1.61 (m, 2 H), 3.38 (t, 1:7.2 Hz, 2 H), 1 i 272'16 273 4'51'3 .01 (s, 2 H), 7.28 (s, 1 H), 7.31 - 7.46 (m, 5 H) "“>_ 1H NMR (300 MHz, N \ NH CHLOROFORM—d)5ppm 0.89 (t, ‘ 1:7.3 Hz, 3 H), 1.24 - 1.40 (m, 2 ° H), 1.43 - 1.59 (m, 2 H), 1.88 — 2.07 (m, 2 H), 2.65 (t, 1:7.4 Hz, 2 2 33021 331 2'46’ E H), 3.24 - 3.37 (m, 2 H), 3.72 (5,3 H), 3.82 (t, J=6.3 Hz, 2 H), 4.54 (br. s., 2 H), 4.99 - 5.14 (m, 1 H), 6.72 - 6.82 (m, 2 H), 7.04 (d, J=8.5 Hz, 2 H), 7.19 (s, 1 H) Exam STRUCTURE M355 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.80 (t, \ J=7.3 Hz, 3 H), 1.20 (dq, J=15.0, _ \ 7.3 HZ, 2 H), 1.33 - 1.47 (m, 2 H), 272.16 273 1.54, E 1.98 (s, 3 H), 3.20 - 3.34 (m, 2 H), 4.74 (br. s., 2 H), 4.79 (br. s., 1 H), 6.78 — 6.84 (m, 2 H), 6.91 — 7.01 (m, 1 H), 7.18 - 7.28 (m, 2 H) 1H NMR (400 MHz, >/ CHLOROFORM-d) 8 ppm 0.97 (t, “47“”\ J=7.3 Hz, 3 H), 1.35 - 1.48 (m, 2 196.13 197 0.49, A H), 1.56 - 1.68 (m, 2 H), 3.44 ~ 3.52 (m, 2 H), 3.80 (s, 3 H), 5.86 / (s, 1 H), 5.97 (s, 2 H), 7.07 - 7.14 (m, 1 H) “:H2 1H NMR (400 MHz, N/ CHLOROFORM-d) 8 ppm 0.92 (t, \ NH J=7.3 Hz, 3 H), 1.03 (t, J=7.4 Hz, 3 — \\\\ H), 1.30 - 1.40 (m, 2 H), 1.50 - 224.16 225 0.83, A 0 1.62 (m, 2 H), 1.83 (m, J=7.5 Hz, g 2 H), 2.27 (s, 6 H), 3.34 - 3.48 (m, 2 H), 3.99 (t, J=6.4 Hz, 2 H), 5.39 - .52 (m, 1 H), 7.63 (s, 1 H) 1H NMR (360 MHZ, s) 8 ppm 0.88 (t, J=7.3 Hz, 3 H), 1.21 - 1.34 (m, 2 H), 1.48 (t, 1:7.3 Hz, 2 o KL H), 2.22 (s, 3 H), 2.24 (s, 3 H), 33120 332 0.38, 3.26 (q, J=7.0 Hz, 2 H), 3.74 (s, 3 / \ H), 4.96 (s, 2 H), 5.54 (s, 2 H), N 0\ 6.62 (s, 1 H), 7.39 (s, 1 H), 8.21 (s, 1 H) 1H NMR (300 MHz, _l CHLOROFORM-d) 8 ppm 0.80 (t, J=7.2 Hz, 3 H), 1.12 - 1.29 (m, 2 H), 1.34 - 1.47 (m, 2 H), 2.03 (s, 3 302.17 303 1.55, E H), 3.21 - 3.31 (m, 2 H), 3.89 (s, 3 H), 4.67 (br. s., 2 H), 4.93 - 5.04 (m, 1 H), 6.55 - 6.62 (m, 1 H), 6.76 (td, 1:74, 2.3 Hz, 1 H), 6.90 - 6.96 (m, 2 H) LCMS Mass Ret 1H NMR STRUCTURE Found Time, [M+H] Metho 1H NMR (300 MHz, fi FORM—d) 8 ppm 0.82 - 0.94 (m, 3 H), 1.22 — 1.39 (m, 2 H), 1.41 - 1.56 (m, 2 H), 3.24 - o \ 290.15 291 1.64,E 3.38 (m, 2 H), 4.51 (br. s., 2 H), 4.92 (s, 2 H), 5.16 (br. s., 1 H), 6.97 - 7.15 (m, 2 H), 7.23 — 7.37 (m, 2 H), 7.40 (s, 1 H) 1H NMR (300 MHz, >—_N NQNH CHLOROFORM-d) 8 ppm 0.84 - 0.93 (m, 9 H), 1.24 - 1.39 (m, 2 H), 1.45 — 1.55 (m, 2 H), 1.53 - o \ 252.20 253 233,5 1.62 (m, 2 H), 1.70 (dd, 1:135, 6.7 Hz, 1 H), 3.28 - 3.38 (m, 2 H), 3.84 (t, 1:6.6 Hz, 2 H), 4.47 (br. s., 2 H), 5.04 - 5.16 (m, 1 H), 7.20 (s, 1 H) 1H NMR (300 MHZ, CHLOROFORM~d) 8 ppm 0.85 - 0.90 (m, 3 H), 0.89 - 0.95 (m, 3 H), 1.25 - 1.44 (m, 4 H), 1.45 - 1.58 (m, 2 H), 1.61 - 1.73 (m, 2 H), 3.27 - 3.39 (m, 2 H), 3.82 (t, J=6.5 Hz, 2 H), 4.57 (br. s., 2 H), .05 - 5.21 (m, 1 H), 7.25 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.85 (t, 1:7.3 Hz, 3 H), 1.20 - 1.36 (m, 2 H), 1.40 - 1.54 (m, 2 H), 3.24 - 11 340.09 341 1.98, E 3.36 (m, 2 H), 4.55 (br. s., 2 H), 4.80 (s, 2 H), 5.00 — 5.11 (m, 1 H), Cl 7.11 (dd, J=8.2, 1.9 Hz, 1 H), 7.35 (s, 1 H), 7.38 (d, J=2.5 Hz, 2 H) 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.85 (t, J=7.3 Hz, 3 H), 1.28 (dd, J=15.2, 7.2 Hz, 2 H), 1.39 - 1.54 (m, 2 H), 3.25 - 3.35 (m, 2 H), 3.84 (s, 3 H), 4.61 (br. s., 2 H), 4.91 (s, 2 H), .07 - 5.17 (m, 1 H), 7.17 (s, 1 H), 7.35 (d, J=8.1 Hz, 2 H), 7.97 (d, J=8.2 Hz, 2 H) —56- STRUCTURE 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.86 (t, 1:1.0 Hz, 3 H), 1.17 - 1.31 (m, 2 H), 1.33 - 1.46 (m, 2 H), 2.98 (t, J=6.5 Hz, 2 H), 3.17 - 3.27 (m, 2 H), 4.03 (t, #66 Hz, 2 H), 4.61 (br. s., 2 H), 4.83 - 4.97 (m, 1 H), 7.15 - 7.22 (m, 3 H), 7.23 - 7.31 (m, 3 H) 1H NMR (300 MHz, CHLOROFORM—d) 8 ppm 0.86 (t, 1:7.3 H2, 3 H), 1.28 (dd, 1:153, 7.3 Hz, 2 H), 1.41 - 1.54 (m, 2 H), 2.29 (s, 3 H), 3.26 - 3.37 (m, 2 H), 4.79 — 4.84 (m, 1 H), 4.87 (s, 2 H), 7.11 - 7.27 (m, 4 H), 7.31 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.87 (t, 1:7.3 Hz, 3 H), 1.24 - 1.37 (m, 2 H), 1.42 - 1.57 (m, 2 H), 3.24 - 1.79, E 3.38 (m, 2 H), 4.54 (br. 5., 2 H), 4.97 (s, 2 H), 5.14 - 5.24 (m, 1 H), 7.17 - 7.27 (m, 2 H), 7.31 - 7.39 (m, 3 H) 1H NMR (300 MHz, FORM—d) 8 ppm 0.88 (t, 1:7.3 Hz, 3 H), 1.25 - 1.39 (m, 2 H), 1.44 — 1.57 (m, 2 H), 2.43 (q, J=6.6 Hz, 2 H), 3.27 - 3.37 (m, 2 1.98, E H), 3.87 (t, J=6.5 Hz, 2 H), 4.51 (br. s., 2 H), 5.02 - 5.09 (m, 2 H), .10 - 5.18 (m, 1 H), 5.79 (ddt, 1:171, 10.3, 6.7, 6.7 Hz, 1 H), 7.20 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.88 (t, 1:7.3 Hz, 3 H), 1.33 (dq, J=15.0, 7.2 Hz, 2 H), 1.44 - 1.57 (m, 2 H), 240.16 241 1.52, E 3.32 (m, 1:71, 71, 5.7 Hz, 2 H), 3.36 (s, 3 H), 3.54 - 3.62 (m, 2 H), 3.90 - 3.96 (m, 2 H), 4.57 (br. 5., 2 H), 5.55 - 5.69 (m, 1 H), 7.38 (s, 1 Mass Exact 1H NMR STRUCTURE Found Time, Mass [M+H] Metho ”“2 1H NMR (300 MHZ, NQNH FORM—d) 6 ppm 0.89 (t, 1:7.3 Hz, 3 H), 1.32 (dq, 1:150, 7.3 Hz, 2 H), 1.45 - 1.59 (m, 2 H), 18 o \ 273.16 274 0.58,E 3.35 (td, 1:7.0, 6.0 Hz, 2 H), 4.59 (br. s., 2 H), 4.92 (s, 2 H), 5.11 - .19 (m, 1 H), 7.20 (s, 1 H), 7.23 / \ (s,2H),8.54-8.59(m,2H) “>7 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.90 (t, \ 1:7.1 Hz, 3 H), 1.25 - 1.39 (m, 2 H), 1.50 (m, J=6.7 Hz, 2 H), 2.04 - 19 300.20 301 2.46,E 2.19 (m, 2 H), 2.66 - 2.79 (m, 2 H), 3.37 (d, 1:4.5 Hz, 2 H), 3.79 - 3.94 (m, 2 H), 5.68 - 5.88 (m, 1 H), 7.05 - 7.37 (m, 6 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.91 (t, NHz—</ \ J=7.3 Hz, 3 H), 1.27 - 1.42 (m, 2 o H), 1.44 - 1.61 (m, 4 H), 1.65 - 1.80 (m, 2 H), 2.07 (q, 1:7.2 Hz, 2 _264.20 265 2.38,E H), 3.36 (td, 1:7.0, 5.9 Hz, 2 H), 3.84 (t, 1:65 Hz, 2 H), 4.60 (br. s., 2 H), 4.90 — 4.98 (m, 1 H), 5.02 (q, 1:1.6 Hz, 1 H), 5.09 - 5.21 (m, 1 H), 5.77 (ddt, 1:170, 10.3, 6.6, 6.6 H2,1H),7.27(s,1H) ":“2 1H NMR (300 MHz, N\/——?—NH CHLOROFORM—d) 6 ppm 0.93 (t, 1:7.3 Hz, 3 H), 1.30 - 1.46 (m, 2 21 \ H), 1.49 - 1.62 (m, 2 H), 3.20 (br. 226.14 227 0.82,E s., 1 H), 3.32 - 3.43 (m, 2 H), 3.88 - 3.94 (m, 2 H), 3.95 - 4.00 (m, 2 H), 4.62 (br. s., 2 H), 5.68 (t, J=5.2 Hz, 1 H), 7.39 OH (s, 1 H) -58— 1H NMR STRUCTURE 1H NMR (300 MHz, FORM-d) 5 ppm 0.94 (t, 1:7.3 H2, 3 H), 1.29 - 1.45 (m, 2 H), 1.55 (quin, 1:7.3 Hz, 2 H), 0.807, 3.39 (q, J=6.8 Hz, 2 H), 4.57 (br. 22 0 273.16 274 E s., 2 H), 4.97 (s, 2 H), 5.08 - 5.19 (m, 1 H), 7.34 (dd, J=7.8, 4.9 Hz, 1 H), 7.44 (s, 1 H), 7.71 (m, J=7.8 / \, Hz, 1 H), 8.62 (dd, 1:4.7, 1.3 Hz, 1 M H), 8.67 (d, 1:1.5 Hz, 1 H) NH; 1H NMR (300 MHz, NLé—NH CHLOROFORM-d) 6 ppm 0.94 (t, 1:7.3 Hz, 3 H), 1.30 — 1.47 (m, 2 H), 1.56 (quin, 1:7.3 Hz, 2 H), 23 0 330.17 331 1.65, E 3.35 - 3.45 (m, 2 H), 3.94 (s, 3 H), 4.62 (br. s., 2 H), 5.00 (s, 2 H), : O 5.15 - 5.25 (m, 1 H), 7.40 (s, 1 H), 7.49 (d, J=7.6 Hz, 1 H), 7.55 - 7.63 O— (m, 1 H), 7.99 - 8.13 (m, 2 H) NH; 1H NMR (300 MHz, NLé—NH CHLOROFORM-d) 6 ppm 0.95 (t, J=7.2 Hz, 3 H), 1.31 - 1.46 (m, 2 H), 1.51 - 1.65 (m, 2 H), 2.01 24 \ Eo 240.16 241 0.97, E (quin, J=6.0 Hz, 2 H), 2.61 (br. s., 1 H), 3.30 - 3.45 (m, 2 H), 3.84 (t, 1:5.9 Hz, 2 H), 4.01 (t, J=6.0 Hz, 2 H), 4.55 (br. s., 2 H), 5.31 - 5.42 (m, 1 H), 7.35 (s, 1 H) 1H NMR (300 MHz, NH. / N/>.N CHLOROFORM—d) 6 ppm 0.95 (t, NH 1:7.3 Hz, 3 H), 1.28 - 1.45 (m, 2 H), 1.47 - 1.60 (m, 2 H), 3.30 - 348.20 349 o 0 2.02, E 3.40 (m, 2 H), 4.60 (br. s., 2 H), 4.87 (s, 2 H), 5.10 (m, 1:5.2 Hz, 1 H), 7.20 (s, 1 H), 7.31 - 7.47 (m, 8 H), 7.49 - 7.56 (m, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.96 (t, 1:7.3 Hz, 3 H), 1.28 - 1.46 (m, 2 ° \ H), 1.50 - 1.63 (m, 2 H), 2.32 (s, 3 277.15 278 1.69, E H), 3.39 (td, J=7.1, 5.9 Hz, 2 H), 4.70 (br. s., 2 H), 5.00 (s, 2 H), .18 - 5.27 (m, 1 H), 6.15 (s, 1 H), 7.45 (s, 1 H) 1H NMR URE Found Time, [M+H] Metho 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.96 (t, 1:7.3 Hz, 3 H), 1.34 - 1.47 (m, 2 H), 1.52 - 1.67 (m, 2 H), 2.51 - 067, E 2.60 (m, 4 H), 2.69 (t, 1:5.4 Hz, 2 H), 3.41 (td, J=7.1, 5.9 Hz, 2 H), 3.71 - 3.81 (m, 4 H), 3.98 (t, 1:5.4 Hz, 2 H), 4.60 (br. s., 2 H), 5.85 - .98 (m, 1 H), 7.44 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM—d) 8 ppm 0.98 (t, 1:7.3 Hz, 3 H), 1.34 - 1.50 (m, 2 H), 1.55 - 1.70 (m, 2 H), 2.06 (0, 1:3.4 Hz, 2 H), 2.15 (dt, 1:130, 268 0.94, E 6.4 Hz, 2 H), 2.37 - 2.47 (m, 2 H), 3.42 (td, 1:7.1, 5.8 Hz, 2 H), 3.96 (t, J=6.0 Hz, 2 H), 4.70 (br. s., 2 H), 5.34 - 5.44 (m, 1 H), 7.32 (s, 1 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.98 (t, J=7.3 Hz, 3 H), 1.34 - 1.50 (m, 2 H), 1.56 - 1.69 (m, 2 H), 2.15 (dt, 1:130, 6.4 Hz, 2 H), 2.39 - 2.47 (m, 2 H), 3.42 (td, J=7.1, 5.8 Hz, 2 H), 3.96 (t, J=6.0 Hz, 2 H), 4.70 (br. s., 2 H), 5.45 - 5.59 (m, 1 H), 7.32 (s, 1 H) 1H NMR (300 MHZ, METHANOL— d4) 8 ppm 0.86 (t, J=7.4 Hz, 3 H), 1.22 - 1.37 (m, 2 H), 1.49 (t, 1:7.5 Hz, 2 H), 2.89 (t, 1:5.0 Hz, 2 H), 3.29 (t, J=7.2 Hz, 2 H), 3.81 (t, J=5.1 Hz, 2 H), 7.16 (s, 1 H) 1H NMR (300 MHZ, METHANOL- d4) 5 ppm 0.97 (t, J=1.0 HZ, 3 H), 1.05 (d, J=6.7 H2, 6 H), 1.27 - 1.48 31 239 2.16, E (m, 2 H), 1.54 - 1.73 (m, 2 H), 1.99 - 2.22 (m, 1 H), 3.45 - 3.60 (m, 2 H), 3.68 - 3.79 (m, 2 H), 7.15 - 7.22 (m, 1 H) LCMS 1H NMR STRUCTURE Found Time, [M+H] Metho 1H NMR (300 MHz, METHANOL— d4) 6 ppm 1.00 - 1.13 (m, 6 H), 1.38 — 1.60 (m, 6 H), 1.65 - 1.78 32 252.20 253 2.36, E (m, 2 H), 1.87 - 1.97 (m, 2 H), 3.56 - 3.64 (m, 2 H), 3.66 - 3.78 (m, 1 H), 4.00 - 4.09 (m, 2 H) 1H NMR (360 MHz, s) 8 ppm 0.85 (t, J=7.3 Hz, 3 H), 1.19 - 1.33 (m, 2 H), 1.41 - 1.53 (m, 2 1.01, H), 3.28 (q, J=6.6 Hz, 2 H), 5.04 (s, 33 "”\ 357.16 358 \ o 2 H), 5.63 (s, 2 H), 6.52 (t, 1:5.9 Hz, 1 H), 7.23 (s, 1 H), 7.37 — 7.45 (m, 2 H), 7.50 (s, 1 H), 7.91 - 7.98 (m, 2 H) 1H NMR (360 MHz, DMSO-ds) 8 ppm 0.87 (t, J=7.3 Hz, 3 H), 1.19 - 3fi£y 1.35 (m, 2 H), 1.40 - 1.53 (m, 2 H), 3.26 (q, J=7.0 Hz, 2 H), 5.00 (s, 0.71, 34 312.17 313 2 H), 5.58 (s, 2 H), 6.62 (t, 1:5.7 H2, 1 H), 6.90 (t, J=6.6 Hz, 1 H), 7.21 - 7.30 (m, 1 H), 7.46 - 7.57 (m, 2 H), 8.00 (s, 1 H), 8.53 (d, J=7.0 Hz, 1 H) 1H NMR (360 MHz, DMSO-ds) 6 ppm 0.87 (t, J=7.5 Hz, 3 H), 1.23 - 1.32 (m, 2 H), 1.42 - 1.53 (m, 2 H), 3.23 - 3.31 (m, 2 H), 3.82 0.98, (s, 3 369.18 370 H), 5.09 (s, 2 H), 5.63 (s, 2 H), 6.48 - 6.56 (m, 1 H), 7.07 (d, J=8.4 Hz, 2 H), 7.15 (s, 1 H), 7.46 (s, 1 H), 7.81 (d, J=8.4 Hz, 2 H) 1H NMR (360 MHz, DMSO-ds) 5 ppm 0.88 (t, 1:7.3 Hz, 3 H), 1.18 — 1.31 (m, 2 H), 1.38 - 1.51 (m, 2 0.78, 291.17 292 H), 2.20 (s, 3 H), 2.33 (s, 3 H), 3.18 — 3.29 (m, 2 H), 4.72 (s, 2 H), .57 (s, 2 H), 6.40 (t, J=5.9 Hz, 1 H), 7.38 (s, 1 H) -61— LCMS Mass Ret Exact 1H NMR URE Found Time, Mass [M+H] Metho 1H NMR (360 MHz, DMSO-ds) 5 «H ppm 0.88 (t, 1:7.3 Hz, 3 H), 1.20 - 1.32 (m, 2 H), 1.38 - 1.49 (m, 2 .. H), 1.81 (d, 1:7.0 Hz, 3 H), 3.21 ___ \\::’\\¥/// (dt,1=13.4, 6.9 Hz, 2 H), 4.62 (d, 0.84, 37 \ 366.22 367 J=12.8 Hz, 1 H), 4.87 (d, 1:124 Hz, 1 H), 5.52 - 5.61 (m, 3 H), 6.12 (t, 1:5.9 Hz, 1 H) N : / 2 7.00 (s, 1 H), 7.15 , (0|, 1:7.0 Hz, 2 H), 7.25 - 7.37 (m, 4 H), 7.99 (s, 1 1H NMR (400 MHz, CHLOROFORM—d) 5 ppm 0.86 - 0.94 (m, 3 H), 1.26 (s, 1 H), 1.29 - NH 1.39 (m, 4 H), 1.60 (t, 1:7.2 Hz, 2 0.99, 38 302.17 303 H), 3.40 - 3.49 (m, 2 H), 3.87 (s, 3 H), 5.50 - 5.64 (m, 1 H), 5.74 - {:2°\ 5.84 (m, 1 H), 6.92 (dd, 1:7.3, 1.3 Hz, 1 H), 6.95 - 7.01 (m, 2 H), 7.11 - 7.17 (m, 1 H), 7.26 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.31 — 0.43 (m, 2 H), 0.63 - 0.78 (m, 2 _ H), 0.99 (t, 1:7.3 Hz, 3 H), 1.16 - 39 \_\i 236.16 237 1.91, E 1.31 (m, 1 H), 1.35 - 1.49 (m, 2 H), 1.65 (quin, J=7.4 Hz, 2 H), 3.43 - 3.59 (m, 2 H), 3.72 (d, 1:7.0 Hz, 2 H), 6.02 — 6.18 (m, 1 H), 7.01 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.77 - 0.85 (m, 3 H), 0.88 (t, 1:7.3 Hz, 3 H), 1.15 - 1.40 (m, 8 H), 1.45 — 1.58 (m, 2 H), 1.62 - 1.73 (m, 2 40 E 294.24 295 2.83, E H), 1.77 (m, 1:133 Hz, 2 H), 3.33 (td, 1:7.0, 5.9 Hz, 2 H), 3.53 - 3.62 (m, 1 H), 3.66 - 3.74 (m, 1 H), 3.81 (t, J=6.6 Hz, 2 H), 4.41 (br. 5., 2 H), 5.03 - 5.14 (m, 1 H), 7.27 (s, 1 H) -52_ Exact 1H NMR STRUCTURE Found Time, Mass [M+H] Metho 1H NMR (360 MHz, s) 8 ppm 0.89 (t, 1:7.3 Hz, 3 H), 1.23 - 1.36 (m, 2 H), 1.52 (t, 1:7.1 Hz, 2 H), 3.27 - 3.33 (m, 2 H), 5.20 (s, 2 323.17 324 0 H), 5.57 (5, 2 H), 6.78 (s, 1 H), _\j 7.43 (s, 1 H), 7.59 - 7.66 (m, 1 H), HN N 7.74 - 7.82 (m, 2 H), 8.01 (d, \N / J=8.4 Hz, 2 H), NH2 8.43 (d, J=8.4 Hz, 1 H) 1H NMR (360 MHz, DMSO-ds) 5 ppm 0.89 (t, 1:7.5 Hz, 3 H), 1.21 - 1.36 (m, 2 H), 1.42 - 1.54 (m, 2 H), 3.23 - 3.30 (m, 2 H), 3.75 (s, 3 0.76, 333.18 334 H), 3.90 (5,3 H), 4.90 (s, 2 H), .59 (5,2 H), 6.72 (t, 1:5.5 Hz, 1 H), 7.14 (d, 1:5.9 Hz, 1 H), 7.44 (s, 1 H), 8.23 (d ,J=5.5 Hz, 1 H) 1H NMR (360 MHz, DMSO-ds) 8 ppm 0.89 (t, 1:7.3 Hz, 3 H), 1.28 $N (dq, 1:149, 7.3 Hz, 2 H), 1.49 (quin, J=7.2 Hz, 2 H), 3.28 (q, F 1.07, o 356.15 357 J=6.6 Hz, 2 H), 4.98 (s, 2 H), 5.60 : O+F (s, 2 H), 6.40 (t, 1:5.9 Hz, 1 H), F 7.35 (s, 1 H), 7.37 - 7.54 (m, 3 H), 7.70 (dd, 1:7.3, 1.5 Hz, 1 H) NH; 1H NMR (400 MHz, NQNH CHLOROFORM— d) 5 ppm 0.95 (t, 1:7.3 Hz, 3 H), 1.38 (dq, 1:151, 7.4 Hz, 2 H), 1.57 (quin, 1:7.3 Hz, 2 H), 3.36 - 3.44 (m, 2 H), 3.92 (s, °— 0.95, 3 H), 3.93 (s, 3 H), 4.63 360.18 361 — 4.72 (m, 2 H), 5.00 (s, 2 H), 5.32 (br. s., 1 H), 7.40 (d, J=7.8 Hz, 1 H), 7.43 (5,1 H), 7.57 (d, J=1.0 Hz, 1 0 H), 7.66 (dd, .|=7.8, 1.5 Hz, 1 H) LCMS Mass Ret Exact 1H NMR STRUCTURE Found Time, Mass [M+H] Metho 1H NMR (360 MHZ, s) 5 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.22 — 1.36 (m, 2 H), 1.49 (s, 2 H), 3.22 - 3.31 (m, 2 H), 3.82 (s, 3 H), 5.09 320.15 321 (5,2 H), 5.57 (s, 2 H), 6.52 (t, J=5.9 Hz, 1 H), 6.94 (d, J=1.5 Hz,1 H), 7.36 (s, 1 H), 7.95 (d, J=1.8 Hz, 1 H) 1H NMR (360 MHz, DMSO-de) 5 ppm 0.88 (t, J=7.5 Hz, 3 H), 1.21 - 1.29 (m, 2 H), 1.29 (t, J=7.0 Hz, 3 H), 1.47 (quin, J=7.4 Hz, 2 H), 0.89, 3.25 (q, J=6.8 Hz, 2 H), 4.29 (q, 46 334.16 335 J=7.1 Hz, 2 H), 4.95 (s, 2 H), 5.60 (s, 2 H), 6.41 (t, J=5.9 Hz, 1 H), 6.76 (d, 1:3.7 Hz, 1 H), 7.28 (d, J=3.3 Hz, 1 H), 7.39 (s, 1 H) 1H NMR (360 MHz, DMSO-ds) 5 ppm 0.89 (t, 1:73 Hz, 3 H), 1.24 (t, J=7.0 Hz, 3 H), 1.26 - 1.34 (m, 2 H), 1.43 - 1.54 (m, 2 H), 3.21 - 0.93, 334.16 335 3.30 (m, 2 H), 4.21 (q, J=7.0 Hz, 2 H), 5.11 (s, 2 H), 5.62 (s, 2 H), 6.42 (t, J=5.9 Hz, 1 H), 6.78 (d, J=1.5 Hz, 1 H), 7. 29 (s, 1 H), 7.78 — 7.86 (m, 1 H) 1H NMR (360 MHz, DMSO-d.) 5 ppm 0.88 (t, J=7.3 Hz, 3 H), 1.26 (dd, 1:152, 7.5 Hz, 2 H), 1.41 - 0.73, 1.53 (m, 2 H), 2.10 (s, 3 H), 3.21 — 290.19 291 3.29 (m, 2 H), 3.73 (s, 3 H), 4.91 (5,2 H), 5.55 (s, 2 H), 6.11 (s, 1 H), 6.44 (t, J=5.9 Hz, 1 H), 7.39 (s, 1 H) 1H NMR (360 MHz, DMSO-ds) 5 ppm 0.88 (t, J=7.3 Hz, 3 H), 1.27 (dd, 1:152, 7.5 Hz, 2 H), 1.46 (t, 0.83, J=7.1 Hz, 2 H), 3.20 - 3.29 (m, 2 378.15 379 H), 3.74 (s, 3 H), 3.77 (s, 3 H), .00 (s, 2 H), 5.68 (s, 2 H), 6.38 - 6.48 (m, 1 H), 7.29 (s, 1 H), 8.46 (S, 1 H) ___J -64— LCMS Mass Ret 1H NMR STRUCTURE Found Time, [M+H] Metho NHZ /__/—— 1H NMR (360 MHz, DMSO-de) 5 N/f.) (t, 1:7.3 Hz, 3 H), 1.18 - \ ppm 0.89 NH 1.31 (m, 2 H), 1.37 - 1.49 (m, 2 H), 2.00 (s, 3 H), 3.19 (q, J=6.8 Hz, 50 0 352.20 353 0'32’ 2 H), 4.61 (br. s., 2 H), 5.53 (s, 2 H), 5.93 (t, 1:5.9 Hz, 1 H), 7.01 (s, 1 H), 7.21 (s, 1 H), 7.32 (dd, J:8.6, 3.5 Hz, 1 H), 7.40 - 7.45 (m, 3 H), 7.82 (s, 1 H) 1H NMR (360 MHz, DMSO-de) 5 ppm 0.89 (t, 1:7.3 Hz, 3 H), 1.23 - 1.34 (m, 2 H), 1.49 (t, 1:7.3 Hz, 2 1.06, H), 3.23 ~ 3.31 (m, 2 H), 5.05 (s, 2 340.15 341 51 D H), 5.54 (s, 2 H), 5.57 (s, 1 H), 7.42 (s, 1 H), 7.63 (m, 1:7.7 Hz, 1 H), 7.55 - 7.71 (m, 1 H), 7.75 - 7.84 (m, 2 H) 1H NMR (350 MHz, DMSO—de) 8 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.21 - 1.35 (m, 2 H), 1.42 - 1.54 (m, 2 52 277.15 278 0.38, H), 2.41 (s, 3 H), 3.27 (q, J=6.7 Hz, 2 H), 4.95 (s, 2 H), 5.51 (s, 2 H), .41 (s, 1 H), 5.50 (t, 1:5.7 Hz, 1 H), 7.42 (s, 1 H) 1H NMR (360 MHz, s) 5 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.21 - 1.35 (m, 2 H), 1.49 (quin, J=7.3 Hz, 2 H), 3.29 (q, J=6.6 Hz, 2 H), 53 338.16 339 1.30, 3.81 (s, 3 H), 4.83 (s, 2 H), 5.55 (s, 2 H), 6.45 (t, 1:5.9 Hz, 1 H), 7.20 (dd, J=12.8, 6.5 Hz, 1 H), 7.38 (s, 1 H), 7.60 (dd, 1:110, 9.5 Hz, 1 F F H) OH 1H NMR (400 MHZ, DMSO-ds) 5 ppm 0.84 (t, 1:5.9 Hz, 3 H), 1.14 - NH; 1.33 (m, 4 H), 1.44 - 1.54 (m, 2 N/ 0.68, H), 1.55 - 1.72 (m, 2 H), 3.40 (t, 54 \ 254.17 255 ”(1 D 1254 Hz, 2 H), 3.67 (s, 3 H), 4.05 - 4.18 (m, 1 H), 4.39 (br. 5., 1 H), O 5.45 (s, 2 H), 5.13 (d, 1:9.0 Hz, 1 / H), 7.34 (s, 1 H) LCMS Mass Ret 1H NMR URE Found Time, [M+H] Metho 1H NMR (400 MHz, DMSO-ds) 6 333—)? ppm 0.86 (t, J=7.4 Hz, 3 H), 1.19 - 1.35 (m, 2 H), 1.45 (dt, 1:135, 4.4 Hz, 1 H), 1.50 - 1.62 (m, 1 H), 55 \C/ 0.52, 226.14 227 D 3.30 - 3.49 (m, 2 H), 3.67 (s, 3 H), 4.05 (td, J=8.8, 5.0 Hz, 1 H), 4.36 /O OH - 4.96 (m, 1 H), 5.46 (s, 2 H), 5.89 (d, J=9.0 H2,1 H), 7.35 (s, 1 H) 1H NMR (400 MHz, CHLOROFORM—d) 8 ppm 0.86 - 0.98 (m, 3 H), 1.29 - 1.43 (m, 4 0.75, 210.15 211 H), 1.55 - 1.65 (m, 2 H), 3.39 (td, 56 D _ 1:7.2, 5.8 Hz, 2 H), 3.78 (s, 3 H), /o 4.42 (br. s., 2 H), 5.14 (br. s., 1 H), 7.37 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.85 (t, J=7.4 Hz, 3 H), 1.15 — 1.34 (m, 2 H), 1.37 - 1.54 (m, 2 0.58, H), 1.56 - 1.73 (m, 2 H), 3.40 57 n<>:N27H (t, — 240.16 241 D J=6.4 Hz, 2 H), 3.67 (s, 3 H), 4.04 - /0 \EV 4.22 (m, 1 H), 4.40 (br. 5., 1 H), .46 (s, 2 H), 6.13 (d, J=8.8 HZ, 1 H), 7.35 (br. s., 1 H) 2% 1H NMR (400 MHz, DMSO-ds) 5 H:x.. ppm 0.84 - 0.93 (m, 3 H), 1.20 — 1.36 (m, 2 H), 1.53 (t, 1:7.4 Hz, 2 H), 3.33 - 3.45 (m, 2 H), 5.11 (s, 2 1.16, 58 348.20 349 H), 7.33 - 7.40 (m, 1 H), 7.43 - O 7.50 (m, 2 H), 7.51 - 7.60 (m, 4 H), 7.64 - 7.73 (m, 3 H), 8.42 - O 8.50 (m, 1 H), 12.15 (d, J=4.8 Hz, 0 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.79 - 0.90 (m, 3 H), 1.16 - 1.34 (m, 4 H), 1.37 - 1.49 (m, 1 N/ N\ NM 0.62, H), 1.53 - 1.67 (m, 1 H), 3.17 - 59 240.16 241 3.51 (m, 2 H), 3.68 (s, 3 H), 3.95 - 4.11 (m, 1 H), 4.67 (br. 5., 1 H), .45 (s, 2 H), 5.89 (d, J=9.0 Hz, 1 H), 7.36 (s, 1 H) -66— LCMS Mass Ret Exact 1H NMR STRUCTURE Found Time, Mass [M+H] Metho NHZ 1H NMR (400 MHz, DMSO-ds) 5 />—N ppm 0.83 - 0.92 (m, 3 H), 1.22 - N NH 1.29 (m, 2 H), 1.32 (t, J=7.0 Hz, 3 60 — 0.15 211 3.93,B H), 1.52 (quin, J=7.3 Hz, 2 H), 3.36 — 3.42 (m, 2 H), 3.96 (q, <0 J=6.9 Hz, 2 H), 7.41 (s, 1 H), 7.48 (br. s., 2 H), 8.36 (t, 1:5.9 Hz, 1 H) 1H NMR (360 MHz, DMSO-ds) 8 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.23 — 1.37 (m, 2 H), 1.44 - 1.55 (m, 2 H), 3.26 (s, 3 H), 3.26 - 3.31 (m, 2 § H), 3.47 (dd, 1:5.5, 3.7 Hz, 2 H), 61 284.18 285 038' 3.56 — 3.60 (m, 2 H), 3.65 (dd, 1:5.5, 3.7 Hz, 2 H), 3.90 (dd, 1:5.3, 3.8 Hz, 2 H), 5.60 (s, 2 H), 6.28 (t, J=5.9 Hz, 1 H), 7.41 (s, 1 / H) 1H NMR (400 MHz, NH; CHLOROFORM-d) 8 ppm 0.96 (t, >/ ”\ J=7.3 Hz, 3 H), 1.33 - 1.48 (m, 2 N NH H), 1.50 - 1.67 (m, 2 H), 3.61 (dd, 62 \28‘ 226.14 227 0.32, 1:109, 6.9 Hz, 1 H), 3.76 (d, J=3.0 Hz, 1 H), 3.79 (s, 3 H), 3.87 - 4.00 0 (m, 1 H), 4.01 - 4.13 (m, 1 H), / 0H 4.45 (br. s., 2 H), 5.22 (d, J=6.8 Hz, 1 H), 7.39 (s, 1 H) 1H NMR (400 MHz, DMSO—ds) 8 NH: ppm 0.89 (t, J=7.0 Hz, 3 H), 1.29 (dd, 1:153, 7.5 Hz, 2 H), 1.24 (m, N/>_N\ J=3.0 Hz, 2 H), 1.32 - 1.38 (m, 3 63 224.16 225 3.23,c __ H), 1.51 - 1.62 (m, 2 H), 3.40 — 3.44 (m, 2 H), 3.98 (q, J=6.9 Hz, 2 <0 H), 7.42 (s, 1 H), 7.49 (br. s., 2 H), 8.39 (t, J=5.8 Hz, 1 H) NH2 1H NMR (400 MHz, N/>_N CHLOROFORM-d) 8 ppm 0.94 (t, \ J=7.3 Hz, 3 H), 1.26 (s, 1 H), 1.37 — (dd, J=1S.1, 7.5 Hz, 2 H), 1.52 64 \1 0‘91' 288.16 289 1.63 (m, 2 H), 3.39 — 3.50 (m, 2 o D H), 3.88 (s, 3 H), 5.31 - 5.44 (m, 1 < é H), 5.60 - 5.71 (m, 1 H), 6.87 - °\ 7.01 (m, 3 H), 7.08 - 7.15 (m, 1 H), 7.33 (s, 1 H).
LCMS Mass Ret Exact 1H NMR STRUCTURE Found Time, Mass [M+H] Metho 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.86 - 0.99 (m, 3 H), 1.18 (d, J=6.5 Hz, 3 H), 1.28 - 1.39 (m, 2 H), 1.44 - 210.15 211 1.55 (m, 2 H), 3.76 (s, 3 H), 4.08 - 4.22 (m, 1 H), 4.40 (br. s., 2 H), 4.94 (d, J=7.8 Hz, 1 H), 7.34 (s, 1 1H NMR (400 MHz, CHLOROFORM—d) 8 ppm 1.82 — 1.93 (m, 2 H), 2.07 - 2.25 (m, 2 0.66, 250.10 251 H), 3.50 (q, J=6.6 Hz, 2 H), 3.77 (s, 3 H), 4.54 (br. s., 2 H), 5.21 - 5.31 (m, 1 H), 7.39 (s, 1 H) Y3Z 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.89 (t, 1:7.3 Hz, 3 H), 1.24 - 1.35 (m, 2 H), 1.50 (t, J=7.2 Hz, 2 H), 3.25 - 3.33 (m, 2 H), 3.83 (s, 3 0.56, 67 0— 346.16 347 H), 4.88 (s, 2 H), 5.57 (s, 1 H), 6.32 (s, 1 H), 7.33 (d, J=7.8 Hz, 1 H), 7.36 (s, 1 H), 7.48 (dd, J=7.7, 1.1 Hz, 1 H), 7.54 (d, 1:1.0 Hz, 1 OH H) 1H NMR (400 MHz, FORM—d) 8 ppm 0.91 (t, 1:7.4 Hz, 3 H), 0.96 (d, 1:7.0 Hz, 3 H), 1.19 (ddd, J=13.6, 8.8, 7.3 Hz, 1 H), 1.53 (ddd, 1:135, 7.5, 4.1 0.61, Hz, 1 H), 1.75 (ddd, J=6.6, 4.2, 2.3 240.16 241 Hz, 1 H), 3.65 - 3.71 (m, 1 H), 3.75 (s, 3 H), 3.77 (d, J=3.0 Hz, 1 OH H), 3.80 (d, 1:3.3 Hz, 1 H), 3.90 - 4.00 (m, 1 H), 4.64 (br. 5., 2 H), .39 (d, 1:7.8 Hz, 1 H), 7.32 (s, 1 Exact 1H NMR STRUCTURE Found Time, Mass [M+H] Metho 1H NMR (400 MHz, FORM-d) 8 ppm 0.91 (t, 1:7.4 Hz, 3 H), 1.23 - 1.36 (m, 2 H), 1.49 - 1.57 (m, 2 H), 1.58 (d, 1.00, J=6.5 Hz, 3 H), 3.37 - 3.47 (m, 2 0 H), 5.39 (d, J=6.5 Hz, 1 H), 7.21 (s, 1 H), 7.27 - 7.33 (m, 2 H), 7.34 - 7.40 (m, 2 H), 7.41 - 7.46 (m, 1 H), 8.43 (s, 1 H), 11.05 - 11.32 (m, 1 H) J 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.83 - 0.92 (m, 3 H), 1.22 — 1.31 (m, 7 H), 1.35 (t, J=6.9 Hz, 3 239 3.56, c H), 1.49 - 1.63 (m, 2 H), 3.40 - 3.44 (m, 2 H), 3.99 (q, J=6.9 Hz, 2 H), 7.47 (br. s., 2 H), 8.39 (t, J=5.8 Hz, 1 H) 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.86 - 0.91 (m, 3 H), 1.24 - 1.30 (m, 2 H), 1.44 - 1.54 (m, 2 H), 3.37 (td, 259 0.94,A J=7.1, 5.9 Hz, 2 H), 4.97 (br. 5., 3 H), 6.92 - 6.97 (m, 2 H), 7.01 — 7.06 (m, 1 H), 7.25 - 7.31 (m, 2 H), 7.58 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.86 (t, J27.3 Hz, 3 H), 1.18 - 1.36 (m, 2 H), 1.45 (dd, 1:8.9, 4.9 Hz, 1 H), 1.51 - 1.62 (m, 1 H), 72 226.14 227 0.32, 3.40 (d, J=16.6 Hz, 2 H), 3.67 (s, 3 H), 3.95 - 4.13 (m, 1 H), 4.65 (br. ., 1 H), 5.44 (s, 2 H), 5.88 (d, OH J=9.0 Hz, 1 H),.7.35 (s, 1 H) “T 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.81 — 0.90 (m, 3 H), 1.17 — 1.37 (m, 3 H), 1.39 - 1.51 (m, 1 H), 1.54 - 1.66 (m, 1 H), 2.51 (dt, 0.63, 1:3.7, 1.8 Hz, 1 H), 3.34 - 3.41 (m, 73 240.16 241 1 H), 3.41 - 3.48 (m, 1 H), 3.68 (s, 3 H), 4.04 (td, 1:8.7, 5.0 Hz, 1 H), 4.43 - 4.91 (m, 1 H), 5.47 (s, 2 H), .90 (d, 1:9.0 Hz, 1 H), 7.36 (s, 1 LCMS Mass Ret 1H NMR STRUCTURE 3:: Found Time, [M+H] Metho 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.91 (t, 1:7.4 Hz, 3 H), 1.30 (dq, 1=14.9, 7.4 Hz, 2 H), 1.49 - 1.61 ° (m, 2 H), 1.95 - 2.09 (m, 2 H), 2.70 (t, 1:7.7 Hz, 2 6 H), 3.42 (q, J=6.8 Hz, 2 H), 3.71 (s, 3 H), 3.72 (s, 3 H), 360.22 361 0.94, D 3.89 (t, J=6.3 Hz, 2 H), 6.72 (dd, of” 1:8.2, 1.9 Hz, 1 H), 6.81 (d, 1:1.8 MW\N/KH, Hz, 1 H), 6.86 (d,1=8.3 Hz, 1 H), 7.36 (d,1=5.8 Hz, 1 H), 7.43 (br. s., 2 H), 8.32 (t, J=6.0 Hz, 1 H), 11.77 (d, 1:5.3 Hz, 1 H) 1H NMR (400 MHz, DMSO—ds) 6 ppm 0.84 (t, 1:6.9 Hz, 3 H), 1.15 - o 1.38 (m, 4 H), 1.58 (m,J=13.3, 13.3, / 7.0 Hz, 1 H), 1.67 - 1.83 (m, 2 H), l 1.84 - 1.99 (m, 6 1 H), 2.27 (s, 3 H), \N 0 389.24 390 0.88, D 2.38 (s, 3 H), 3.41 (t, 1:6.4 Hz, 2 H), NHmN Hz 3.97 (s, 3 H), 4.38 (dt, 1:90, 47 Hz, MW/RH 1 H), 5.35 (s, 2 H), 7.51 (br. s, 2 H), 7.77 (s, 1 H), 8.53 (s, 1 H), 8.96 (br. ., 1 H), 12.20 (br. s., 1 H) 1H NMR (400 MHz, s) 5 ppm 0.86 (t, 1:7.3 Hz, 3 H), 1.18 — 0 1.36 (m, 2 H), 1.36 - 1.50 (m, 1 H), / 1.50 - 1.63 (m, 1 H), 2.22 (S, 3 H), I 2.24 (s, 3 H), 6 3.29 — 3.48 (m, 2 H), \N 361.21 362 0.75, D 3.74 (s, 3 H), 4.03 (td, 1:8.7, 4.6 Hz, 0H 0 1 IN 1 H), 4.68 (br. s., 1 H), 4.91 - 5.05 /\/\ / (m, 2 H), 5.53 (s, 2 H), 6.19 (0, 1:8.8 Hz, 1 H), 7.44 (s, 1 H), 8.21 (s, l_ 1 H) 1H NMR (400 MHz, DMSO~d6) 5 ppm 0.89 (t, 1:7.3 Hz, 3 H), 1.22 - 1.35 (m, 2 H), 1.50 (quin, 1:7.3 Hz, 2 H), 3.24 - 3.30 (m, 2 H), 4.51 (d, °“fi/ ° \N 302.17 303 0.75, 0 1:5.3 H2, 2 H), 6 4.95 (s, 2 H), 5.19 /\/\Nmm (t, J=S.6 Hz, 1 H), 5.52 (s, 2 H), 6.42 (t, 1:5.8 Hz, 1 H), 7.24 - 7.29 (m, 1 H), 7.29 - 7.34 (m, 2 H), 7.35 - 7.40 (m. 2 H) T LCMS STRUCTURE 1H NMR Time, Method 7.24 - 7.29 (m, 1 H), 7.29 - 7.34 (m, 2 H), 7.35 - 7.40 (m, 2 H) 1H NMR (400 MHz, DMSO-da) 5 ppm 0.90 .3 Hz, 3 H), 1.30 (dq, J=14.9, 7.3 Hz, 2 H), 1.51 78 (quin, J=7.3 Hz, 2 H), 3.26 - 3.32 274.15 275 0.59, D (m, 2 H), 5.24 (5, 2 H), 6 5.68 (s, 2 H), 6.78 (1:, J=5.8 Hz, 1 H), 7.46 (s, 1 H), 7.76 (dd, 1:8.4, 4.9 Hz, 1 H), 7.93 (dd, 1:8.5, 1.5 Hz, 1 H), 9.21 _[ (dd, 1:5.0, 1.5 Hz, 1 H) 1H NMR (400 MHz, DMSO—de) 5 ppm 0.85 (t,J=7.0 Hz, 3 H), 1.15 - 1.34 (m, 4 H), 1.36 - 1.50 (m, 1 79 H), 1.51- 1.64 (m, 1 H), 2.11 (s, 3 334.21 335 0.7, D H), 3.39 - 3.46 (m, 2 6 H), 3.73 (s, 3 H), 4.02 (td, 1:8.8, 4.8 Hz, 1 H), 4.66 (br. 5., 1 H), 4.94 (5,2 H), .56 (5, 2 H), 5.85 (d, J=8.8 Hz, 1 H), 6.09 (s, 1 H), 7.43 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.84 (t, J=6.9 Hz, 3 H), 1.14 - 1.34 (m, 4 H), 1.37 - 1.51 (m, 1 H), 1.52 - 1.67 (m, 1 H), 3.36 - 80 3.48 (m, 2 H), 3.99 - 6 4.11 (m, 1 360.19 361 0.63, D H), 4.69 (br. 5., 1 H), 5.10 (s, 2 H), .54 (s, 2 H), 6.00 (d, J=8.8 Hz, 1 H), 7.46 (s, 1 H), 7.68 (br. 5., 1 H), 7.72 (dd, 1:7.3, 1.3 Hz, 1 H), 7.93 - 8.02 (m, 2 H), 8.03 (s, 1 H) ._.1 1H NMR (400 MHz, DMSO-da) 5 ppm 0.84 (t,J=7.2 Hz, 3 H), 1.11 - 1.37 (m, 4 H), 1.47 — 1.63 (m, 2 H), 1.63 - 1.79 (m, 2 H), 2.13 (s, 3 348.23 H), 3.40 (t, 1:6.3 Hz, 6 2 H), 3.75 349 0.73, D (5,3 H), 4.30 (m, J=8.0 Hz, 1 H), .08 (s, 2 H), 6.21 (s, 1 H), 7.48 (br. s., 2 H), 7.55 (d, 1:5.3 Hz, 1 H), 8.11 (d, 1:8.8 Hz, 1 H), 11.96 (C), 1:5.3 H2, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.77 - 0.91 (m, 3 H) 1.17 - 1.37 (m, 4 H) 1.75 - 1.91 (m, 2 H) 1.93 - 2.09 (m, 2 H) 2.74 (t, 372.22 373 1.15, D J=7.65 Hz, 2 H) 3.63 (s, 3 H) 3.87 (q, 1:602 Hz, 2 H) 4.58 (q, J=7.28 Hz, 1 H) 5.71 (br. 5., 2 H) 6.53 (d, 1:828 Hz, 1 H) 7.15 - 7.35 (m, 5 i H) 7.43 (br. 5., 1 H) _, WC 2012/136834 Mass Exact LEE/:5 STRUCTURE Found 1H NMR Mass Time,_ [M+H] Method 1H NMR (360 MHz, DMSO-ds) 5 ppm 0.85 (t,J=7.3 H2, 3 H), 1.17 - 1.31 (m, 2 H), 1.33 - 1.46 (m, 2 H), 3.16 - 3.25 (m, 2 H), 3.71 (dd, NH 316.19 317 0.95, 0 1:5.5, 3.7 Hz, 2 H), 3.96 (dd, ©/\°/\/o \ 1:55, 3.7 Hz, 2 H), 4.55 (s, 2 H), l RN14 5.60 (s, 2 H), 6.26 (t, 1:5.5 Hz, 1 H), 7.26 - 7.37 (m, 5 H), 7.41 (S, 1 1H NMR (400 MHz, DMSO—ds) a H ppm 0.86 .28 Hz, 3 H) 1.20 - 1.31 (m, 2 H) 1.36 ~ 1.49 (m, 2 \ NH H) 3.17 - 3.27 (m, 2 H) 4.16 (dd, 303.17 304 0.65, D / 0f” J=5.27, 3.26 Hz, 2 H) 4.26 — 4.44 MANHZ (m, 2 H) 5.57 (s, 2 H) 6.25 (s, 1 H) 6.93 - 7.09 (m, 2 H) 7.44 (s, 1 H) ) 8.30 - 8.52 (m, 2 H) not available 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 - 0.92 (m, 2 H) 1.18 - 1.36 (m, 2 H) 1.42 - 1.57 (m, 2 H) 86 I'M HNH 263.15 264 0.58, D 3.23 — 3.52 (m, 2 H) 5.16 (s, 2 H) / 0 \N 7.53 (br. 5., 2 H) 7.61 (d, 1:5.02 , Hz, 1 H) 8.09 (s, 1 H) 8.38 (br.s, 1 N H2 H) 12.08 (s, 1 H) 1H NMR (400 MHz, DMSO—dg) 8 ppm 0.86 (t,J=7.4O Hz, 3 H) 1.19 - 1.32 (m, 2 H) 1.49 — 1.59 (m, 1 H) 1.66 - 1.79 (m, 2 H) 1.83 - 1.93 (m, 1 H) 3.35 - 3.48 (m, 2 H) 3.90 377.21 378 0.7, D (s, 3 H) 4.09 (5,3 H) 4.35 - 4.51 (m, 1 H) 5.32 (s, 2 H) 7.52 (br. 5., 2 H) 7.56 (br. 5., 1 H) 7.71 (d, 1:5.27 Hz, 1 H) 8.53 (d, J=6.27 Hz, 1 H) 8.82 (br. s., 1 H) 12.01 (d, 1:4.27 H2,1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.84 - 0.91 (m, 3 H), 1.21 — 1.36 (m, 2 H), 1.47 - 1.55 (m, 2 H), 1.57 - 1.78 (m, 2 H), 3.45 (dd, 1:6.9, 6.1 Hz, 4 H), 3.76 (s, 3 H), 4.06 - 4.22 (m, 1 H), 4.89 (s, 2 H), .31 (5,2 H), 6.07 (br. s., 1 H), 6.40 (d, 1:6.1 Hz, 1 H), 7.47 (s, 1 H), 7.67 (d, J=6.S Hz, 1 H) -72_ STRUCTURE 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.84 (t, 1:6.78 Hz, 3 H) 0.99 (t, 1:7.15 H2, 3 H) 1.11 - 1.36 (m, 4 H) 1.49 (m, 1:5.00 Hz, 2 H) 1.77 (q, J=6.78 Hz, 2 H) 2.97 (quin, 32521 326 0'87' H NH SWN 1:6.78 Hz, 2 H) 3.67 (5,3 H) 3.90 \ (m, 1:4.00 Hz, 2 H) 4.05 - 4.25 I A”: (m, 1 H) 5.40 (br. s., 2 H) 6.17 (d, 1:9.03 Hz, 1 H) 6.99 (br. t, 1:100, 1.00 Hz, 1 H) 7.35 (s, 1 H) 1H NMR (400 MHz, CHLOROFORM- d) 8 ppm 3.78 (s o/ 3 H), 4.06 (tt, 1:5.7, 1.5 Hz, 2 H), ”—2—..3 4.44 (br. 5., 2 H), 5.15 (dq, 1:103 18010 181 047‘ D \ N \ /N 1.4 Hz, 1 H), 5.23 (br. s, 1 H), 5.23 NH, (dq,1=17.1, 1.7 Hz, 1 H), 5.94 (ddt, 1:172, 10.3, 5.6, 5.6 Hz, 1 J H), 7.39 (s, 1 H) 1H NMR (400 MHz, / CHLOROFORM— d) 6 ppm 0.05 - ° 0.13 (m, 2 H), 0.42 - 0.52 (m, 2 91 ”PF“ 208.13 209 H), 0.65- 0.80 (m, 1 H), 1.50 (q, 065 D <{_/ N—/( ’ 1:7.0 Hz, 2 H), 3.49 7.0, 5.9 "”2 Hz, 2 H), 3.73 - 3.80 (m, 3 H), 4.42 (br. 5., 2 H), 5.27 (br. 5., 1 H), 7.36 (s, 1 H) ._ __________,__ 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.84 (t, J=7.5 Hz, 3 H), 1.37 - o/ 1.54 (m, 1 H), 1.54- 1.71 (m, 1 92 ‘2; H), 3.38 (dt, 1:107, 5.3 Hz, 1 H), NH \ /~ 212.13 213 0.42, D 3.45 (dt,1=10.4, 5.1Hz, 1 H), 3.68 /_$ ””342 (s, 3 H), 3.85 - 4.02 (m, 1 H), 4.66 OH (t, #54 Hz, 1 H), 5.45 (br. s, 1 H), .88(d,1=8.8 Hz, 1 H), 7.36 (s, 1 1H NMR (400 MHz, DMSO-de) 5 I ppm 0.87 (dd, #67, 4.9 Hz, 6 H), 1.31 - 1.49 (m, 2 H), 1.50- 1.64 93 “TN NH \NJ‘NHz (m' 1 H)' 3‘37 ‘ 3'44 (m’ 2 H)' 240.16 241 0.61, D Q/OH 3.67 (s, 3 H), 4.15 (tq, 61:9.7, 4.8 i Hz, 1 H), 4.65 (br. 5., 1 H), 5.42 (s, 2 H), 5.88 (d, 1:9.3 Hz, 1 H), 7.35 (s, 1 H) 1H NMR (300 MHz, | CHLOROFORM- d) 8 ppm 0.98 (t, 1:7.3 Hz, 3 H), 1.35 - 1.49 (m, 2 330.17 331 1.65, E 0 H), 1.54- 1.74 (m, 2 H), 3.36 - I“#51112 3.47 (m, 2 H), 3.88 - 3.96 (m, 3 H), 4.84 (br. s., 2 H), 5.19 (s, 2 H), 6.15 (br.s., 1 H), 6.94 - 7.05 (m, 2 I’— ) LCMS M355 Exact Ret URE Found 1H NMR Mass H), 7.45 (s, 1 H), 7.86 - 7.98 (m, 2 1H NMR (300 MHz, METHANOL— d4) 5 ppm 0.84 (t, J=7.3 Hz, 3 H), 1.17 - 1.33 (m, 2 H), 1.36 - 1.52 0! 290.15 291 1.67,E (m, 2 H), 3.26 (t, J=7.1 Hz, 2 H), 1f" 4.86 (S, 2 H), 6.94 - 7.05 (m, 2 H), MNH N/JNHZ 7.17 (s, 1 H), 7.29 - 7.40 (m, 2 H), 3 labile protons not seen. —————-+— 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.88 (t,J=7.0 Hz, 3 H), 1.21 - 1.36 (m, 4 H), 1.46 - 1.51 (m, 2 96 H), 1.52 (0!, 1:6.5 Hz, 3 H), 3.22 - 300.20 301 N“ HA,“ 109,0 3.29 (m, 2 H), 5.17 (q, J=6.3 H2,1 H), 5.41 (s, 2 H), 6.34 (t, 1:5.9 Hz, 1 H), 7.20 (s, 1 H), 7.23 - 7.29 (m, 1 H), 7.29 - 7.36 (m, 2 H), 7.38 - 7.44 (m, 2 H) 1H NMR (400 MHz, CHLOROFORM- d) 5 ppm 1.68 - 1.87 (m, 4 H), 3.46 (q, J=6.5 HZ, 2 97 (I) fju 214.12 215 0.53.0 H), 3.77 (S, 2 H), 4.43 (br. 5, 2 H), FWNH \N/KHZ 4.38 - 4.48 (m, 1 H), 4.55 (t, J=5.9 Hz, 1 H), 5.19 (br. 5., 1 H), 7.37 (s, 1H NMR (400 MHz, DMSO-de) 5 ppm 0.90 (t, J=7.4 Hz, 3 H), 1.29 (dq, 1:149, 7.3 Hz, 2 H), 1.45 - 1.50 (m, 2 H), 1.52 (d, J=6.5 Hz, 3 98 fur:° \N I 286.18 287 0.96,D H), 3.23 - 3.30 (m, 2 H), 5.16 (q, 1:6.4 Hz, 1 H), 5.41 (s, 2 H), 6.33 (t,J=5.9 Hz, 1 H), 7.20 (s, 1 H), 7.23 - 7.29 (m, 1 H), 7.29 - 7.36 (m, 2 H), 7.37 - 7.44 (m, 2 H) 1H NMR (400 MHz, DMSO-da) 5 Cg. ppm 0.90 (t, J=7.4 Hz, 3 H), 1.29 (dq, 1:150, 7.3 Hz, 2 H), 1.44 - 99 O 1.50 (m, 2 H), 1.52 (d, 1:6.3 H2, 3 286.18 287 097,0 H), 3.23 - 3.29 (m, 2 H), 5.17 (q, nIE" H2 J=6.3 Hz, 1 H), 5.42 (s, 2 H), 6.35 (t, 1:59 Hz, 1 H), 7.20 (s, 1 H), 7.22 - 7.29 (m, 1 H), 7.29 - 7.36 (m, 2 H), 7.38 - 7.44 (m, 2 H) LCMS URE Bet 1” NMR Time, Method 1H NMR (300 MHz, CHLOROFORM- (1)5 ppm 0.95 (t, 1:7.3 Hz, 3 H), 1.32- 1.48 (m, 2 H), 1.51 - 1.61 (m, 2 H), 1.62 - 1.73 (m, 1 H), 1.88 - 1.98 (m, 2 1.4, E H), 1.98 - 2.10 (m, 1 H), 3.38 (td, 1:7.0, 5.8 Hz, 2 H), 3.73 — 3.81 (m, 1 H), 3.82 - 3.95 (m, 3 H), 4.13 - 4.27 (m, 1 H), 4.73 (br. s., 2 H), .84 (br. s., 1 H), 7.42 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM- d) 5 ppm 0.89 (t, 1:7.4 Hz, 3 H), 1.26 - 1.43 (m, 2 NH H), 1.47 - 1.61 (m, 2 H), 3.35 (td, 101 \"-\__ 1:7.0, 5.8 Hz, 2 H), 4.53 (br. 273.16 274 s., 2 128] F H), 4.97 (s, 2 H), 5.91 (br. 5.,1 H), 7.16 - 7.24 (m, 1 H), 7.30 (0!, 1:7.8 Hz, 1 H), 7.38 (s, 1 H), 7.66 (td, 1:7.7, 1.6 Hz, 1 H), 8.55 (01, I 1:47 Hz, 1 H) 1H NMR (400 MHz, 01450-115) 5 ppm 0.88 (t, 1:7.3 Hz, 3 H), 1.26 (dq, 1:14.8, 7.3 Hz, 2 H), 1.38 - )/—~ 1.50 (m, 2 H), 1.82 (d, 1:7.3 Hz, "L24” 3 H), 3.12 - 3.29 (m, 2 H), 4.63 (d, 102 :—\_ 1:125 Hz, 1 H), 4.87 (d, 1:129 36622 367 0.83, D (‘Q Hz, 1 H), 5.51 (s, 2 H), 5.58 (q, 1 =6.9 Hz, 1 H), 6.08 (t, 1:5.9 Hz, 1 / H), 7.01 (s, 1 H), 7.12 - 7.18 (m, 2 H), 7.25 — 7.30 (m, 1 H), 7.27 (s, 1 H), 7.30 — 7.37 (m, 2 H), 7.97 (s, 1 1H NMR (300 MHz, CHLOROFORM—d) 5 ppm 0.82 (t, O O 1:7.3 Hz, 3 H), 1.18 - 1.33 (m, 2 H), 1.38 - 1.51 (m, 2 H), 3.22 - 103 1 376.19 377 2.52, F 3.34 (m, 2 H), 4.50 (br. 0 s., 2 H), 4.92 (s, 2 H), 5.05 - 5.15 (m, 1 H), /\/\ I“(L442 7.13 (s, 1 H), 7.32 - 7.41 (m, 4 H), 7.43 - 7.52 (m, 1 H), 7.63 — 7.74 ..__l___________..__r.. (m, 4 H) _____~.__T___ 1H NMR (300 MHz, CHLOROFORM- d) 5 ppm 0.89 9W0H (td, 1:7.4, 5.0 Hz, 6 H), 1.20 (s, 3 268.19 269 H), 1.25 - 1.39 (m, 2 H), 1.44 - 1.741,.
\N 1.62 (m,4 H), 1.81-2.20(m, 1 /\/\N / H), 3.33 (td, 1:7.0, 5.8 Hz, 2 H), 3.60 - 3.69 (m, 2 H), 4.55 (br. s., 2 H), 5.40 (br. s., 1 H), 7.19 (s, 1 H) M355 Exact R215 STRUCTURE Found 1H NMR Mass Time,.
[M+H] Method 1H NMR (300 MHz, 0,, CHLOROFORM-d) 5 ppm 0.84 - 0.93 (m, 3 H), 1.27 (5, 6 H), 1.28 - 105 1.39 (m, 2 H), 1.45 - 1.58 (m, 2 254.17 255 1.56, F H), 3.34 (td, 1:7.0, 5.8 Hz, 2 H), Mm.“IN NANHZ 3.62 - 3.65 (m, 3 H), 4.62 (br. 5., 2 H), 5.37 - 5.55 (m, 1 H), 7.32 (5, 1 f H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.86 (t, J=7.3 Hz, 3 H), 1.15 - l 1.35 (m, 2 H), 1.44 - 1.60 (m, 2 106 o o ij m” H), 3.23 (5, 2 H), 3.35 - 3.38 (m, 1 ”0'16 241 0'64' D H), 3.40- 3.47 (m, 1H), 3.77 (5, 3 2 H), 4.36 - 4.49 (m, 1 H), 7.39 (5, 1 H), 7.44 (br. 5., 2 H), 8.16 (d, l— 1:8.8 Hz, 1 H), 11.88 (br. 5., 1 H) ___4 1H NMR (300 MHz, CHLOROFORM- d) 5 ppm 0.97 (t, N>,—~\ 1:72 H2, 3 H), 1.32 - 1.48 (m, 2 \=2‘ H,W H), 1.52 - 1.66 (m, 2 H), 2.01 - 107 :3 2.14 (m, 2 H), 2.78 (t, 1:7.5 Hz, 2 336 18 337 2 57 F H), 3.33 - 3.47 (m, 2 H), 3.91 (t, J=6.1 Hz, 2 H), 4.55 (br. 5., 2 H), .12 (br. 5., 1 H), 6.74 - 6.88 (m, 2 H), 7.07 - 7.22 (m, 1 H), 7.31 (5, 1 #4 H) 1H NMR(3OO MHz, m2 CHLOROFORM— d) 5 ppm 0.89 (t, l 5 J=7.3 Hz, 3 H), 1.24 - 1.40 (m, 2 — "H H), 1.44 - 1.58 (m, 2 H), 1.96 - 108 ° 2.09 (m, 2 H), 2.73 - 2.90 (m, 2 37811 379 162’ F H), 3.26 — 3.43 (m, 2 H), 3.87 (t, 1:6.1 Hz, 2 H), 4.43 (br. 5., 2 H), .09 (br. 5., 1 H), 6.93 — 7.06 (m, 1 H), 7.11 - 7.22 (m, 3 H), 7.48 (d, J=8.2 Hz, 1 H) 1H NMR (300 MHz, FORM— (1)5 ppm 0.83 - c 0.97 (m, 3 H), 1.25 - 1.41 (m, 2 109 H), 1.50 (dt, J=l4.6, 7.3 Hz, 2 H), 334.16 335 2.68. F 1.93 — 2.05 (m, 2 H), 2.68 (t, 1:7.5 of») Hz, 2 H), 3.24 - 3.40 (m, 2 H), MW (KHZ 3.82 (t, J=6.2 Hz, 2 H), 4.42 (br. 5., 2 H), 4.95 (br. 5., 1 H), 7.01 - 7.12 (m, 2 H), 7.16 - 7.22 (m, 3 H) W0 2012!136834 —76— STRUCTURE 1H NMR(300 MHz, my” CHLOROFORM- (1)5 ppm 0.88 (t, N/_\ NH J=7.3 HZ, 3 H), 1.31(dq,]=15.0, 0 LL 7.3 Hz, 2 H), 1.43- 1.57 (m, 2 H), C: 314.21 315 2-54, F 1.65 - 1.78 (m, 4 H), 2.61 (t, J=6.9 Hz, 2 H), 3.27 - 3.38 (m, 2 H), 3.77 - 3.89 (m, 2 H), 4.48 (br. 5., 2 H), 5.09 (br. s., 1 H), 7.09 — 7.16 (m, 3 H), 7.18 - 7.23 (m, 3 H) 1H NMR (300 MHz, CHLOROFORM- d) 5 ppm 0.88 (t, )—~ 1:7.3 Hz, 3 H), 1.24 — 1.43 (m, 4 NE?— \—\_\ PM H), 1.44— 1.55 (m, 2 H), 1.55 - E 1.65 (m, 2 H), 1.66 - 1.77 (m, 2 32823 329 2.75, F H), 2.57 (t, J=7.6 Hz, 2 H), 3.25 - 3.37 (m, 2 H), 3.80 (t, J=6.5 Hz, 2 H), 4.45 (br. s., 2 H), 5.07 (br. 5., 1 H), 7.07 - 7.15 (m, 3 H), 7.17 - 7.24 (m, 3 H) 1H NMR (400 MHz, s) 5 ppm 0.86 (t, J=7.28 Hz, 3 H) 1.11 (d, 1:6.53 Hz, 3 H) 1.20 - 1.35 (m, 2 H) 1.36 - 1.59 (m, 2 H) 1.94 - 315 1.12, 0 2.05 (m, 2 H) 2.65 - 2.78 (m, 2 H) \N 3.83 (t, J=6.40 Hz, 2 H) 4.07 - I NAN” 4.18 (m, 1 H) 5.60 (s, 2 H) 5.99 (d, 1:8.53 Hz, 1 H) 7.14 - 7.32 (m, 5 H) 7.33 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ) ppm 0.79 - 0.87 (m, 3 H) 1.18 - 1.31 (m,4 H) 1.42 - 1.59 (m, 2 H) N {11 1.59 - 1.75 (m, 2 H) 1.94 - 2.02 113 — (m,2H)2.66—2.75(m,2H)3.41 35824 359 1.0410 — 3.50 (m, 2 H) 3.79 - 3.87 (m, 2 H) 4.10 - 4.18 (m, 1 H) 4.44 ~ 4.49 (m, 1 H) 5.71 (br. 5., 2 H) 6.25 (br. ., 1 H) 7.12 - 7.31 (m, 5 H) 7.33 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (t, 1:7.28 Hz, 6 H) 1.13 - 1.38 (m, 4 H) 1.38 - 1.54 (m, 4 114 H) 1.95 - 2.09 (m, 2 H) 2.72 (t, NH 342.24 343 1.25, D of\ J=7.15 Hz, 2 H) 3.71 - 3.85 (m, 2 1 Mk1 H) 4.01 -4.21 (m, 1 H) 5.59 (br.
Hz 5., 2 H) 5.92 (d, 1:9.03 Hz, 1 H) ) 7.29 (s, 1 H) 7.15 - 7.43 (m, 5 H) T————__WLCMS hnass Exact Ret STRUCTURE Found 1H NMR Mass Time, [nn+H] Method 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.82 - 0.88 (m, 3 H) 0.89 (d, J=6.86 Hz, 3 H) 1.06 — 1.17 (m, 1 H) 1.44 - 1.53 (m, 1 H) 1.71 - 1.78 115 (m, 1 H) 1.95 - 2.04 (m, 2 H) 2.72 344.22 345 0.98, D (t, J=7.67 Hz, 2 H) 3.48 — 3.60 (m, 2 H) 3.84 - 3.90 (m, 2 H) 3.90 - 3.96 (m, 1 H) 4.38 (t, 1:5.25 Hz, 1 H) 5.21 (br. s., 2 H) 5.55 (d, 1:8.88 Hz, 1 H) 7.14 - 7.31 (m, 5 H) 7.37 (s, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.86 (t, 1:7.40 Hz, 3 H) 1.21 — 1.33 (m, 2 H) 1.42 - 1.53 (m, 2 116 H) 3.24 - 3.31 (m, 2 H) 5.04 (s, 2 329.15 330 0.9, D H) 5.58 (s, 2 H) 6.52 (t, 1:5.90 Hz, 1 H) 6.73 (dd,1:3.51, 1.76 Hz, 1 H) 6.99 (s, 1 H) 7.14 (d,1=3.26 Hz, 1 H) 7.49 (s, 1 H) 7.96 (dd, , 0.50 Hz, 1 H) T 1H NMR (400 MHz, DMSO—de) 5 ppm 0.89 (t,J=7.40 Hz, 3 H) 1.28 117 (quin, 1:1.00 Hz, 2 H) 1.43 - 1.52 290.19 291 0.75, D (m, 2 H) 2.22 (s, 3 H) 3.21 — 3.27 (m, 2 H) 3.68 (s, 3 H) 4.76 (s, 2 H) .48 (s, 2 H) 6.10 (s, 1 H) 6.26 (t, 1:5.65 Hz, 1 H) 7.40 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.86 (t, 1:7.40 Hz, 3 H) 1.20 - 1.30 (m, 2 H) 1.40 - 1.49 (m, 2 353.19 H) 2.27 (s, 3 H) 3.21 - 3.29 (m, 2 354 0.97, D H) 4.87 (s, 2 H) 5.56 (s, 2 H) 6.40 (t, 1:5.77 Hz, 1 H) 7.37 (s, 1 H) 7.53 — 7.60 (m, 3 H) 7.71 — 7.77 (m, 2 H) _) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.88 (t,J=7.28 Hz, 3 H) 1.21 - 1.33 (m, 2 H) 1.41 - 1.52 (m, 2 119 H) 3.16 - 3.29 (m, 2 H) 4.95 (s, 2 330.13 331 0.99, D H) 5.58 (s, 2 H) 6.39 (t, 1:5.77 Hz, 1 H) 6.78 (d,1:3.01 Hz, 1 H) 7.21 (dd, 1:3.51, 1.25 Hz, 1 H) 7.38 (s, 1 H) 1H NMR (400 MHz, 011450-116) 5 ppm 0.88 (t, J=7.40 Hz, 3 H) 1.22 - 1.32 (m, 2 H) 1.42 - 1.52 (m, 2 320.15 321 0.79, D H) 3.21 - 3.28 (m, 2 H) 3.81 (s, 3 H) 4.94 (s, 2 H) 5.57 (s, 2 H) 6.38 (t, 1:5.65 Hz, 1 H) 6.75 (d, 1:3.51 Hz, 1 H) 7.29 (d,J=3.51 Hz, 1 H) ~78- Exact STRUCTURE Found 1H NMR nflass 7.39 (s, 1 H) 1H NMR (400 MHz, DMSO—de) 8 ppm 0.89 (t,J=7.28 Hz, 3 H) 1.20 - 1.35 (m, 2 H) 1.39 - 1.55 (m, 2 121 H) 3.21 - 3.30 (m, 2 H) 5.11 (5,2 341.15 342 0.89, 0 H) 5.54 (s, 2 H) 6.58 (s, 1 H) 7.47 (s, 1 H) 7.93 (d, 1:8.03 H2, 1 H) 8.14 — 8.22 (m, 1 H) 8.85 - 8.93 (m, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t, J=7.28 Hz, 3 H) 1.23 - 1.37 (m, 2 H) 1.45 - 1.58 (m, 2 122 H) 2.48 (s, 3 H) 3.29 - 3.33 (m, 2 287.17 288 0.79, D H) 4.93 (s, 2 H) 5.54 (s, 2 H) 6.75 (s, 1 H) 7.20 (d, J=7.78 Hz, 1 H) 7.37 (d, 1:7.53 Hz, 1 H) 7.40 (s, 1 H) 7.71 (t, 1:7.65 H2,1 H) 1H NMR (400 MHz, DMSO—ds) 5 ‘l ppm 0.82 - 0.91 (m, 3 H) 1.18 - 1.28 (m, 2 H) 1.38 - 1.47 (m, 2 H) 3.19 - 3.27 (m, 2 H) 5.50 (s, 2 H) .52 (s, 2 H) 6.49 (s, 1 H) 7.44 (s, 323.17 324 0.87, D 1 H) 7.71 (ddd, , 7.03, 1.13 Hz, 1 H) 7.81 (ddd, J=8.09, 6.96, 1.25 Hz, 1 H) 7.85 (d,J=S.52 Hz, 1 H) 8.02 (d, 1:8.03 Hz, 1 H) 8.38 - 8.42 (m, 1 H) 8.48 (d, 1:5.77 H2, 1 T174 NMR (400 MHz, DMSO-de) 5 ppm 0.88 (t,J=7.2 Hz, 3 H), 1.16 - 1.37 (m, 4 H), 1.53 (quin, 1:7.3 124 Hz, 2 H), 2.03 (s, 3 H), 3.37 (q, 300.20 301 1.08, D J=6.6 Hz, 2 H), 4.36 (br. 5., 2 H), 4.83 (5,2 H), 7.29 - 7.58 (m, 5 H), 8.30 (t, 1:5.9 Hz, 1 H), 12.68 (br. s., 1 H) 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.87 (t, 1:7.28 Hz, 3 H) 1.19 - 1.38 (m, 2 H) 1.40 - 1.51 (m, 1 H) 1.51 - 1.62 (m, 1 H) 1.94 - 2.02 125 (m, 2 H) 2.66 - 2.76 (m, 2 H) 3.38 330.21 331 0.9, D - 3.48 (m, 2 H) 3.83 (td, J=6.34, 2.64 Hz, 2 H) 4.00 - 4.10 (m, 1 H) 4.69 (br. s., 1 H) 5.48 (s, 2 H) 5.72 - 5.79 (m, 1 H) 7.05 - 7.33 (m, 5 H) 7.35 (s, 1 H) -—-—.—.—_—l J LCMS Mass Exact Ret STRUCTURE Found 1H NMR Mass Time {M H] I Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.86 (t, J=7.40 Hz, 3 H) 1.19 - 1.31 (m, 2 H) 1.37 - 1.48 (m, 2 126 M\ kL - 4.23 NH 327.17 H) 3.20 - 3.27 (m, 2 H) 4.13 328 0.84,D (m, 2 H) 4.30 - 4.42 (m, 2 H) 5.57 o/\/° \N (5,2 H) 6.22 (s, 1 H) 7.12 - 7.20 Hz (m, 2 H) 7.45 (s, 1 H) 7.75 - 7.83 (m,2H) 1H NMR (400 MHz, DMSO-da) 5 ppm 0.80 ~ 0.91 (m, 3 H) 1.20 — \ 1.32 (m, 2 H) 1.37 - 1.50 (m, 2 H) (EL KL 3.17 - 3.28 (m, 2 H) 3.73 (s, 3 H) NH 332.18 333 094,0 4.13 (dd, 1:552, 326 Hz, 2 H) W0 \N 4.23 (dd, 1:5.52, 3.26 Hz, 2 H) .56 (s, 2 H) 6.20 (s, 1 H) 6.49 - N/ ”2 6.59 (m, 3 H) 7.16 - 7.22 (m, 1 H) 7.45(s,1H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.76 (t, J=7.28 Hz, 3 H) 1.11 - 1.21 (m, 2 H) 1.32 (t, 1:7.15 Hz, H04 2 H) 3.15 - 3.22 (m, 2 H) 4.32 (9 — 4.36 (m, 2 H) 4.52 - 4.56 (m, 2 H) 353.19 354 079,0 5.57 (s, 2 H) 6.24 (s, 1 H) 7.07 (d, / o/Vo \N 1:5.27 Hz, 1 H) 7.55 (s, 1 H) 7.52 - / 7.58 (m, 1 H) 7.74 (ddd, 1:8.41, 6.90, 1.25 Hz, 1 H) 7.95 (d, 1:803 Hz, 1 H) 8.12 (dd,1=8.28, 1.00 Hz, 1 H) 8.73 (d,J=5.27 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.78 - 0.93 (m, 3 H) 1.12 - \0 1.35 (m, 2 H) 1.39 - 1.54 (m, 2 H) 129 a H 3.18 — 3.28 (m, 2 H) 4.07 - 4.17 NH 362.20 363 0.92, D (m, 2 H) 4.21 (dd, 1:5.52, 3.01 0 /\/° \N I l Hz, 2 H) 5.58 (br. s., 2 H) 6.09 - J / H” 6.12 (m, 1 H) 6.14 (d, 1:2.26 Hz, 2 H) 6.21 (s, 1 H) 7.45 (s, 1 H) 1H NMR (400 MHz, s) 5 ppm 0.86 (t,J=7.28 Hz, 3 H) 1.20 \O - 1.31 (m, 2 H) 1.39 - 1.48 (m, 2 130 C(° H) 3.21 - 3.28 (m, 2 H) 3.67 (s, 3 NH 362.20 363 0.87,D H) 3.77 (s, 3 H) 4.11 — 4.18 (m, 2 o/\/° \N H) 4.22 - 4.29 (m, 2 H) 5.56 (s, 2 NéLNHz H) 6.18 (t, 1:590 Hz, 1 H) 6.66 - 6.74 (m, 2 H) 6.96 - 7.01 (m, 1 H) 7.47 (s,1H) -80— _____.___—_—_.___1 LCMS Mass Exact Ret STRUCTURE Found 1H NMR nnass Time, [M+H] nflethod 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (t, 1:7.28 Hz, 3 H) 1.18 - 1.30 (m, 2 H) 1.36 - 1.47 (m, 2 H) 3.17 - 3.28 (m, 2 H) 4.12 - 4.22 371 1.05, D (m, 2 H) 4.33 — 4.43 (m, 2 H) 5.61 (5,2 H) 5.98 (s, 1 H) 7.09 - 7.15 (m, 1 H) 7.33 (d, 1:853 Hz, 1 H) 7.47 (s, 1 H) 7.63 (d, 1:7.78 Hz, 2 1H NMR (400 MHz, 416) 5 ppm 0.85 (t, 1:7.28 Hz, 3 H) 1.19 - 1.32 (m, 2 H) 1.37 - 1.49 (m, 2 H) 3.17 - 3.28 (m, 2 H) 3.83 (s, 3 H) 3.82 (s, 3 H) 4.16 (dd, 1:5.27, 391 0.86, D 3.26 Hz, 2 H) 4.32 (dd, 1:5.27, 3.26 Hz, 2 H) 5.59 (s, 2 H) 6.18 (s, 1 H) 7.14 (d,1=8.53 Hz, 1 H) 7.45 - 7.53 (m, 2 H) 7.59 (dd, 1:853, 2.01 H2, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.86 (t,J=7.4O Hz, 3 H) 1.20 - 1.34 (m, 2 H) 1.40 - 1.52 (m, 2 H) 3.14 - 3.28 (m, 2 H) 3.58 (s, 3 392.21 393 0.84, D H) 3.75 (5,6 H) 4.13 (dd, 1:5.52, 3.26 Hz, 2 H) 4.23 (dd, 1:5.52, 3.01 Hz, 2 H) 5.58 (s, 2 H) 6.22 (s, 1 H) 6.28 (s, 2 H) 7.46 (s, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.85 (t, 1:7.40 Hz, 3 H) 1.20 - 1.30 (m, 2 H) 1.39 — 1.48 (m, 2 H) 3.20 - 3.28 (m, 2 H) 3.73 (s, 3 H) 3.81 (s, 3 H) 4.13 - 4.19 (m, 2 390.19 391 0.83, D H) 4.34 (dd, 1:5.27, 3.26 Hz, 2 H) .56 (s, 2 H) 6.20 (s, 1 H) 6.63 (dd, 1:866, 2.38 Hz, 1 H) 6.68 (d, 1:2.26 H2, 1 H) 7.46 (s, 1 H) 7.71 Hg1=853 Hz, 1 H) 1H NMR (400 MHz, 011/150-1116) 5 ppm 0.85 (t, 1:7.40 Hz, 3 H) 1.18 - 1.34 (m, 2 H) 1.36 - 1.47 (m, 2 135 H) 3.17 - 3.27 (m, 2 H) 4.13 - 4.23 370.16 371 1.06, D (m, 2 H) 4.29 - 4.41 (m, 2 H) 5.57 (5,2 H) 6.21 (s, 1 H) 7.17 (m, 1:8.53 Hz, 2 H) 7.46 (s, 1 H) 7.67 (m, 1:8.53 Hz, 2 H) WO 36834 Exact Ret STRUCTURE Found 1H NMR Mass Time, [M+H) Method 1H NMR (400 MHz, 011450-116) 5 ppm 0.81 (t, 1:7.40 Hz, 3 H) 1.16 - 1.25 (m, 2 H) 1.34 — 1.42 (m, 2 H) 3.19 - 3.25 (m, 2 H) 4.24 — 4.28 NH 35914 360 0.77, D (m, 2 H) 4.55 - 4.60 (m, 2 H) 557 (5,2 H) 6.16 (s, 1 H) 7.07 (d, 1:5.27 Hz, 1 H) 7.50 (s, 1 H) 7.53 (d, 1:5.52 H2, 1 H) 8.07 (d, 1:5.52 Hz, 1 H) 8.55 (d, 1:5.52 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t, 1:7.40 Hz, 3 H) 1.22 — 1.34 (m, 2 H) 1.44 - 1.54 (m, 2 344.18 H) 3.25 - 3.30 (m, 2 H) 3.61 (s, 3 345 0.88, D H) 3.69 (5,2 H) 4.93 (s, 2 H) 5.50 (5,2 H) 6.39 (s, 1 H) 7.22 (d, J=6.00 Hz, 1 H) 7.33 (s, 1 H) 7.28 - 7.37 (m, 2 H) 7.38 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.89 (t, J=7.40 Hz, 3 H) 1.20 - 1.37 (m, 2 H) 1.42 — 1.57 (m, 2 344.18 H) 2.02 - 2.19 (m, 2 H) 3.26 - 3.32 345 0.94, D (m, 2 H) 4.07 - 4.18 (m, 4 H) 4.89 (5,2 H) 5.52 (5,2 H) 6.31 (s, 1 H) 6.88 - 7.04 (m, 2 H) 7.12 (d, 1:6.70 Hz, 1 H) 7.37 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.88 (t, J=7.28 Hz, 3 H) 1.22 - 1.36 (m, 2 H) 1.42 — 1.57 (m, 2 139 H) 2.20 (s, 3 H) 3.22 — 3.29 (m, 2 385.17 386 0.93, D H) 4.84 - 4.98 (m, 2 H) 5.01 (s, 2 H) 5.50 (s, 2 H) 6.59 (s, 1 H) 7.13 (d,J=5.77 Hz, 1 H) 7.40 (s, 1 H) 8.34 (d, 1:5.52 Hz, 1 H) 1H NMR (400 MHz, 017150-116) 83—71 ppm 0.86 (t, 1:7.28 Hz, 3 H) 1.18 - 1.34 (m, 2 H) 1.37 - 1.52 (m, 2 H) 3.23 — 3.28 (m, 2 H) 3.69 (s, 3 NH 362.20 H) 3.74 (s, 3 H) 4.07 — 4.15 (m, 2 363 0.71, D H) 4.15 - 4.26 (m, 2 H) 5.56 (s, 2 H) 6.20 (s, 1 H) 6.47 (dd, 1:8.66, 2.89 Hz, 1 H) 6.60 (d,1=3.01 Hz, 1 H) 6.85 (d, 1:8.78 Hz, 1 H) 7.45 (5, 1 H) 1H NMR (400 MHz, DMSO—de) 5 ppm 0.77 (t, J=7.28 Hz, 3 H) 1.12 - 1.26 (m, 2 H) 1.28 - 1.37 (m, 2 141 kL NH 383.20 384 0.82, D H) 3.15 - 3.25 (m, 2 H) 3.90 (s, 3 H) 4.29 - 4.34 (m, 2 H) 4.51 (dd, 1:5.14, 3.14 Hz, 2 H) 5.58 (s, 2 H) 6.24 (s, 1 H) 6.93 (d, J=5.27 Hz, 1 W0 136834 Exact STRUCTURE Mass H) 7.17 (dd, 1:9.16, 2.64 Hz, 1 H) 7.32 (d, 1:2.51 Hz, 1 H) 7.52 (5,1 H) 8.00 (d, 1:9.29 Hz, 1 H) 8.65 (d, 1:5.27 Hz, 1 H) 1H NMR (400 MHz, DMSO-da) 5 ppm 0.77 (t,J=7.4O H2, 3 H) 1.13 - 1.19 (m, 2 H) 1.28 - 1.35 (m, 6 H) 1.28 - 1.35 (m, 2 H) 3.05 - 3.15 (m, 1 H) 3.16 - 3.21 (m, 2 H) 3.89 (s, 3 H) 4.29 - 4.32 (m, 2 H) 4.50 - 4.52 (m, 2 H) 5.57 (s, 2 H) 6.22 (s, 1 H) 6.83 (s, 1 H) 7.08 (dd, 1:9.29, 2.51 Hz, 1 H) 7.25 (d, 1:2.51 H2, 1 H) 7.52 (s, 1 H) 7.93 (d, 1:9.03 H2,1 H) 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.86 (t, 1:7.40 Hz, 3 H) 1.20 - 1.35 (m, 2 H) 1.38 - 1.51 (m, 2 H) 3.22 - 3.28 (m, 2 H) 4.09 - 4.25 \ NH 303.17 304 0.68, D (m, 2 H) 4.27 - 4.40 (m, 2 H) 5.60 / ONO \N (5,2 H) 6.27 (s, 1 H) 7.31 - 7.37 / (m, 1 H) 7.41- 7.45 (m, 1 H) 7.45 (s, 1 H) 8.19 (dd, 1:4.52, 1.25 Hz, 1 H) 8.33 (d,J=2.76 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.87 (t, 1:7.28 Hz, 3 H) 1.19 - 1.25 (m, 2 H) 1.39 (t, 1:7.40 Hz, 2 H) 3.17 - 3.22 (m, 2 H) 3.90 (s, 3 H) 4.11 - 4.22 (m, 2 H) 4.59 (m, 144 —N_/_ E 383.20 384 0.6S,D 1:490, 4.90 Hz, 2 H) 5.53 (s, 2 H) .86 (s, 1 H) 5.97 (d, 1:7.53 Hz, 1 H) 6.99 (d, 1:880 Hz, 1 H) 7.11 (d, 1:2.26 Hz, 1 H) 7.32 (s, 1 H) 8.04 (d, J=7.78 Hz, 1 H) 8.09 (d, 1:9.03 Hz, 1 H) .L.._~. 1H NMR (300 MHz, CHLOROFORM—d) 5 ppm 0.76 — 0.87 (m, 3 H), 1.14 - 1.31 (m, 5 H), 1.33 — 1.57 (m, 3 H), 1.80 (m, 145 jig/H\N J=11.4, 5.1, 2.7 Hz, 1 H), 3.31 - 330.21 331 2.18,F Hz 3.43 (m, 1 H), 3.45 - 3.56 (m, 1 H), 4.03 (0], 1:3.3 Hz, 1 H), 4.44 (s, 2 H), 4.81 - 4.89 (m, 1 H), 4.91 (s, 2 H), 7.27 - 7.35 (m, 5 H), 7.39 (s, 1 H) ~83- LCMS ______.______j nnass Exact Ret STRUCTURE Found 1H NMR Mass Time, [M+H] Method 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.91 (t, J=7.3 Hz, 3 H), 1.30 (dq, J=14.9, 7.4 Hz, 2 H), 1.55 (quin, J=7.3 Hz, 2 H), 1.97 - 2.08 (m, 2 H), 2.69 - 2.78 (m, 6 2 H), 330.21 331 1.03, D 3.42 (q, 1:6.8 Hz, 2 H), 3.73 (s, 3 H), 3.90 (t, J=6.3 Hz, 2 H), 6.73 - 6.78 (m, 1 H), 6.78 - 6.83 (m, 2 H), 7.17 — 7.25 (m, 1 H), 7.37 (s, 1 H), 7.43 (br. 5., 2 H), 8.32 (t, J=6.0 Hz, 1 H), 11.83 (br. s., 1 H) 1H NMR (400 MHz, *1 CHLOROFORM—d) 5 ppm 0.90 (t, 1:7.4 H2, 3 H), 1.24 - 1.37 (m, 2 H), 1.55 (t, 1:7.3 Hz, 2 H), 1.96 - 147 2.07 (m, 2 H), 2.65 - 2.74 (m, 2 360.22 361 1.02, D H), 3.42 (q, J=6.9 Hz, 2 H), 3.71 (s, 6 H), 3.89 (t, J=6.1 Hz, 2 H), 6.31 - 6.35 (m, 1 H), 6.38 (d, 1:2.3 Hz, 2 H), 7.34 (s, 1 H), 7.39 (br. s., 2 H), 8.31 (s, 1 H) ~———..______T.——._—_.._—____—___ 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t, 1:7.4 Hz, 3 H), 1.23 - 1.36 (m, 2 H), 1.49 - 1.60 (m, 2 H), 1.92 - 2.04 (m, 2 H), 2.68 (t, 1:7.5 Hz, 2 H), 3.41 (q, 61:6.8 Hz, 360.22 361 1.03, D 2 H), 3.67 (s, 3 H), 3.71 (5,3 H), 3.89 (t, J=6.3 Hz, 2 H), 6.69 - 6.77 (m, 2 H), 6.84 - 6.91 (m, 1 H), 7.34 (s, 1 H), 7.41 (br. 5., 2 H), 8.31 (t, 1:5.9 Hz, 1 H), 11.70 (s, 1 _(_H)__._______________ 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t, 1:7.4 Hz, 3 H), 1.24 - 1.37 (m, 2 H), 1.49 - 1.61 (m, 2 H), 1.92 - 2.05 (m, 2 H), 2.67 - 2.76 (m, 2 H), 3.41 (q, 6 J=6.9 Hz, 330.21 331 1.06, D 2 H), 3.76 (s, 3 H), 3.90 (t, 1:6.3 Hz, 2 H), 6.87 (td, 1:7.4, 1.0 Hz, 1 H), 6.96 (d, 1:7.5 Hz, 1 H), 7.11 - 7.23 (m, 2 H), 7.33 (s, 1 H), 7.40 (br. s., 2 H), 8.31 (t, 1:5.9 Hz, 1 H), 11.67 (br. s., 1 H) 1H NMR (400 MHz, s) 5 ppm 0.90 (t, 1:7.4 Hz, 3 H), 1.24 - 1.36 (m, 2 H), 1.55 (quin, 1:7.3 360.22 361 1.02, D Hz, 2 H), 1.93 - 2.04 (m, 2 H), 2.69 - 2.76 (m, 2 H), 6 3.41(q, J=6.8 Hz, 2 H), 3.70 (s, 3 H), 3.78 (s, 3 H), 3.91 (t, 1:6.4 Hz, 2 H), W0 2012/136834 ~84~ STRUCTURE 6.79 (dd, 1:7.5, 1.5 Hz, 1 H), 6.87 - 6.92 (m, 1 H), 6.99 (t, 1=7.9 Hz, 1 H), 7.36 (s, 1 H), 7.44 (br. s., 2 H), 8.31 (t, J=6.0 Hz, 1 H), 11.81 (s, 1 H) 1H NMR (400 MHz, s) 5 ppm 0.91 (t,.l=7.3 Hz, 3 H), 1.30 (dq, 1:14.9, 7.4 Hz, 2 H), 1.55 r: (quin,1=7.3 Hz, 2 H), 1.93 - 2.04 (m, 2 H), 2.68 (t,J=7.5 6 Hz, 2 H), 151 3.42 (q, 1:6.8 Hz, 2 H), 3.88 344.18 (t, 345 1’ 0 1:6.1 H2, 2 H), 5.94 - 5.99 (m, 2 \ H), 6.67 (dd, 1:7.9, 1.6 Hz, 1 H), l MN” “A“: 6.82 (d, 1:6.0 Hz, 1 H), 6.83 (s, 1 H), 7.36 (s, 1 H), 7.42 (br. s., 2 H), 8.31 (t, 1:5.9 Hz, 1 H), 11.77 (br. s., 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.86 - 0.95 (m, 3 H), 1.24 — 1.36 (m, 2 H), 1.55 (quin,1=7.3 Hz, 2 H), 1.97 - 2.07 (m, 2 H), 152 °' 2.82 - 2.90 (m, 2 H), 3.42 6 368.12 369 (6), 1.13, D 1:6.8 Hz, 2 H), 3.92 (t, 1:6.1 Hz, 2 Y” H), 7.37 (s, 1 H), 7.38 - 7.40 (m, 2 MNH \ Hz H), 7.43 (br. s., 2 H), 7.55 - 7.61 (m, 1 H), 8.32 (t, 1:5.9 Hz, 1 H), 1180 (br. s., 1 H) I 1H NMR (400 MHz, DMSO-de) 5—) ppm 0.91 (t,J=7.3 Hz, 3 H), 1.31 F (dq,1=14.9, 7.4 Hz, 2 H), 1.56 (quin,1=7.3 Hz, 2 H), 1.99 - 2.11 368.18 369 (m, 2 H), 2.87 (t, 1:7.8 6 Hz, 2 H), 1.15, D 3.38 - 3.47 (m, 2 H), 3.92 (t, 1:6.1 / N Hz, 2 H), 7.38 (s, 1 H), 7.43 (br. 5., MN” \ 1 H), 7.48 (0!, 1:8.0 Hz, 2 H), 7.66 (d, 1:8.0 Hz, 2 H), 8.33 (t, 1:6.0 H2,1 H), 11.83 (br. s., 1 H) I ._l __1 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.84 (t, 1:6.90 Hz, 3 H) 1.22 W“ — 1.36 (m, 4 H) 1.44 - 1.67 (m, 2 H) 1.95 - 2.08 (m, 2 H) 2.73 (t, 154 W s N 1:7.65 Hz, 2 H) 3.41 - 3.64 (m, 2 344.22 345 038, D o H) 3.81 - 3.96 (m, 2 H) 4.05 - 4.20 (m, 1 H) 4.80 (br. s., 1 H) 6.69 (br. s., 2 H) 6.99 (d, 1:8.53 Hz, 1 H) 7.14 - 7.34 (m, 5 H) 7.39 (s, 1 H) 7.90 (br. s., 1 H) 2012/056388 LCMS Mass Exact Ret STRUCTURE Found 1H NMR Mass Time, [M+H} Method My” 1H NMR (400 MHz, DMSO-ds) 5 1.1;?L\_ ppm 0.89 (t, 1:1.00 H2, 3 H) 1.20 0 - 1.37 (m, 2 H) 1.47 - 1.60 (m, 2 155 $1., 340.16 341 099,0 H) 3.39 - 3.47 (m, 2 H) 5.53 (s, 2 H) 7.55 - 7.67 (m, 5 H) 7.71 (s, 1 H) 7.97 - 8.08 (m, 2 H) 8.59 (s, 1 H) 12.05 (br.s., 1 H) 1H NMR (400 MHz, DMSO—ds) 5 NH;—N/ ppm 0.86 (t, 1:7.40 Hz, 3 H) 1.21 am\ - 1.33 (m, 2 H) 1.44 - 1.57 (m, 2 156 3‘: H) 3.36 - 3.46 (m, 2 H) 5.34 (s, 2 340.16 341 097,0 N H) 7.58 (br. s., 2 H) 7.67 (s, 1 H) (”G 7.63 - 7.70 (m, 2 H) 7.72 — 7.78 (m, 1 H) 8.10 - 8.18 (m, 2 H) 8.50 (s, 1 H) 11.98 (br. 5., 1 H) 1H NMR (400 MHz, 00450-116) 5 ppm 0.90 (t, J=7.40 Hz, 3 H) 1.25 - 1.37 (m, 2 H) 1.50 - 1.61 (m, 2 \N / H) 3.39 - 3.50 (m, 2 H) 5.39 (s, 2 157 H) 7.54 (br. 5., 2 H) 7.59 (d, 323.17 324 _\_\ 0 033,0 1:4.77 Hz, 1 H) 7.69 (t, 1:7.40 Hz, NH N 1 H) 7.81 - 7.91 (m, 2 H) 8.08 (d, \N / J=8.28 Hz, 1 H) 8.12 (d, J=8.03 Hz, 1 H) 8.57 (d, J=8.78 Hz, 1 H) 8.68 (br. 5., 1 H) 11.94 (br. 5., 1 H) J 1H NMR (400 MHz, DMSO-de) 5 ppm 0.91 (t, J=7.28 Hz, 3 H) 1.00 (d, J=6.78 Hz, 6 H) 1.31 - 1.41 (m, 2 H) 1.48 - 1.63 (m, 4 H) 1.70 - \ N 1.80 (m, 1 H) 3.33 - 3.42 (m, 2 H) 158 o / \ _<_/N H 4.28 - 4.37 (m, 2 H) 4.75 (s, 2 H) 409.25 410 121,0 o __N>_N2 .62 (s, 2 H) 7.08 (t, 1:1.00 Hz, 1 H) 7.31 (t, 1:7.28 Hz, 1 H) 7.49 (s, 1 H) 7.57 (d, J=8.53 Hz, 1 H) 7.66 (dd, 1:7.15, 1.38 Hz, 1 H) 7.79 (dd, J=7.78, 1.25 Hz, 1 H) 8.12 (s, 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.89 (t, J=7.28 Hz, 3 H) 1.27 - 1.37 (m, 2 H) 1.49 - 1.57 (m, 2 H) 3.32 - 3.39 (m, 2 H) 5.10 (s, 2 H) 5.53 (s, 2 H) 6.83 (s, 1 H) 7.23 - 363 O.89,D 7.28 (m, 1 H) 7.48 (s, 1 H) 7.56 (dd, 1:6.90, 1.13 Hz, 1 H) 7.59 - 7.62 (m, 1 H) 8.25 (d, J=8.03 Hz, 1 H) 8.28 (s, 1 H) 8.88 (d, 1:1.00 Hz, 1 H) 11.64 (s, 1 H) —86- M355 Exact L22”: .
STRUCTURE Found 1H NMR Mass Tlme,_ [M+H] Method 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90(t,1=7.3 Hz, 3 H), 1.30 ° (dq,1=14.9, 7.3 Hz, 2 H), 1.55 /° (quin,1=7.3 Hz, 2 H), 1.94 - 2.12 160 T (m, 2 H), 2.70 (t, 1:7.7 6 Hz, 2 H), 390.23 391 0.95, D 3.37 - 3.44 (m, 2 H), 3.62 (5, 3 H), o 3.70 - 3.79 (m, 6 H), 3.89 (t, 1:6.3 INELNHZ/ N Hz, 2 H), 6.51 (s, 2 H), 7.27 (br. 5., 2 H), 7.39 (s, 1 H), 8.15 (t, 1:5.6 . Hz, 1 H) T 1H NMR (400 MHz, s) 5 ppm 0.90 (t, J=7.3 Hz, 3 H), 1.30 o J, (dq, 1:149, 7.4 Hz, 2 H), 1.55 (quin, J=7.3 Hz, 2 H), 1.89 - 2.03 161 (m, 2 H), 2.64 .3 6 Hz, 2 H), 390.23 391 0.97, D 3.38 - 3.46 (m, 2 H), 3.65 (s, 3 H), 3.74 (s, 3 H), 3.76 (s, 3 H), 3.87 (t, 1:6.4 Hz, 2 H), 6.66 (s, 1 H), 6.75 (s, 1 H), 7.39 (s, 1 H), 7.48 (br. s., 2 H), 8.30 (t, 1:5.9 Hz, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.90 (t, 1:7.4 Hz, 3 H), 1.31 (dq, 1:149, 7.4 Hz, 2 H), 1.55 (quin, 1:7.3 Hz, 2 H), 1.98 - 2.09 (m, 2 H), 2.87 - 2.96 (m, 6 2 H), 1.15. D 3.36 - 3.44 (m, 2 H), 3.97 (t, J=6.3 Hz, 2 H), 7.17 (br. 5., 2 H), 7.42 (s, 1 H), 7.43 (t, 1:7.5 Hz, 1 H), 7.55 (d,1=7.8 Hz, 1 H), 7.63 (t, 1:7.5 Hz, 1 H), 7.69 (0, 1:7.8 Hz, 1 H), 7.97 (t, 1:5.6 Hz, 1 H) 1H NMR (400 MHz, DMSO~d5) 5 ppm 0.90 (t,.|=7.4 Hz, 3 H), 1.30 (dq, 1:149, 7.4 Hz, 2 H), 1.55 (quin,1=7.3 Hz, 2 H), 1.88 - 2.01 (m, 2 H), 2.63 (t,J==7.4 6 Hz, 2 H), 3.37 - 3.44 (m, 2 H), 3.75 (s, 3 H), 1.05, D 3.73 (s, 3 H), 3.86 (t, 1:6.4 Hz, 2 H), 6.44 (dd, 1:8.3, 2.5 Hz, 1 H), 6.52 (d, 1:2.3 Hz, 1 H), 7.02 (d, 1:8.0 Hz, 1 H), 7.29 (br. 5., 2 H), 7.35 (s, 1 H), 8.14 (t, 1:5.9 Hz, 1 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t, J=7.3 Hz, 3 H), 1.30 (dq,1=14.9, 7.3 Hz, 2 H), 1.55 (quin,1=7.3 Hz, 2 H), 1.90 - 2.03 1.02, D (m, 2 H), 2.66 (t, 1:7.5 6 Hz, 2 H), 3.37 - 3.46 (m, 2 H), 3.73 (s, 3 H), 3.76 (s, 6 H), 3.86 - 3.95 (m, 2 H), 6.72 (d,1=8.5 Hz, 1 H), 6.86 (d, LCMS Mass Exact Ret STRUCTURE Found 1H NMR nnass Time, [M+H] Method I 1:8.5 Hz, 1 H), 7.38 (s, 1 H), 7.46 (br. s., 2 H), 8.30 (t, 1:5.9 Hz, 1 H), br.s., 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (t, J=7.40 Hz, 3 H) 1.21 - 1.34 (m, 2 H) 1.41 — 1.57 (m, 2 H) 1.57 - 1.70 (m, 2 H) 1.94 - 2.01 165 (m, 2 H) 2.69 - 2.75 (m, 2 H) 3.38 344.22 345 0.97, D - 3.46 (m, 2 H) 3.82 (td, 1:6.34, 1.88 Hz, 2 H) 4.11 -4.18 (m, 1 H) 4.45 (t, 1:5.02 Hz, 1 H) 5.48 (s, 2 H) 6.00 (d, 1:8.78 Hz, 1 H) 7.11 ~ 7.31 (m, 5 H) 7.33 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t, .l=7.40 Hz, 3 H) 1.02 - 1.14 (m, 2 H) 1.23 - 1.38 (m, 2 H) 1.46 - 1.59 (m, 2 H) 3.36 - 3.46 323.17 (m, 2 H) 5.13 (s, 2 H) 5.55 (s, 2 H) 324 5.32, G 6.79 (br. 5., 1 H) 7.48 (s, 1 H) 7.70 (ddd, 1:8.16, 6.90, 1.00 Hz, 1 H) 7.78 - 7.85 (m, 1 H) 8.00 (d, 1:1.00 Hz, 1 H) 7.99 (s, 1 H) 8.16 (d,J=7.S3 Hz, 1 H) 9.34 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.92 (t, J=7.3 Hz, 3 H), 1.27 - 1.38 (m, 2 H), 1.51 - 1.63 (m, 2 H), 3.40 - 3.48 (m, 2 H), 3.78 (t, 167 3° 376.23 377 1.18, D J=6.1 Hz, 2 H), 4.32 (t, 1:8.0 Hz, 1 H), 7.13 - 7.22 (m, 2 H), 7.25 - 7.36 (m, 10 H), 7.49 (br. 5., 2 H), 8.33 (t, 1:6.0 Hz, 1 H), 12.01 (s, 1 H). 214 1H NMR (400 MHz, DMSO~d5) 5 ©\/° ppm 0.87 (t,.|=7.3 Hz, 3 H), 1.12 (d, 1:6.8 Hz, 3 H), 1.19 - 1.31 (m, 168 1 (J34), 2 H), 1.39 - 1.50 (m, 1 H), 1.52 - 300.20 jk 301 106,0 1.64 (m, 1 H), 2.03 (s, 3 H), 4.07 (br. s., 2 H), 4.15 - 4.27 (m, 1 H), 4.78 - 4.91 (m, 2 H), 7.35 - 7.43 (m, 3 H), 7.44 - 7.48 (m, 2 H), 1— 7.92 (d, 1:8.8 Hz, 1 H) _3____ 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.91 (t,J=7.3 H2, 3 H), 1.31 (dq, 1:149, 7.4 Hz, 2 H), 1.55 O (quin, 1:7.3 Hz, 2 H), 1.96 - 2.09 368.12 369 1.19, D (m, 2 H), 2.74— 2.83 (m, 6 2 H), 3.42 (q, 1:6.8 Hz, 2 H), 3.90 (t, 1:6.1 Hz, 2 H), 7.25 (dd, 1:8.3, 2.0 Hz, 1 H), 7.38 (s, 1 H), 7.44 (br. s., 1 H), 7.53 (d, 1:2.0 Hz, 1 H), 7.55 Exact STRUCTURE hnass (d, J=8.0 H2, 1 H), 8.31 (t, J=5.9 Hz, 1 H), 11.84 (br. s., 1 H) 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.90 .3 Hz, 3 H), 1.24 - 1.33 (m, 2 H), 1.35 (t, 1:7.2 Hz, 3 H), 1.55 (m, 1:7.3, 7.3, 7.3, 7.3 Hz, 2 H), 3.42 (q, 61:6.9 Hz, 2 H), 346 4.38 (q, 1:7.1 Hz, 1 H), 5.26 (s, 2 H), 7.56 (br. s, 2 H), 7.57 (s, 1 H), 7.85 (dd, 1:5.0, 1.5 Hz, 1 H), 8.04 (s, 1 H), 8.61 (t, 1:5.8 Hz, 1 H), 8.82 (dd, 1:5.0, 0.8 Hz, 1 H), 12.05 (br. s., 1 H) 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.90 (t,J=7.4 H2, 3 H), 1.31 (dq, 1:149, 7.4 Hz, 2 H), 1.59 (quin, J=7.3 Hz, 2 H), 3.44 (q, 303. 17 304 0.75, D 1:6.9 Hz, 2 H), 4.07 (s, 3 6 H), .36 (s, 2 H), 7.41 - 7.51 (m, 1 H), 7.52 - 7.69 (m, 4 H), 8.71 (d, 1:6.8 Hz, 1 H), 9.06 (br. s., 1 H), 12.08 (br. s., 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.87 (t, 1:7.4 Hz, 3 H), 1.22 — 1.36 (m, 2 H), 1.52 (quin, J=7.3 Hz, 2 H), 3.03 (dd, 1:171, 2.0 Hz, 2 H), 3.32 (q, 1:6.9 6 Hz, 2 H), 435.23 436 1.02, D 3.40 (dd, 1:172, 6.1 Hz, 2 H), 3.77 (s, 3 H), 4.95 (s, 2 H), 5.29 — .37 (m, 1 H), 5.94 (br. s., 2 H), 7.07 (t, 1:5.6 Hz, 1 H), 7.14 - 7.22 (m, 2 H), 7.22 - 7.30 (m, 3 H), 7.45 (s, 1 H), 8.12 (s, 1 H) 1H NMR (400 MHz, DMSO—ds) 8 ppm 0.90 (t,J=7.3 Hz, 3 H), 1.31 (dq, 1:150, 7.4 Hz, 2 H), 1.52 - 1.62 (m, 2 H), 1.62 - 1.86 (m, 6 H), 1.97 - 2.13 (m, 2 H), 6 3.43 (0), 387.23 388 0.96, D 1:6.9 H2, 2 H), 3.96 (s, 3 H), 5.11 ~ .20 (m, 1 H), 5.35 (s, 2 H), 7.62 (br. 5,2 H), 7.65 (d, 1:3.5 Hz, 1 H), 7.68 (s, 1 H), 8.30 (s, 1 H), 9.06 (t, 1:5.4 H2, 1 H), 12.21 (br. s., 1 H) WO 36834 -89— LCMS Mass Exa“ STRUCTURE Found Bet 1H NMR Mass Time, [M+H] Method 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t,J=7.3 H2, 3 H), 1.30 (dq, 1:150, 7.4 Hz, 2 H), 1.57 o (quin, J=7.3 Hz, 2 H), 1.98 - 2.10 174 Q I (m, 1 H), 2.28 - 2.43 (m, 6 1 H), 0 389.21 390 0.73, D 3.42 (q, 1:6.9 Hz, 2 H), 3.79 (td, °f\~ 1:8.4, 4.8 Hz, 1 H), 3.83 - 3.94 (m, M\”/LNHZ 3H)395(s3H)527(s2H)I ' I I - I r .30 - 5.37 (m, 1 H), 7.49 - 7.69 (m, 4 H), 8.31 (s, 1 H), 8.92 (br. 5., 1 H), 11.99 - 12.13 (m, 1 H) 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.35 - 0.44 (m, 2 H), 0.61 - 0.69 (m, 2 H), 0.90 (t, 1:7.4 Hz, 3 o H), 1.23 — 1.39 (m, 1 H), 1.23 - I 1.39 (m, 2 H), 1.58 6 (quin, 1:7.3 175 VA \ 373.21 374 0.52, D H2, 2 H), 3.43 (q, 1:6.9 Hz, 2 H), of}, 4.00 (s, 3 H), 4.18 (d, J=7.3 H2, 2 M\”A“ I H)S33(52H)762(br52H)l ‘ I 1 - - , , 7.64 (d, 1:5.0 Hz, 1 H), 7.69 (s, 1 H), 8.34 (s, 1 H), 9.04 (t, J=S.6 Hz, 1 H), 12.16 (d, J=4.8 Hz, 1 H) 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.89 (t, 1:7.4 Hz, 3 H), 1.28 (dq, 1:150, 7.4 Hz, 2 H), 1.44 — / N 1.56 (m, 2 H), 3.29 (q, 1:6.9 Hz, 2 176 I \ H), 5.09 (s, 2 H), 5.52 6 (br. s, 2 31616 317 0.65, D H), 6.59 (t, 1:5.9 Hz, 1 H), 7.43 (s, 1 H), 7.68 (br. 5., 1 H), 7.79 (dd, MNH \NJNHZ 1:7.5, 1.3 Hz, 1 H), 7.96 (dd, 1:7.5, 1.3 Hz, 1 H), 7.98 - 8.02 (m, 1 H), 8.04 (br. s, 1 H) 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.89 (t,J=7.3 Hz, 3 H), 1.20 - I 1.38 (m, 2 H), 1.44 — 1.56 (m, 2 H), 1.95 - 2.06 (m, 2 H), 2.73 — 177 301.19 302 0.74, D 2.80 (m, 2 H), 3.23 - 6 3.32 (m, 2 o H), 3.82 (1:, 1:6.3 H2, 2 H), 5.49 (s, | 2 H), 6.32 (t, 1:5.9 Hz, 1 H), 7.23 - MN \ N ”2 7.29 (m, 2 H), 7.34 (s, 1 H), 8.42 - ) 8.51 (m, 2 H) mF—M—‘fl—‘W1HNMR(400 MHz, DMSO-ds) 6 >§N ppm 0.89 (t, J=7.3 Hz, 3 H), 1.20 - 178 0% 1.34 (m, 2 H), 1.52 (quin, J=7.3 291.17 292 0.77, D Hz, 2 H), 2.31 (s, 3 H), 2.36 (s, 3 °f\~ H), 3.37 (q, J=6.8 Hz, 6 2 H), 4.85 MNH \NJNHZ (5,2 H), 7.57 (br. s., 3 H), 8.32 (t, J=5.9 Hz, 1 H), 12.26 (br. 5., 1 H) PCT/EPZO12/056388 LCMS STRUCTURE Time, Method 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t,.l=7.4 Hz, 3 H), 1.24 - 1.36 (m, 2 H), 1.51 - 1.59 (m, 2 179 H), 3.37 — 3.45 (m, 2 H), 3.92 (s, 3 303.17 304 0.77, D H), 5.21 (s, 2 H), 7.50 (br. 5., 2 H), 7.58 - 7.66 (m, 2 H), 7.79 (d, J=7.8 Hz, 1 H), 8.28 (0!, 1:4.3 Hz, 1 H), 8.73 - 8.91 (m, 1 H), 11.86 (d, 1:5.5 Hz, 1 H) 1H NMR (400 MHz, s) 5 ppm 0.90 (t,J=7.40 Hz, 3 H) 1.18 - 1.37 (m, 2 H) 1.51 - 1.66 (m, 2 H) 3.33 - 3.53 (m, 2 H) 3.93 (s, 3 333.18 334 0.75, D H) 4.17 (s, 3 H) 5.44 (s, 2 H) 7.62 (br. 5., 2 H) 7.73 (d, 1:7.03 Hz, 1 H) 7.83 (br. s., 1 H) 8.63 (d, J=6.78 Hz, 1 H) 9.58 (t, 1:5.90 Hz, 1 H) 12.45 (br. 5., 1 H) 7 1H NMR (400 MHz, DMSO-ds) 5 4 ppm 0.89 (t, J=7.28 Hz, 3 H) 1.17 - 1.32 (m, 2 H) 1.47 - 1.56 (m, 2 344.16 345 0.93, D H) 3.35 - 3.43 (m, 2 H) 3.97 (s, 3 H) 5.02 (s, 2 H) 7.11 (s, 1 H) 7.48 (br. 5., 2 H) 7.56 (s, 1 H) 8.35 (t, 1:6.02 Hz, 1 H) 11.85 (br. 5., 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.86 (t, 1:7.28 Hz, 3 H) 1.15 - 1.31 (m, 2 H) 1.32 - 1.48 (m, 2 H) 3.15 - 3.26 (m, 3 H) 4.03 (s, 3 326.19 327 0.75, D H) 5.26 (s, 2 H) 5.51 (s, 2 H) 6.28 (s, 1 H) 7.15 (td, 1:7.53, 0.75 Hz, 1 H) 7.43 (s, 1 H) 7.36 - 7.49 (m, 1 H) 7.62 (d, J=8.53 Hz, 1 H) 7.79 - 7.89 (m, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.84 (t,J=1.00 Hz, 3 H) 1.12 - 1.27 (m, 2 H) 1.31 - 1.46 (m, 2 183 H) 3.13 - 3.27 (m, 2 H) 3.77 (s, 3 386.21 387 0.79, D H) 3.85 (s, 3 H) 3.96 (s, 3 H) 5.18 (5,2 H) 5.48 (s, 2 H) 6.26 (s, 1 H) 7.12 (d, 1:9.29 H2, 2 H) 7.42 (s, 1 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.90 (1:, 1:7.4 Hz, 3 H), 1.48 - 1.60 (m, 2 H), 1.71 - 1.80 (m, 2 184 H), 3.43 - 3.49 (m, 2 H), 5.65 (s, 2 323.17 324 0.93, D H), 7.56 (br. s., 2 H), 7.67 (d, 1:5.0 Hz, 1 H), 7.71 - 7.77 (m, 2 H), 8.05 - 8.14 (m, 2 H), 8.60 (dd, 1:8.3, 1.3 Hz, 1 H), 8.67 (t, 1:5.9 W0 2012!136834 LCMS Mass Exam STRUCTURE Found 3‘“ 1H NMR Mass Time, {M+”1 Method H2, 1 H), 9.04 (dd, J=4.3, 1.8 H2, 1 H), 12.01 (d, 1:4.8 Hz, 1 H) 1H NMR (400 MHz, CHLOROFORM- (1)8 ppm 0.89 (t, 1:7.3 Hz, 3 H), 1.21 (d, 1:6.5 Hz, 3 H), 1.28- 1.40 (m, 2 H), 1.43 - | 1.62 (m, 2 H), 3.45 (s, 2 H), 4.23 \ o 185 IN: (dd, 1:7.9, 7.2 Hz, 1 H), 5.29 (s, 2 33719 338 0.95 0 H), 6.70 (d, 1:8.5 Hz, 1 H), 7.40 (s, 1 H), 7.54 (d, 1:8.5 Hz, 1 H), 7.56 - 7.60 (m, 1 H), 7.74 :8.5, 7.0, 1.4 Hz, 1 H), 7.85 (dd, 1:8.0, 1.0 Hz, 1 H), 8.08 (d, 1:8.5 Hz, 1 H), 8.22 (d, 1:8.3 Hz, 1 H) 1H NMR (400 MHz, CH LOROFORM- d) 8 ppm 0.80 — 0.89 (m, 3 H), 1.20 - 1.35 (m, 5 H), 1.44 (d,1:3.5 Hz, 1 H), 1.59 (dd, 1:8.3, 5.8 Hz, 2 H), 1.86 - 1.98 (m, 1 H), 3.11 - 3.40 (m, 2 | H), 3.55 (dd, J=10.8, 3.0 Hz, 1 H), 186 °IN 3.59 (dd, 1:5.0, 3.3 Hz, 1 H), 4.14 (Amt 381 22' 382 0 9 0‘ - 4.27 (m, 1 H), 5.25 NH (s, 2 H), 6.32 N” (d, 1:8.8 Hz, 1 H), 7.46 (s, 1 H), ' °” 7.48 (d, 1:8.5 Hz, 1 H), 7.57 (ddd, 1:8.1, 7.0, 1.3 Hz, 1 H), 7.75 (ddd, 1:8.5, 7.0, 1.4 Hz, 1 H), 7.84 (d, J=8.3 Hz, 1 H), 8.07 (d, 1:8.5 Hz, 1 H), 8.21 (d, J=8.5 Hz, 1 H) taken on the free base 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.87 (t,1=7.3 Hz, 3 H), 1.21 - \ 1.36 (m, 2 H), 1.47 — 1.63 (m, 1 H), 1.69 - 1.88 (m, 2 H), 1.89 ~ 187 I 2.04 (m, 1 H), 2.29 (s, 3 6 H), 2.43 \ ° \N 37523 376 0.81, 0 (5,3 H), 3.41 (t, J=6.5 Hz, 2 H), I (*4); 4.03 (5,3 H), 4.36—4.50(m, 1 H), .41 (5,2 H), 7.53 (br. 5., 2 H), "”on., 7.86 (d,1=5.5 Hz, 1 H), 8.62 (s, 1 H), 9.19 (d, 1:8.8 Hz, 1 H), 1235 (d, 1:5.3 Hz, 1 H) 1H NMR (400 MHz, CHLOROFORM- d) 5 ppm 0.85 (t, ( 1:7.40 Hz, 3 H) 1.25 - 1.43 (m, 3 | N;L~ 367.20 368 H) 1.50 - 1.59 (m, 2 H) 1.82 - 1.94 0.78, H NH H2 (m, 1 H) 2.92 - 3.32 (m, 1 H) 3.42 - 3.51 (m, 1 H) 3.53 - 3.60 (m, 1 H) 4.11 - 4.23 (m, 1 H) 4.83 (s, 2 I H) 5.22 (s, 2 H) 5.73 (d, J=8.78 Hz, 1 H) 7.46 (d,J=8.53 Hz, 1 H) 7.53 (5,1 H) 7.55 - 7.59 (m, 1 H) 7.73 (ddd, 1:8.47, 6.96, 1.38 Hz, 1 H) 7.82 (d, J=8.03 Hz, 1 H) 8.08 (d, J=8.28 Hz, 1 H) 8.18 (d, J=8.53 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.79 - 0.87 (m, 3 H), 1.15 - 1.21 (m, 4 H), 1.22 - 1.28 (m, 6 H), 4.16 — 4.40 (m, 1 H), 5.35 — .40 (m, 2 H), 7.40 - 7.48 (m, 2 365.22 366 1.13, D H), 7.50 - 7.54 (m, 1 H), 7.62 - 7.68 (m, 1 H), 7.73 - 7.77 (m, 1 H), 7.78 - 7.85 (m, 1 H), 7.99 - 8.07 (m, 2 H), 8.31 — 8.38 (m, 1 H), 8.45 - 8.51 (m, 1 H), 11.47 - 11.58 (m, 1 H) 1H NMR (300 MHz, CHLOROFORM— (1)5 ppm 0.84 (t, J=7.4 Hz, 3 H), 1.14 - 1.55 (m, 6 H), 1.75 - 1.90 (m, 1 H), 3.30 - 316.19 317 0.84, D 3.43 (m, 1 H), 3.45 - 3.57 (m, 1 H), 4.06 (ddd, 1:113, 5.2, 3.3 Hz, 1 H), 4.42 (s, 2 H), 4.80 - 4.86 (m, 1 H), 4.90 (s, 2 H), 7.27 - 7.34 (m, H), 7.40 (s, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.89 (t, J=7.28 Hz, 3 H) 1.12 - 1.40 (m, 2 H) 1.43 — 1.60 (m, 2 191 H) 2.68 (s, 3 H) 3.32 - 3.48 (m, 2 293.13 294 0.71, D H) 5.07 (s, 2 H) 7.57 (br. 5., 2 H) 7.61 (br. s., 1 H) 7.78 (s, 1 H) 8.45 (t, J=5.90 Hz, 1 H) 12.21 (br. s., 1 1H NMR (400 MHz, DMSO—de) 5 1 ppm 0.87 (t, J=7.4 Hz, 3 H), 1.16 - 1.35 (m, 2 H), 1.51 - 1.63 (m, 2 H), 3.48 - 3.55 (m, 2 H), 4.28 (d, J=6.0 H2,1 H), 5.41 (s, 2 H), 7.51 (br. 5., 2 H), 7.58 (d, J=5.5 Hz, 1 353.19 3S4 0.78, D H), 7.68 (td, 1:75, 1.0 Hz, 1 H), 7.79 (d, J=8.5 Hz, 1 H), 7.85 (ddd, 1:8.5, 7.0, 1.4 Hz, 1 H), 8.07 (d, 1:73 Hz, 1 H), 8.11 (d, J=8.5 Hz, 1 H), 8.18 (d, J=9.0 Hz, 1 H), 8.55 (d, J=8.5 Hz, 1 H), 11.83 (d, J=5.5 Hz, 1 H) W0 2012/136834 MESS Exact LEE/:5 URE Found 1H NMR Mass Time,.
[M+H] Method 1H NMR (400 MHz, DMSO-ds) 5 CE\>—\N ppm 0.89 (t, 1:7.40 Hz, 3 H) 1.25 / - 1.36 (m, 2 H) 1.47 - 1.55 (m, 2 193 ° \>'””2 —N 312.17 313 H)3.25-3.29(m,2H)S.13(s,2 0.76, D FrNH H) 5.58 (s, 2 H) 6.71 (t, 1:5.77 Hz, 1 H) 7.19 (br. s., 2 H) 7.51 (s, 1 H) 7.53 (br. s., 1 H) 7.59 (br. 5., 1 H) L 12.60 (br.s., 1 H) 1H NMR (400 MHz, DMSO-da) 5 ppm 0.84 (t, J=6.9 Hz, 3 H), 1.14 - NH: V 1.35 (m, 4 H), 1.59 - 1.80 (m, 2 H), 2.29 (s, 3 H), 2.42 (5,3 H), 194 "$.15 S 3.51 - 3.61 (m, 2 H), 6 4.02 (s, 3 0 37523 376 0.82, 0 H), 4.26 - 4.39 (m, 1 H), 5.41 (s, 2 N/ \ o H), 7.54 (br. 5., 2 H), 7.86 (d, — ‘ J=3.3 Hz, 1 H), 8.61 (s, 1 H), 9.00 (d, J=8.0 Hz, 1 H), 12.41 (d, 1:3.3 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.88 (t, J=7.6 Hz, 3 H), 1.18 — 1.39 (m, 2 H), 1.56 - 1.69 (m, 1 H), 1.69 ~ 1.84 (m, 1 H), 3.53 - «IINH 3.68 (m, 2 H), 4.33 - 6 4.45 (m, 1 195 o _..N N \ / Hz 353.19 H), 6.08 (s, 2 H), 7.55 (br. s., 2 H), 354 0.76,D \ N 7.96 - 8.08 (m, 2 H), 8.17 (t, 1:7.5 Hz, 1 H), 8.33 (d, 1:8.3 Hz, 1 H), 8.41 (01, 1:63 Hz, 1 H), 8.65 (01, 1:65 Hz, 1 H), 8.70 (d, 1:8.5 Hz, 1 H), 9.10 - 9.28 (m, 1 H), 12.58 (br.
L S., 1 H) 7 1H NMR (300 MHz, CHLOROFORM- (1)5 ppm 0.95 (t, 0H 1:7.1 Hz, 3 H), 1.30 - 1.48 (m, 3 H), 1.49 - 1.67 (m, 2 H), 3.44 (s, 3 196 0 0“ IN 27017 H), 3.55 - 3.64 (m, 1 H), 3.67 (t, 271 137' F s H Hg J=4.4 Hz, 2 H), 3.73 - 3.80 (m, 1 H), 3.97 - 4.04 (m, 2 H), 4.09 (d, 1:2.6 Hz, 1 H), 4.80 (br. s., 2 H), .91 (0!, 1:7.0 Hz, 1 H), 7.47 (s, 1 ~_l___ H) 1H NMR (300 MHz, H CHLOROFORM- d) 8 ppm 0.86 - NH; {1H 0.97 (m, 3 H), 1.24 - 1.43 (m, 4 “)1 NS H), 1.46 - 1.72 (m, 2 H), 3.40 - 197 — 3.45 (m, 3 H), 3.48 (br. 5, 1 H), 284.18 285 ° 1.62, F g 3.60 (dd, 1=11.1, 6.7 Hz, 1 H), 3.67 (t, J=4.3 Hz, 2 H), 3.72 - 3.81 °\ (m, 1 H), 4.00 (q, 1:3.9 Hz, 2 H), 4.04 - 4.14 (m, 1 H), 4.92 (br. 5., 2 L H), 5.96 (d, 1:7.4 Hz, 1 H), 7.45 (s, LCMS URE 1H NMR Time, Method 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.77 - 0.84 (m, 3 H), 1.14 - 1.34 (m, 5 H), 1.48 (d, J=5.8 Hz, 2 H), 1.56 - 1.67 (m, 1 H), 3.39 - 3.51 (m, 2 H), 4.07 (d, 1:5.0 H2, 1 198 H), 4.72 (br. s., 1 H), 5.63 (5,2 H), 367.20 368 0.85, D 6.35 (d, 1:9.0 Hz,_1 H), 7.47 (s, 1 H), 7.62 (ddd, J=8.1, 6.8, 1.1 Hz, 1 H), 7.69 (d, 1:8.5 Hz, 1 H), 7.79 (ddd, 1:8.4, 6.9, 1.5 Hz, 1 H), 7.98 - 8.05 (m, 2 H), 8.41 (d,1=8.5 Hz, 1 H) 1H NMR (400 MHz, DMSO-da) 6 ppm 0.88 — 0.94 (m, 3 H), 1.20 - 1.37 (m, 2 H), 1.55 (quin, 1:7.3 199 N\_?—NH\‘\_ H2, 2 H), 3.42 (q, 1:68 Hz, 2 H), 274.15 275 0.65, 0 .22 (s, 2 H), 7.59 (br. 5., 2 H), 7.66 (br. s., 1 H), 8.51 (t, 1:5.9 Hz, 1 H), 8.68 (s, 2 H), 9.02 (s, 1 H), 12.24 (br. s., 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.96 (t, 1:7.2 Hz, 3 H), 1.36 - 1.50 (m, 3 H), 1.50 - 1.69 (m, 3 H), 2.00 - 2.14 (m, 2 H), 2.72 (t, 1:7.4 Hz, 2 360.22 361 2.21, F H), 3.58 - 3.66 (m. 1 H), 3.80 (s, 3 H), 3.91 (t, J=6.3 Hz, 2 H), 4.05 (0), 1:5.9 Hz, 1 H), 4.59 (br. 5., 2 H), .25 (0, 1:69 Hz, 1 H), 6.80 - 6.88 (m, 2 H), 7.11 (d, J=8.5 Hz, 2 H), 7.34 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.85 - 0.96 (m, 3 H), 1.23 - 1.43 (m, 5 11H, N S H), 1.46 - 1.71 (m, 2 H), 1.99 - N PM 2.13 (m, 2 H), 2.71 (t, 1:7.5 Hz, 2 201 H), 3.57 - 3.66 (m, 1 H), 3.74 (0), 374.23 375 2.43, F 1:3.2 H2, 1 H), 3.78 (s, 3 H), 3.90 (t, 1:63 Hz, 2 H), 4.03 (t, 1:5.5 Hz, 1 H), 4.63 (br. 5., 2 H), 5.26 (d, 1:7.1 Hz, 1 H), 6.80 - 6.89 (m, 2 H), 7.10 (d,1=8.5 H2, 2 H), 7.32 (s, 1 H) Exact STRUCTURE Mass 1H NMR (300 MHz, CH LOROFORM-d) 5 ppm 0.94 (t, 1:7.3 Hz, 3 H), 1.32 - 1.52 (m, 3 H), 1.53 - 1.68 (m, 2 H), 2.59 (s, 3 317.19 H), 3.58 - 3.68 (m, 1 H), 3.74 - 318 1.35, F 3.84 (m, 1 H), 4.12 (td, 1:6.9, 3.0 Hz, 1 H), 4.61 (br. s., 2 H), 4.99 (s, 2 H), 5.94 (d, 1:7.1 Hz, 1 H), 7.15 (dd, 1:11.7, 7.7 Hz, 2 H), 7.49 (s, 1 H), 7.62 (t, 1:7.7 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.85 - 0.96 (m, 3 H), 1.18 - 1.46 (m, 5 H), 1.50 - 1.72 (m, 2 H), 2.59 (s, 3 331.20 H), 3.58 - 3.69 (m, 1 H), 3.75 - 332 1.63, F 3.84 (m, 1 H), 4.09 (td, 1:6.9, 2.6 Hz, 1 H), 4.62 (br. s., 2 H), 5.00 (s, 2 H), 5.95 (d, 1:7.0 Hz, 1 H), 7.15 (dd, 1:123, 7.8 Hz, 2 H), 7.49 (s, 1 H), 7.62 (t, 1:7.7 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.97 (t, 1:7.2 Hz, 3 H), 1.32 - 1.49 (m, 3 H), 1.51 - 1.70 (m, 3 H), 1.98 - 2.14 (m, 2 H), 2.70 (t, 1:7.5 Hz, 1 374.20 H), 3.59 - 3.71 (m, 1 H), 3.74 - 375 2.26, F 3.83 (m, 1 H), 3.91 (t, 1:6.4 Hz, 1 H), 3.99 - 4.15 (m, 1 H), 4.68 (br. s., 2 H), 5.26 - 5.33 (m, 2 H), 5.92 - 5.95 (m, 2 H), 6.59 - 6.66 (m, 1 H), 6.69 (d, 1:1.4 Hz, 1 H), 6.72 - 6.78 (m, 1 H), 7.33 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.84 (t, J=7.28 Hz, 3 H) 1.15 — 1.30 (m, 2 H) 1.43 - 1.57 (m, 1 H) 1.57 - 1.69 (m, 1 H) 1.69 - 1.87 (m, 2 H) 3.37 - 3.45 (m, 2 H) 4.24 356.20 357 0.66, D - 4.43 (m, 1 H) 5.30 (s, 2 H) 7.28 (t, 1:6.53 H2, 1 H) 7.55 (br. s., 2 H) 7.70 (s, 1 H) 7.62 - 7.77 (m, 1 H) 7.81 (d, 1:878 Hz, 1 H) 8.31 (s, 1 H) 8.27 - 8.35 (m, 1 H) 8.81 (d, 8 H2, 1 H) 12.15 (br. s., 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.89 (t,1=7.40 Hz, 3 H) 1.15 - 1.33 (m, 2 H) 1.35 (5,3 H) 1.43 - 266.17 267 0.72, D 1.56 (m, 2 H) 3.12 - 3.30 (m, 2 H) 3.91(s, 2 H) 4.28 (d, 1:5.77 Hz, 2 H) 4.46 (d, 1:5.77 Hz, 2 H) 5.50 (s, 2 H) 6.20 (t, 1:5.90 Hz, 1 H) 7.41 —T “nass Exact STRUCTURE Found nnass 1H NMR (400 MHz, s) 5 ppm 0.83 (t, 1:1.00 Hz, 3 H) 1.13 - 1.33 (m, 4 H) 1.47 - 1.61 (m, 1 H) 1.61 - 1.78 (m, 2 H) 1.79 - 1.89 (m, 1 H) 3.29 — 3.47 (m, 2 H) 4.27 § 37021 371 071,0 — 4.38 (m, 1 H) 5.37 (s, 2 H) 7.47 OH (br. s., 1 H) 7.57 (br. s., 2 H) 7.73 (br. s., 1 H) 7.86 - 8.01 (m, 2 H) 8.35 (d, J=9.03 Hz, 1 H) 8.42 (s, 1 H) 8.94 (d, J=6.27 Hz, 1 H) 12.19 l___ (br. s., 1 H) 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.84 (t, 1:7.03 Hz, 3 H) 1.13 - 1.36 (m, 4 H) 1.52 - 1.67 (m, 1 OH H) 1.71 - 1.84 (m, 2 H) 1.88 - 2.00 (m, 1 H) 3.33 - 3.48 (m, 2 H) 4.42 208 s (m, J=8.80, 4.60, 4.60 Hz, 1 H) ~\ NH %//\\// 38122 382 I 086.0 6.02 (s, 2 H) 7.51 (br. s., 2 H) 7.96 / 0%| ‘”/"A” (t, 1:1.00 Hz, 1 H) 7.96 (t, 1:1.00 Hz, 1 H) 8.13 (t, 1:7.65 Hz, 1 H) 8.21 - 8.47 (m, 1 H) 8.32 (d, J=1.00 Hz, 1 H) 8.65 (s, 1 H) 8.64 (d,J=1.00 HZ, 1 H) 9.17 (br. s., 1 H) 12.34 (br. s., 1 H)" 1H NMR (400 MHz, DMSO-de) 5 ppm 0.89 (t, 1:7.4 Hz, 3 H), 1.29 0%/ (dq, 1:149, 7.3 Hz, 2 H), 1.57 \ \" (quin,1=7.3 Hz, 2 H), 3.43 (dd, ° / W” 209 J=13.6, 6.8 Hz, 2 H), 5.38 6 (5,2 "M 312.17 313 0.69, D H), 7.48 (td, 1:6.7, 1.3 Hz, 1 H), ffNH 7.62 (br. s., 2 H), 7.72 (s, 1 H), 7.87 - 8.02 (m, 2 H), 8.46 (s, 1 H), 8.82 (t, 1:5.9 Hz, 1 H), 8.94 (d, J=6.8 Hz, 1 H), 12.29 (br. s., 1 H) 1H NMR (400 MHz, DMSO-de) 5 T?) ppm 0.90 (t, 1:7.4 Hz, 3 H), 1.22 - _ \_\_ 135 (m, 2 H), 1.49 - 1.60 (m, 2 210 0 H), 3.37 - 3.47 (m, 2 H), 5.18 (s, 2 297.16 298 0.85, D H), 7.49 — 7.62 (m, 3 6 H), 7.71 (m, J=8.5 Hz, 2 H), 7.86 - 7.93 (m, 2 H), 8.51 (t, J=5.9 Hz, 1 H), 12.17 - 12.31 (m, 1 H) W0 2012/136834 LCMS Mass ‘3“ URE Found 3“ 1H NMR Mass Time, [NH-H] Method 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.89 (t, J=7.4 Hz, 3 H), 1.21 - m1/ 1.37 (m, 2 H), 1.48 - 1.62 (m, 2 211 N\>—NH2 H), 3.41 (0), J=6.8 Hz, 2 H), 5.33 (5, —~ 313.17 314 0.59. D 2 H), 7.60 (br. 5., 2 6 H), 7.69 (br. /_/_“” 5., 1 H), 8.09 (d, 1:4.5 Hz, 1 H), 8.50 - 8.67 (m, 2 H), 8.85 (01, 1:43 Hz, 1 H), 9.32 (5, 1 H), 12.29 (br. s., l H) )— 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (t,J=7.3 Hz, 3 H), 1.17 (d, J=6.5 Hz, 3 H), 1.19 - 1.29 (m, 2 H), 1.40 - 1.55 (m, 1 H), 1.57 - / 1.72 (m, 1 H), 4.21 - 6 4.35 (m, 1 212 I \ 337.19 338 H),5.81(s,2H),7.47 ,2 H), 03410 7.66 (br. 5., 1 H), 7.78 - 7.86 (m, 1 2 IN H), 7.95 (t, 1:7.3 Hz, 1 H), 8.08 MN“ N/ H2 (br. 5., 1 H), 8.15 (d, J=8.0 Hz, 1 H), 8.48 (d, J=8.3 Hz, 1 H), 8.56 (d, 1:5.8 H2, 1 H), 11.73 (br. 5., 1 1 J H) T_- 1H NMR (400 MHz, DMSO-ds) 5 N>/—"\ ppm 0.88 (t,J=7.4 H2, 3 H), 1.27 213 L\— Edq,1=14.9, 7.4 H2,)2 H), 1&51quin, J=7.3 Hz, 2 H , 3.38 q, 291.15 292 0.75, 0 1:6.9 Hz, 2 H), 5.20 (d, 6 J=1.8 Hz, 2 H), 7.51 (br. 5., 2 H), 7.54 - 7.62 N/ \ (m, 2 H), 7.84 (ddd, 1:9.9, 8.6, -— 1.1 H2,1 H), 8.39 - 8.53 (m, 2 H), 11.85 (d, 1:5.5 Hz, 1 H) 1H NMR (400 MHz, DMSO—ds) 6 ppm 0.86 (t,.|=7.3 Hz, 3 H), 1.18 - 0 | 1.35 (m, 2 H), 1.36 - 1.48 (m, 1 / H), 1.51 - 1.64 (m, 1 H), 3.31 — 214 I \ 3.49 (m, 2 H), 3.78 (5,3 6 H), 3.90 N 36319 364 055’ D (5, 3 H), 3.99 - 4.09 (m, 1 H), 4.68 OH O Al IN (br. 5., 1 H), 4.86 - 4.97 (m, 2 H), NH “25% 5.59 (s, 2 H), 6.38 (d, J=8.8 Hz, 1 H), 7.14 (d, 1:5.5 Hz, 1 H), 7.49 (s, 1 H), 8.23 (d, 1:5.5 Hz, 1 H) l— 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (t, J=7.3 Hz, 3 H), 1.14 - 1.33 (m, 2 H), 1.49 — 1.72 (m, 2 H), 3.47—3.61 (m,2H),4.21- 215 4.33 Sm, 1 H), 5.41 (5, 2 6 H), 7.50 on __N 34218 343 0.6, 0 / N \ \ , Hz (td,J—6.S, 1.5 Hz, 1 H), 7.61 (br.
N 5., 2 H), 7.78 (s, 1 H), 7.91 - 8.03 (m, 2 H), 8.22 (d, 1:9.0 Hz, 1 H), 8.48 (5, 1 H), 8.97 (d,1=6.8 Hz, 1 H), 12.42 (br. 5., 1 H) W0 36834 -98— [.——'—-—--—‘—-_———’——"" ExaCt ‘ STRUCTURE Found Bet 1H NMR Mass Time, 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.80 (t, 1:7.2 Hz, 3 H), 1.08 - 1.18 (m, 2 H), 1.18 - 1.27 (m, 2 8.,/ N\ H), 1.27—1.37(m,1H),1.49— / >51... 1.61(m,1H),3.27-63.33(m,2 “N H), 3.92 - 4.04 (m, 1 H), 4.65 (br. 216 N .5 367.20 368 O.82,D s.,1H),5.47-5.63(m,4H),6.08 on (d,J=9.0 Hz, 1 H), 7.51 (5,1 H), 7.66 - 7.74 (m, 1 H), 7.78 - 7.83 (m, 1 H), 7.85 (d, 1:55 H2,1 H), 8.02 (d, J=8.0 Hz, 1 H), 8.40 (d, J=8.5 Hz, 1 H), 8.48-(d,1=5.8 Hz, 1 1H NMR (400 MHz, DMSO—ds) 5 ppm O.84(t,1=6.9 Hz, 3 H), 1.15 - m5 M 1.37 (m, 4 H), 1.58 - 1.79 (m, 2 ">71 N5 H), 3.50- 3.64 (m, 2 H), 3.93 (s, 3 217 —— H), 4.16 (s, 3 H), 64.25 -4.37 (m, 37721 378 0.73, 0 0 1 H), 5.37 — 5.47 (m, 2 H), 7.58 (br. 5., 2 H), 7.71 (d, J=6.8 Hz, 1 __ \ H), 7.81 (d, 1:4.3 H2,1 H), 8.62 (d, J=6.8 Hz, 1 H), 8.89 (d, 1:8.8 H2, 1 H), 12.30- 12.47 (m, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.82 (t, 1:7.0 Hz, 3 H), 1.09 - 1.36 (m, 4 H), 1.61 (q, 1:7.2 Hz, 2 \ \N O‘Qwflz H), 3.45 ' 359 (m, 2 H); 4-18 - 218 4.31 (m, 1 H), 5.33 - 6 5.45 (m, 2 Mg. 35620 357 0.68, 0 8E1 H), 7.47 (t, 1:6.7 Hz, 1 H), 7.59 (br. s., 2 H), 7.76 (s, 1 H), 7.86 - 8.02 (m, 2 H), 8.20 (d, 1:9.0 Hz, 1 H), 8.45 (s, 1 H), 8.94 (0!, 1:6.8 Hz, 1 H), 12.33 (br. 5., 1 H) 1H NMR (400 MHz, DMSO-c/g) 5 ppm 0.85 (t,J=7.3 Hz, 3 H), 1.18 (d, J=6.5 Hz, 3 H), 1.20 - 1.29 (m, 2 H), 1.41 - 1.56 (m, 1 H), 1.67 (dd, 1:134, 6.7 Hz, 1H), 4.24 - / 4.36 (m, 1 H), 5.84 (br. 5., 2 H), 219 I \ 337.19 338 0.94, D 7.47 (br. s., 2 H), 7.70 (br. s., 1 H), o 7.80 - 7.89 (m, 1 H), 7.98 (t, 1:7.2 /\/he I: H2, 1 H), 8.11 (br. 5., 1 H), 8.17 NH “2 (d,1=8.3 Hz, 1 H), 8.50 (d, J=8.3 Hz, 1 H), 8.57 (d, J=6.0 Hz, 1 H), 8.71 (br. 5., 1 H), 11.79 (br. s., 1 It LCMS Mass Exact Ret STRUCTURE Found 1H NMR Mass Time,.
[M+H] Method 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.90 (1:, 1:7.4 Hz, 3 H), 1.30 N/52‘ L\_"\ m (dq,1=14.9, 7.3 Hz,2 H), 1.54 (dt, 1:145, 7.4 Hz, 2 H), 1.97 (quin, 282.17 283 0.76, D J=6.7 Hz, 2 H), 2.55 6 (t,1=7.4 Hz, 2 H), 3.37 - 3.45 (m, 2 H), 3.61 (5, ° 3 H), 3.93 (t, 1:6.1 Hz, 2 H), 7.39 (5, 1 H), 7.47 (br. 5., 2 H), 8.34 (t, J=5.8 Hz, 1 H), 11.96 (br. 5., 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t, J=7.3 Hz, 3 H), 1.19 (d, J=6.3 Hz, 6 H), 1.30 (dq, o 1:149, 7.4 Hz, 2 H), 1.54 (dt, 221 A 1:145, 7.4 Hz, 2 H), 1.89 - 6 2.02 31020 311 0.91, 0 o (m, 2 H), 3.36 - 3.44 (m, 2 H), 3.92 (t, 1:6.1 H2, 2 H), 4.90 (quin, Mmf?“\N/LNHZ J=6.3 Hz, 1 H), 7.36 (s, 1 H), 7.41 (br. 5., 2 H), 8.35 (t, J=6.0 Hz, 1 H), 11.73 (br. s., 1 H) 1H NMR (400 MHz, DMSO-ds) 5 CES\)—\N ppm 0.89 (t, J=7.28 Hz, 2 H) 1.22 - 1.40 (m, 2 H) 1.42 - 1.58 (m, 2 222 H) 3.25 - 3.38 (m, 2 H) 5.39 (s, 2 —~ 329.13 330 0.2710 NH H) 5.63 (s, 1 H) 6.56 (t, 1:5.77 Hz, [J— 1 H) 7.43 - 7.61 (m, 2 H) 8.01 (d, 1:7.53 Hz, 1 H) 8.13 (dd, 1:7.91, 0.63 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 8 ppm 0.83 (t, 1:7.00 Hz, 3 H) 1.17 — 1.34 (m, 4 H) 1.53 - 1.67 (m, 2 H) 1.71 - 1.83 (m, 2 H) 3.46 (t, 1:6.30 H2, 2 H) 4.34 (m, 1:7.80 Hz, 1 H) 5.33 (5,2 H) 7.49 (br. 5., 381.22 382 0.86, D 2 H) 7.64 (d, 1:552 Hz, 1 H) 7.79 (t, 1:7.50 Hz, 1 H) 7.91 (t, 1:753 Hz, 1 H) 8.10 (s, 1 H) 8.06 (d, 1:8.30 Hz, 1 H) 8.26 (d, 1:828 Hz, 1 H) 8.46 (d, 1:8.78 Hz, 1 H) 9.48 (s, 1 H) _l_ 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.88 (t, 1:7.40 H2, 3 H) 1.19 - 1.31 (m, 2 H) 1.51 (quin, J=7.28 Hz, 2 H) 3.39 (m, 1:6.80, 6.80, 6.80 Hz, 2 H) 5.24 (s, 2 H) 6.78 (s, 312.17 313 0.26, 0 1 H) 6.92 .90 Hz, 1 H) 7.25 (dd, J=8.28, 7.28 Hz, 1 H) 7.47 (br. s., 2 H) 7.55 (d, 1:5.77 Hz, 1 H) 7.70 (d, 1:9.03 Hz, 1 H) 8.42 (t, 1:5.77 Hz, 1 H) 8.65 (d, 1:7.03 Hz, 1 H) 11.74 (d, 1:5.77 Hz, 1 H) -1 oo- STRUCTURE 1H NMR 1H NMR (300 MHz, FORM-d) 5 ppm 0.74 - 0.88 (m, 3 H), 1.14 - 1.36 (m, 4 H), 1.40 - 1.65 (m, 2 H), 1.77 - 1.93 (m, 2 H), 2.00 (quin, J=6.9 Hz, 2 H), 2.64 (td, 1:7.4, 2.4 Hz, 2 H), 3.38 - 3.42 (m, 1 H), 3.46 (dd, 1:114, 2.6 Hz, 1 H), 3.52 (dd, 1:5.1, 2.2 Hz, 1 H), 3.72 (s, 3 H), 3.84 (td, 1:6.3, 1.8 Hz, 2 H), 4.06 (d, 1:2.7 Hz, 1 H), 4.48 (br. 5., 2 H), 4.89 (d, J=8.7 Hz, 1 H), 6.72 - 6.80 (m, 2 H), 7.02 (d, J=8.7 Hz, 2 H), 7.25 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.85 (t, 1:7.2 Hz, 3 H), 1.24 - 1.39 (m, 3 H), 1.41 - 1.54 (m, 2 H), 1.85 (d, 1:5.4 Hz, 1 H), 2.00 (t, J=6.9 Hz, 2 H), 2.64 (td, 1:7.4, 2.1 Hz, 2 H), 3.42 (s, 1 H), 3.46 (dd, 1:114, 2.6 Hz, 1 H), 3.52 (d, 1:2.6 Hz, 1 H), 3.72 (s, 3 H), 3.84 (td, J=6.4, 1.4 Hz, 2 H), 4.01 - 4.17 (m, 1 H), 4.46 (br. 5., 2 H), 4.85 (br. 5., 1 H), 6.71 - 6.82 (m, 2 H), 6.97 - 7.08 (m, 2 H), 7.26 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 8 ppm 0.90 (t, 1:7.3 Hz, 3 H), 1.22 - 1.50 (m,4 H), 1.52 - 1.67 (m, 2 H), 1.83 4 2.05 (m, 1 H), 2.58 (s, 3 H), 3.43 - 3.55 (m, 1 H), 3.56 - 3.65 (m, 1 H), 4.20 (br. 5., 1 H), 4.60 - 4.76 (m, 2 H), 4.99 (s, 2 H), 5.82 (d, J=8.7 Hz, 1 H), 7.14 (t, 1:6.8 Hz, 2 H), 7.50 (s, 1 H), 7.61 (1:, J=7.7 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM—d) 5 ppm 0.92 (t, 1:1.0 Hz, 3 H), 1.22 - 1.43 (m, 5 or H), 1.47- 1.71 (m, 2 H), 1.97 — 2.12 (m, 2 H), 2.64 — 2.75 (m, 2 38821 H), 3.63 (dd, 1:109, 6.8 Hz, 1 H), 389 2.4, F o 3.74 - 3.83 (m, 1 H), 3.91 (t, J=6.3 d. X“ Hz, 2 H), 3.97 - 4.10 (m, 1 H), ‘f 4.57 (br. s., 2 H), 5.26 (d, 1:6.7 Hz, 1 H), 5.94 (5,2 H), 6.59 - 6.66 (m, 1 H), 6.69 (d, 1:1.5 Hz, 1 H), 6.72 — 6.78 (m, 1 H), 7.35 (s, 1 H) ~101- LCMS Exact Ret STRUCTURE 1H NMR Mass Time, [M+H] Method 1H NMR (300 MHz, CHLOROFORM~d) 5 ppm 0.90 (t, 1:1.0 Hz, 3 H), 1.30 - 1.46 (m, 5 NHz H), 1.48 - 1.73 (m, 3 H), 1.95 (tdd, N/ N\ R 254.17 255 1:11.2, 11.2, 5.5, 2.7 Hz, 1 H), N 159,1: 3.54 (dd, 1:113, 2.7 Hz, 1 H), 3.58 - 3.67 (m, 1 H), 3.79 (s, 3 H), / 4.16 (dd, 1:5.7, 3.0 Hz, 1 H), 4.99 (br. s., 2 H), 5.10 (d,1=8.5 Hz, 1 H), 7.32 (s, 1 H) 1H NMR (360 MHz, DMSO-ds) 5 ppm 0.89 (t,.l=7.32 Hz, 3 H) 1.03 2r) — 1.20 (m, 3 H) 1.29 (m, 1:7.70 H2, 2 H) 1.52 (d,1:6.95 Hz, 2 H) 230 Q3 3.38 (m, 1:7.00 Hz, 2 H) 3.48 - 387.23 388 575,63 3.63 (m, 2 H) 4.07 (q, 1:7.20 Hz, 4 N):o H) 4.53 (s, 2 H) 7.19 — 7.29 (m, 3 °> H) 7.30 - 7.38 (m, 2 H) 7.42 (s, 1 H) 7.45 — 7.56 (m, 2 H) 8.09 - 8.32 (m, 1 H) 11.84- 12.01 (m, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.86 (t, 1:7.40 Hz, 3 H) 1.19 - 1.30 (m, 2 H) 1.48 - 1.58 (m, 1 H) 1.65 - 1.78 (m, 2 H) 1.82 - 1.92 OHb'nINH 5 231 _.N (m, 1 H) 3.35 - 3.45 (m, 2 H) 4.37 /E~\.E - 4.45 (m, 1 H) 5.93 (s, 2 H) 7.49 , \ 2 367.20 368 0.8,D (br. s., 2 H) 7.80 (br. s., 1 H) 7.90 (t, 1:7.40 Hz, 1 H) 8.04 (t, 1:6.90 Hz, 1 H) 8.22 (d,1=8.03 H2, 2 H) L 8.54 - 8.63 (m, 2 H) 8.88 (br. 5., 1 H) 12.04 (br. s., 1 H) 1H NMR (360 MHz, s) 5 ppm 0.91 (t,J=7.32 H2, 3 H) 1.17 N)/_N\ (t, 1:7.14 Hz, 3 H) 1.32 (m, _° i 1:7.40, 7.40, 7.40, 7.40, 7.40 Hz, 232 § 2 H) 1.56 (m, 1:7.30, 7.30, 7.30, 297.18 298 4.18,G 7.30 Hz, 2 H) 3.38 - 3.48 (m, 2 H) c§=0 3.88 (t, 1:5.12 Hz, 2 H) 4.01 (q, 1:7.20 H2, 2 H) 7.32 - 7.40 (m, 2 H) 7.44 (br. s., 2 H) 8.32 (t, J=5.67 H2,1 H) 11.71 (br. s., 1 H) 1H NMR (360 MHz, DMSO-ds) 5 ppm 0.90 (t,J=7.32 Hz, 3 H) 1.19 — 1.34 (m, 8 H) 1.45 - 1.58 (m, 2 224.16 225 4.53, G H) 3.35 - 3.43 (m, 2 H) 4.41 (m, 1:6.00, 6.00, 6.00, 6.00 Hz, 1 H) 7.35 - 7.54 (m, 3 H) 8.26 (t, J=6.04 Hz, 1 H) 11.89 (br. 5., 1 H) 2012/056388 ~102- STRUCTURE 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.90 (t,1=7.4 Hz, 3 H), 1.10 (d, 1:6.0 Hz, 6 H), 1.24 - 1.35 (m, 2 H), 1.S4(quin,1=7.3 Hz, 2 H), 268.19 269 0.84, D 3.40 (q, 1:6.9 Hz, 2 6 H), 3.62 (dt, 1:122, 6.1 Hz, 1 H), 3.68 (dd, 1:5.3, 4.0 Hz, 2 H), 4.01 - 4.07 (m, 2 H), 7.36 - 7.52 (m, 3 H), 8.27 (t, 1:5.9 Hz, 1 H), 11.77 (br. 5., 1 H) 1H NMR (400 MHz, DMSO—dg) 5 ppm 0.90 (t,J=7.3 Hz, 3 H), 1.30 (dq, 1:149, 7.3 Hz, 2 H), 1.49 — 1.57 (m, 2 H), 1.57 - 1.67 (m, 1 H), 1.97 - 2.09 (m, 1 H), 6 2.59 - 266.17 267 0.71, D 2.71 (m, 1 H), 3.40 (q, 1:6.8 Hz, 2 H), 3.52 (dd, J=8.7, 5.4 Hz, 1 H), 3.65 (q,1=7.7 Hz, 1 H), 3.72 - 3.85 (m, 3 H), 3.86 - 3.93 (m, 1 H), 7.32 - 7.48 (m, 3 H), 8.30 (t, 1:5.9 H2, 1 H), 11.88 (br. s., 1 H) 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.91 (t, 1:7.4 H2, 3 H), 1.32 (sxt, 1:7.4 Hz, 2 H), 1.52 - 1.65 (m, 2 H), 3.46 (q,1:6.8 Hz, 2 H), 236 5.43 (5,2 H), 7.59 (br. 6 5., 2 H), 324.17 325 0.71, D’ 7.65 (d, 1:4.5 Hz, 1 H), 7.81 (dd, 1:8.2, 4.4 Hz, 1 H), 8.05 (d, 1:8.5 Hz, 1 H), 8.64 - 8.77 (m, 3 H), 9.20 (dd, 1:4.4, 1.9 Hz, 1 H), 12.13 (br. 5., 1 H) 1H NMR (400 MHz, DMSO~d5) 5 ppm 0.84 (m, 1:7.20, 7.20 Hz, 3 H) 1.14 - 1.34 (m, 4 H) 1.55 (m, 1:16.10, 8.00, 8.00 Hz, 2 H) 1.62 - 237 1.78 (m, 2 H) 2.23 (5,2 H) 3.39 348.23 349 0.73, D (m, 1:6.40, 6.40 Hz, 2 H) 3.69 (s, 3 H) 4.23 - 4.33 (m, 1 H) 4.93 (s, 2 H) 6.15 (s, 1 H) 7.46 (br. 5., 1 H) 7.52 (s, 1 H) 8.04 (d, 1:9.03 Hz, 1 H) 11.92 (d, 1:5.27 H2,1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.93 (t, 1:7.2 H2, 3 H), 1.29 - 1.47 (m, 3 H), 1.49 - 1.64 (m, 3 H), 1.87 - 238 2.00 (m, 1 H), 2.07 (quin, 1:6.9 388.21 389 2.34, F Hz, 2 H), 2.66 - 2.73 (m, 2 H), 3.46 - 3.57 (m, 1 H), 3.58 - 3.68 (m, 1 H), 3.91 (td,1=6.4, 1.4 Hz, 2 H), 4.16 (ddd,1=11.2, 5.4, 3.0 Hz, 1 H), 4.52 (s, 2 H), 4.93 (d, 1:8.7 ~103- LCMS Mass Exam STRUCTURE Found Bat 1H NMR Mass Time, [M+H] Method H2, 1 H), 5.94 (s, 2 H), 6.60 - 6.65 (m, 1 H), 6.69 (d, J=1.5 Hz, 1 H), 6.72 — 6.77 (m, 1 H), 7.34 (s, 1 H) ) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.88 - 1.01 (m, 3 H), 1.22 - 1.51 (m, 3 H), 1.54 - 1.71 (m, 2 H), 3.62 (dd, 1:110, 6.7 Hz, 1 H), 3.78 (dd, 239 1:110, 3.2 Hz, 1 H), 4.11 (td, 303.17 304 1.42, F 1:6.8, 3.0 Hz, 1 H), 4.56 (br. 5., 2 H), 4.92 - 5.13 (m, 2 H), 6.21 (d, 1:7.0 Hz, 1 H), 7.30 (m, 1:5.4 Hz, 1 H), 7.36 (d, 1:7.7 Hz, 1 H), 7.52 (s, 1 H), 7.74 (td, 1:7.7, 1.6 Hz, 1 H), 8.61 (d,1=4.7 Hz, 1 H) 1H NMR (400 MHz, s) 5 ppm 0.73 - 0.87 (m, 3 H) 1.08 - 7) 1.19 (m, 2 H) 1.19 - 1.31 (m, 2 H) 1.43 — 1.59 (m, 2 H) 1.59 - 1.75 (m, 2 H) 3.35 - 3.42 (m, 2 H) 4.03 240 (s, 3 H) 4.20- 4.33 (m, 1 H) 5.44 384.23 385 0.88, D (5,2 H) 7.16 (t, 1:7.40 Hz, 1 H) 7.43 (br. s, 1 H) 7.43 (t, 1:7.70 Hz, 1 H) 7.51 (s, 1 H) 7.65 (d, 1:8.53 Hz, 1 H) 7.88 (d, J=8.03 Hz, 1 H) 8.08 (d, 1:8.78 Hz, 1 H) 11.70 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.84 (m, 1:7.00, 7.00 Hz, 3 H) 1.14 - 1.35 (m, 4 H) 1.53 - 1.66 (m, 2 H) 1.68 - 1.83 (m, 2 H) 3.40 (m, 1:6.70, 6.70 Hz, 2 H) 3.91 241 (s, 361.21 362 0.88, D 3 H) 4.28 - 4.41 (m, 1 H) 5.22 (s, 2 H) 7.49 (br. s., 2 H) 7.61 (d, 1:1.00 Hz, 1 H) 7.61 (s, 1 H) 7.77 (d, J=7.78 Hz, 1 H) 8.26 (d, 1:4.52 H2, 1 H) 8.53 (d, 1:8.03 Hz, 1 H) 11.84 (cl, 1:5.50 Hz, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.79 - 0.87 (m, 3 H) 1.16 - 1.34 (m, 4 H) 1.54 - 1.63 (m, 1 H) 1.68 - 1.79 (m, 2 H) 1.85 - 1.95 242 (m, 1 H) 2.17 (s, 3 H) 2.24 (s, 3 H) 375.23 376 3.38 - 3.46 (m, 2 H) 4.33 - 4.43 (m, 1 H) 5.30 (s, 2 H) 7.48 (br. 5., 2 H) 7.74 (d,J=4.77 Hz, 1 H) 8.29 (5,1 H) 8.87 (d,1=8.53 Hz, 1 H) 11.99 (br. s., 1 H)" W0 2012/136834 ~104- LCMS ExaCt STRUCTURE Bet Mass Time, Method 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.90 (t, 1:1.0 Hz, 3 H), 1.30 - 1.46 (m, 5 H), 1.51 - 1.75 (m, 2 H), 3.57 4 3.68 (m, 1 H), 3.75 - 3.84 (m, 1 H), 4.09 (td, 1:6.9, 2.9 Hz, 1 H), 1.66, F 4.63 (br. s., 2 H), 4.94 - 5.12 (m, 2 H), 6.25 (0!, 1:7.0 H2, 1 H), 7.28 — 7.32 (m, 1 H), 7.37 (d, 1:7.7 H2,1 H), 7.52 (s, 1 H), 7.74 (td, 1:7.7, 1.8 Hz, 1 H), 8.62 (d, 1:4.1 Hz, 1 1H NMR (300 MHz, CHLOROFORM—d) 8 ppm 0.85 - 0.94 (m, 3 H), 1.23 - 1.44 (m, 5 H), 1.46 - 1.71 (m, 2 H), 1.94 (m, 1:140, 11.3, 5.3, 3.0 Hz, 2 H), 2.06 (quin, 1:6.9 Hz, 2 H), 2.70 (td, 1:7.4, 1.6 Hz, 2 H), 3.45 - 403 2.46, F W5NH / 3.57 (m, 1 H), 3.58 — 3.68 (m, 1 H), 3.85 — 3.98 (m, 2 H), 4.13 (ddd,1=11.2, 5.4, 3.0 Hz, 1 H), 4.53 (5,2 H), 4.94 (d, 1:8.7 Hz, 1 H), 5.93 (s, 2 H), 6.60 - 6.65 (m, 1 H), 6.68 (d,1=1.5 Hz, 1 H), 6.71 - )— 6.77 (m, 1 H), 7.35 (s, 1 H) 4————1H NMR (400 MHz, s) 5 W ppm 0.78 - 0.87 (m, 3 H) 1.16 - 1.33 (m,4 H) 1.52 - 1.62 (m, 1 H) "37-1 “ii/JN 1.63 - 1.78 (m, 2 H) 1.81 - 1.91 “‘ (m, 1 H) 3.35 — 3.42 (m, 2 H) 3.89 391.22 392 0.77, D 0 (5,3 H) 4.08 (s, 3 H) 4.32 — 4.41 "8r: (m, 1 H) 5.29 (s, 2 H) 7.52 (s, 1 H) 7.51 (s, 2 H) 7.68 (d, 1:5.52 H2, 1 H) 8.51 (d, J=6.02 Hz, 1 H) 8.74 (br. s., 1 H) 11.90 (s, 1 H)" _) ____r._.____ 1H NMR (400 MHz, DMSO—ds) 5 OH ppm 0.78 - 0.90 (m, 3 H) 1.15 - 52H 1.29 (m, 2 H) 1.40 - 1.62 (m, 2 H) 1.63 - 1.78 (m, 2 H) 2.23 (s, 3 H) 246 \N \u NH /\ 334.21 335 0.66, D 3.32 - 3.43 (m, 2 H) 3.70 (s, 3 H) \ 1 o11*“ 4.25 - 4.33 (m, 2 H) 4.93 (s, 2 H) NéLNHz 6.15 (s, 1 H) 7.47 (br. 5., 2 H) 7.52 (s, 1 H) 8.04 (d,1=8.78 Hz, 1 H) 11.93 (s, 1 H) ~105- LCMS Mass STRUCTURE 3:: Found 7:: 1H NMR [M+H] ’ Method 1H NMR (400 MHz, DMSO-ds) 5 ppm -0.05 - 0.01 (m, 2 H) 0.77 - 0.87 (m, 3 H) 1.12 - 1.35 (m, 4 H) 1.48 - 1.59 (m, 2 H) 1.66 - 1.79 1,. (m, 2 H) 1.90 (d, J=7.03 Hz, 3 H) 247 9.0,. 3.41 1% - 3.47 (m, 2 H) 4.25 - 4.36 \N 42426 425 0‘27’ D (m, 1 H) 4.85 (d, 0 Hz, 1 H) rrKs“ 5.12 (d, 1:13.05 Hz, 1 H) 5.81 (d, 1:703 Hz, 1 H) 7.27 — 7.43 (m, 5 H) 7.45 - 7.61 (m, 2 H) 7.54 (br. s, 1 H) 7.95 - 8.05 (m, 1 H) 9.47 (s, 1 P _L H) 12.16 (br. 5., 1 H) ) 1H NMR (400 MHz, DMSO—ds) 5 NH: ,” \ o , ppm 0.87 —0.93 (m, 3 H) 1.22 - N— \__7____ 1.35 (m, 2 H) 1.54 (m, 1:100, 248 NH 1.00, 1.00 Hz, 2 H) 3.33 - 3.43 (m, 220.13 221 0.75, D 2 H) 4.79 (d,J=2.51 HZ, 2 H) 7.50 (d,J=4.02 Hz, 1 H) 7.56 (br. 5., 2 H) 8.51 (t, J=5.77 Hz, 1 H) 12.02 ’— _f_(br. 5., 1 H)1H NMR (400 MHz, DMSO—dg) 5 ppm 0.87 (t, 1:7.40 H2, 3 H) 1.21 - 1.31 (m, 2 H) 1.49 - 1.58 (m, 1 OH H) 1.58 - 1.69 (m, 1 H) 1.70 - 1.85 (m, 2 H) 3.38 - 3.50 (m, 2 H) 4.30 - 4.42 (m, 1 H) 5.35 (s, 2 H) 7.51 249 s \ NH '*~«/\ l 357.20 368 0.84, D (br. 5., 2 H) 7.65 (d, 1:5.52 Hz, 1 / 0 \N H) 7.81 (t, 1:7.53 Hz, 1 H) 7.93 (t, , 1:7.40 H2, 1 H) 8.08 (d, 1:803 H2, 1 H) 8.13 (s, 1 H) 8.29 (d, 1:8.28 Hz, 1 H) 8.46 (d, 1:878 Hz, 1 H) 9.52 (s, 1 H) 11.84 (0!, 1:5.27 Hz, 1 H) 1H NMR (600 MHz, DMSO-ds) 5 ppm 0.84 (t,J=7.0 Hz, 3 H), 1.05 (d,1=7.0 Hz, 3 H), 1.06 (d, 1:7.0 Hz, 3 H), 1.16 - 1.32 (m, 4 H), 250 1.45 - 1.55 (m, 2 H), 6 1.80 (q, 324.22 , 325 1.02, D N SW 1:6.9 Hz, 2 H), 2.48 (spt, 1:6.9 Hz, ”b 1 H), 3.67 (s, 3 H), 3.95 - 4.03 (m, 1 A”: 2 H), 4.13 - 4.21 (m, 1 H), 5.37 (s, 2 H), 6.20 (d, 1:9.1 H2,1 H), 7.35 J (5, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 <\:>§N— ppm 0.85 (t, J=7.4 Hz, 3 H), 1.20 (d, J=6.8 Hz, 3 H), 1.21 - 1.28 (m, 251 / 2 H), 1.44 - 1.56 (m, 1 H), 1.71 32619 327 079, 0 0 (dd, 1:134, 7.4 Hz, 1H), 4.21 - M 4.36 (m, 1 H), 5.37 (d, 1:1.8 Hz, 2 NH H2 H), 7.47 (t, 1:6.7 Hz, 1 H), 7.59 L (br. 5., 2 H), 7.73 (s, 1 H), 7.86 - W0 2012/136834 -’l 06- 8.00 (m, 2 H), 8.36 - 8.46 (m, 2 H), 8.93 (d, J=6.5 Hz, 1 H), 12.24 (br. 5., 1 H) )— T“ H NMR (400 MHz, DMSO-dg) 5 ppm 0.87 (t, 1:7.4 Hz, 3 H), 1.24 I (d,J=6.5 Hz, 3 H), 1.25 - 1.33 (m, / 2 H), 1.47 — 1.60 (m, 1 H), 1.71 - 252 | \ 347.20 1351'“, 1 H), 3.91 6 (s, 3 H), 4.12 348 0.86, D (s, 3 H), 4.28 - 4.42 (m, 1 H), 5.36 Aim°I§N (5,2 H), 7.57 (br. s, 2 H), 7.63 (d, / 1:6.5 Hz, 1 H), 7.72 - 7.80 (m, 1 H), 8.56 (d, J=6.5 Hz, 1 H), 8.99 — 9.10 (m, 1 H), 12.27 (br. s., 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.85 (t, 1:7.4 Hz, 3 H), 1.21 Q”— (d, #65 HZ, 3 H), 1.23 - 1.29 (m, 2 H), 1.45 — 1.58 (m, 1 H), 1.66 — 253 W/ 1.80 (m, 1 H), 4.21 - 64.38 (m, 1 326.19 327 0.79, 0 H), 5.33 - 5.45 (m, 2 H), 7.44 - A/L | 7.55 (m, 1 H), 7.62 (br. s., 2 H), R NH ”2 7.76 (s, 1 H), 7.89 - 8.02 (m, 2 H), 8.40 ~ 8.52 (m, 2 H), 8.96 (d, J=6.8 Hz, 1 H), 12.39 (br. s., 1 H) 1H NMR (400 MHz, DMSO-ds) 5 N-~~/ ppm 0.86 (t, J=7.3 Hz, 3 H), 1.17 - 4% 1.35 (m, 2 H), 1.36 - 1.47 (m, 1 254 D H), 1.47 - 1.60 (m, 1 H), 2.11 (s, 3 In)" 320.20 321 0.62, D H), 3.36 — 3.47 (m, 2 6 H), 3.73 (s, w H: 3 H), 4.05 (td, 1:8.8, 4.9 Hz, 1 H), 2% 4.66 (br. s., 1 H), 4.94 (5,2 H), on 5.58 (s, 2 H), 5.86 (d, 1:9.0 H2, 1 Pr‘ __4_ Hi), 6.10 (s, 1 H), 7.43 (s, 1 H) H_NMR (400 MHz, DMSO~d5) 5 \w ppm 0.84 (t,J=7.0 Hz, 3 H), 1.11 - «J‘ 1.38 (m, 4 H), 1.39 - 1.67 (m, 2 255 H), 2.23 (s, 3 H), 3.38 - 3.52 (m, 2 334.21 335 0.72, D H), 3.70 (s, 3 H), 6 4.13 - 4.24 (m, N "A”: 1 H), 4.93 (s, 2 H), 6.16 (s, 1 H), M 7.47 (br. s., 2 H), 7.53 (d, 1:53 on Hz, 1 H), 7.79 (d, 1:9.0 Hz, 1 H), 11.96 (d, 1:5.3 Hz, 1 H) I ——1 1H NMR (400 MHz, DMSO-ds) 5 m 0 ppm 0.86 (t,J=7.3 Hz, 3 H), 1.17 - , ,, 1.33 (m, 2 H), 1.39- 1.50 (m, 1 256 H), 1.50 - 1.62 (m, 1 H), 3.37 - 346.18 347 \ 0.55, 0 3.48 (m, 2 H), 4.01 - 6 4.14 (m, 1 ' (sz m H), 4.69 (br. s., 1 H), 5.10 (s, 2 H), N 5.54 (s, 2 H), 6.00 (d, 1:9.0 Hz, 1 OH H), 7.46 (s, 1 H), 7.68 (br. s., 1 H), 7.72 (dd, J=7.S, 1.3 Hz, 1 H), 7.94 2012/056388 -1 07- Mass Exact LEE/:5 STRUCTURE Found 1H NMR Mass Time, [MW] Method - 8.03 (m, 2 H), 8.03 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 \ ppm 0.86 (t,1=7.3 Hz, 3 H), 1.13 - —<\/‘\ 1.34 (m, 2 H), 1.46 — 1.60 (m, 2 H), 2.24 (s, 3 H), 3.38 - 3.53 (m, 2 257 ”IN 320.20 321 0.63, D H), 3.70 (s, 3 H), 4.18 - 4.28 (m, 1 NH (Lung H), 4.93 (s, 2 H), 6.16 (s, 1 H), (V 7.48 (br. s., 2 H), 7.54 (d, 1:5.5 0H Hz, 1 H), 7.78 (d, 1:8.8 Hz, 1 H), 11.97 (d, 1:5.5 Hz, 1 H) “I 1H NMR(400 MHz, DMSO—ds) 8 ppm 0.87 (t,J=7.4 Hz, 3 H), 1.18 - / N 1.37 (m, 2 H), 1.58 (q, 1:7.7 H2, 2 \ H), 3.45- 3.58(m, 2 H), 4.21- 4.32 (m, 1 H), 5.37 6 (s, 2 H), 7.54 258 \ 353.19 354 0.79. D (br. s., 2 H), 7.69 (d, 1:5.0 H2, 1 N Hz H), 7.84 (t, 1:7.5 Hz, 1 H), 7.97 (t, Hw5 1:7.5 Hz, 1 H), 8.11 (d,1=8.3 Hz, 1 on H), 8.21 (s, 1 H), 8.32 (t, 1:8.5 H2, 2 H), 9.58 (s, 1 H), 11.98 (d, 1:5.0 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.84 (t, 1:6.8 Hz, 3 H), 1.15 - / 1” 1.35 (m, 4 H), 1.38 - 1.57 (m, 1 259 H), 1.57 - 1.68 (m, 1 H), 3.38 - \ 361.18 362 0.5, 0 [A 3.50 (m, 2 H), 4.04 - 6 4.17 (m, 1 Sun "2 H), 5.12 (S, 2 H), 6.51(br. 5., 2 H), 6.71 (d, 1:7.8 Hz, 1 H), 7.62 — 7.74 (m, 2 H), 7.90 - 7.98 (m, 2 H) 1H NMR (400 MHz, DMSO—ds) 5 W o ppm 0.86 (t,J=7.3 Hz, 3 H), 1.26 / 1" (dq, 1:149, 7.3 Hz, 2 H), 1.43 - 260 1.63 (m, 2 H), 3.38 - 3.50 (m, 2 347.16 \ 348 0.44, D I KL“: H), 4.13 (td, 1:8.7, 5.1H2, 1 H), M5 5.12 (s, 2 H), 6.50 (br. 5., 2 H), 6.69 (d, 1:8.5 H2, 1 H), 7.63 - 7.70 (m, 2 H), 7.93 - 7.97 (m, 2 H) 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.86 (dd, 1:6.02, 4.52 Hz, 6 H) 1.14 - 1.29 (m, 1 H) 1.46 - 1.67 N 54,”k 254-17 (m, 4 H) 3.34 — 3.43 (m, 2 H) 3.66 255 3_71’ G o (s, 3 H) 4.22 (m,1=8.7o, 8.70, / \N I (H11, 4.40 Hz, 1 H) 4.37 (t,1=5.40 Hz, 1 H) 5.43 (s, 2 H) 6.12 (d, 1:9.03 Hz, 1 H) 7.34 (s, 1 H) -108— Exact STRUCTURE 1H NMR Mass 1H NMR (360 MHz, DMSO-de) 5 ppm 0.91 (t, 1:7.50 Hz, 3 H) 1.31 (dq, 1:14.96, 7.46 Hz, 2 H) 1.58 (quin,1=7.41 H2, 2 H) 1.66 (d, 1:6.22 Hz, 3 H) 3.43 (q,1=6.59 Hz, 287.17 288 4.59, G 2 H) 5.66 (q, 1:6.10 Hz, 1 H) 7.57 (m, 1:4.80 Hz, 3 H) 7.71 (t, 1:5.90 Hz, 1 H) 7.87 (cl, 1:8.05 Hz, 1 H) 8.25 (t, 1:7.50 Hz, 1 H) 8.75 (d, 1:4.76 Hz, 1 H) 8.84 (t, 1:5.85 Hz, 1 H) 12.10 (cl, 1:4.39 Hz, 1 H) 1H NMR (400 MHz, CHLOROFORM—d) 8 ppm 0.90 (t, 1:7.2 Hz, 3 H), 1.17 (d,1=6.5 Hz, 3 H), 1.29 - 1.40 (m, 2 H), 1.40 - 263 1.59 (m, 2 H), 3.86 (s, 3 H), 3.93 347.20 348 0.86, D (5,3 H), 4.07 - 4.20 (m, 1 H), 4.71 (br. 5., 2 H), 5.02 (s, 2 H), 6.28 (0!, 1:8.3 Hz, 1 H), 6.85 (d,1=5.5 H2, 1 H), 7.59 (s, 1 H), 8.26 (d,1=5.5 Hz, 1 H) 1H NMR (400 MHz, DMSO~d6) 5“ ppm 0.86 (t,J=7.3 Hz, 3 H), 1.16 - 1.30 (m, 2 H), 1.43 - 1.63 (m, 2 H), 1.63 - 1.80 (m, 2 H), 2.14 (s, 3 264 H), 3.40 (t, 1:6.4 Hz, 6 2 H), 3.75 334.21 335 0.65, D (5,3 H), 4.26 - 4.39 (m, 1 H), 5.08 (s, 2 H), 6.23 (s, 1 H), 7.53 (br. 5., 2 H), 7.59 (d,1=4.8 H2, 1 H), 8.10 (d, 1:8.8 Hz, 1 H), 12.22 (d, 1:5.0 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.94 (t, 1:1.0 Hz, 3 H), 1.19 (d, 1:6.5 Hz, 3 H), 1.31 - 1.44 (m, 2 H), 1.45 - 1.58 (m, 2 H), 1.98 - 2.11 (m, 2 358.20 H), 2.70 (t, 1:7.5 Hz, 2 H), 3.89 359 (’6, 2.62, F 1:6.3 Hz, 2 H), 4.15 (m, 1:8.4, 6.6, 6.6, 6.6 Hz, 1 H), 4.44 (5,2 H), 4.90 .4 Hz, 1 H), 5.94 (s, 2 H), 6.60 - 6.66 (m, 1 H), 6.69 (0], 1:1.5 Hz, 1 H), 6.72 - 6.77 (m, 1 H), 7.32 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.86 - 0.94 (m, 3 H), 1.25 - 1.45 (m, 5 298.20 299 1.7, F H), 1.46 - 1.69 (m, 2 H), 1.86 - 2.00 (m, 1 H), 2.05 (s, 1 H), 3.43 (s, 3 H), 3.46 - 3.56 (m, 1 H), 3.57 — 3.63 (m, 1 H), 3.64 - 3.69 (m, 2 —1 09- M355 Exact £2.15 STRUCTURE Found 1H NMR Mass Time,.
Method H), 3.96 - 4.04 (m, 2 H), 4.06 - 4.24 (m, 1 H), 5.18 (br. s., 2 H), [—1 5.72 (d, 1:8.8 Hz, 1 H), 7.45 (s, 1 _L H) 1H NMR (300 MHz, ,H FORM-d) 6 ppm 0.93 (t, / \ H2 1:1.0 Hz, 3 H), 1.18 (d,J=6.5 Hz, 3 267 ’N 254.17 H), 1.29 - 1.60 (m, 4 H), 3.44 (s, 3 NH 255 1.75, F H), 3.60- 3.70 (m, 2 H), 3.95 - 4.02 (m, 2 H), 4.05 ~ 4.21 (m, 1 L H), 4.53 (br. s., 2 H), 5.51 (d, J=7.8 Hz, 1 H), 7.46 (s, 1 H) “I— 1H NMR (300 MHz, CHLOROFORM—d) 6 ppm 0.92 (t, \0 1:7.2 Hz, 3 H), 1.30 - 1.49 (m, 4 S H), 1.51 - 1.65 (m, 2 H), 1.85 - 1.98 (m, 1 H), 3.43 (s, 3 H), 3.52 268 at?"I “A“? 284.18 285 1.46. F (dd,1=11.4, 2.6 Hz, 1 H), 3.60 (td, M 1:59, 2.5 Hz, 1 H), 3.63 - 3.69 (m, Z 2 H), 3.95 - 4.03 (m, 2 H), 4.14 on (ddd,1=8.3, 5.5, 2.7 Hz, 1 H), 4.85 (br. 5., 2 H), 5.65 (d, J=8.7 Hz, 1 [ H), 7.48 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.74 - 0.93 (m, 3 H) 1.30 (m, [0 1:100, 100, 1.00 Hz, 2 H) 1.43 - 1.65 (m, 2 H) 3.09 - 3.18 (m, 2 H) 269 3.40 — 3.45 (m, 2 H) 3.49 - 3.60 295.20 296 0.63, D (m, 2 H) 3.72 - 3.88 (m, l H) 3.88 | - 4.13 (m, 5 H) 4.25 (t, 1:4.77 Hz, Mm (.3412 2 H) 7.45 (s, 1 H) 7.51 (br. 5., 2 H) 9.31 (t, 1:5.77 Hz, 1 H) 11.69 (br. _1_ 5., 1 H) 12.01 (br.s., 1 H) .1 1H NMR (400 MHz, DMSO-da) 6 ppm 0.85 (t,J=7.4 Hz, 3 H), 1.24 (dq, 1:147, 7.4 Hz, 2 H), 1.39 - : 1“ 1.56 (m, 2 H), 1.56 - 1.73 (m, 2 D H), 3.41 (br. 5., 2 H), 6 4.09 - 4.22 I?» 36019 361 0'61’ D (m, 1 H), 4.44 (br. s., 1 H), 5.10 (s, I“ 2 H), 5.54 (s, 2 H), 6.26 (6], 1:90 Hz, 1 H), 7.45 (s, 1 H), 7.68 (br. 5., 1 H), 7.74 (d, 1:7.5 Hz, 1 H), 7.93 - 8.03 (m, 2 H), 8.06 (br. s., 1 H) OH 1H NMR (400 MHz, DMSO—ds) 6 ppm 0.80 - 0.92 (m, 3 H) 1.17 - 271 s 1.36 (m, 4 H) 1.47 - 1.65 (m, 2 H) \ NH 'v/\ I 317.19 318 0.64, D 1.67 - 1.81 (m, 2 H) 4.29 - 4.37 \N (m, 1 H) 5.26 (s, 2 H) 7.52 (br. 5., / 2 H) 7.62 (d,J=5.02 Hz, 1 H) 7.99 _[_(dd, J=8.03, 5.52 Hz, 1 H) 8.19 (d, W0 2012f136834 410- F LCMS nflass Exact Ret STRUCTURE Found 1H NMR nnass Time, [M+H] Method J=8.78 Hz, 1 H) 8.51 (d, J=8.03 Hz, 1 H) 8.87 (d,J=5.02 Hz, 1 H) 9.02 (s, 1 H) 11.98 (s, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 (t, J=7.15 Hz, 3 H) 1.10 - 1.38 (m, 4 H) 1.56 (dd, 6, 7.53 Hz, 2 H) 1.74 (dd, J=13.68, .90 Hz, 2 H) 4.25 - 4.39 (m, 2 H) ~\ N “4/"~/’ 33120 332 072,0 4.25 - 4.39 (m, 1 H) 5.19 (s, 2 H) / ofiNMAW 7.52 (br. s., 2 H) 7.61 (s, 1 H) 7.66 (dd, 1:7.78, 5.02 Hz, 1 H) 8.16 (t, J=8.41 Hz, 2 H) 8.69 (d, 1:4.27 Hz, 1 H) 8.83 (s, 1 H) 12.08 (br. s., 1 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.81 - 0.91 (m, 3 H) 1.17 - OH 1.32 (m, 2 H) 1.47 - 1.60 (m, 2 H) sf 3.41 - 3.54 (m, 2 H) 4.20 - 4.34 273 \ NH "’”/\ | (m, 1 H) 5.21 (s, 2 H) 7.50 (br. s., 303.17 304 059,0 / 2 H) 7.59 (d, 1:4.77 Hz, 1 H) 7.78 l A... (dd, J=7.65, 5.40 Hz, 1 H) 8.00 (d, 1:9.03 Hz, 1 H) 8.29 (d, J=7.53 Hz, 1 H) 8.75 (d,J=4.27 Hz, 1 H) 8.92 (5,1 H) 11.95 (br. s., 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.85 (t,J=7.03 Hz, 3 H) 1.13 OH - 1.36 (m, 4 H) 1.47 - 1.66 (m, 2 H) 3.40 - 3.52 (m, 2 H) 4.16 - 4.30 274 \ N W | (m, 1 H) 5.24 (s, 2 H) 7.53 (br. s., 317.19 318 057,0 9/ o 2 H) 7.62 (d,J=4.02 Hz, 1 H) 7.86 / (dd, 1:7.91, 5.40 Hz, 1 H) 8.02 (d, 1:878 Hz, 1 H) 8.39 (d, J=8.03 Hz, 1 H) 8.80 (d, 1:4.27 Hz, 1 H) 8.98 (s, 1 H) 12.08 (br. s., 1 H) 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.73 - 0.91 (m, 6 H) 0.94 - 1.16 (m, 1 H) 1.33 - 1.47 (m, 1 H) 275 1.49 - 1.75 (m, 3 H) 3.38 (m, NHS 254.17 255 O.67,D 1:9.00 Hz, 2 H) 3.67 (s, 3 H) 3.93 — 4.18 (m, 1 H) 4.34 (t, J=1.00 Hz, 1 H) 5.44 (br. s., 2 H) 5.94 (d, 1:1.00 Hz, 1 H) 7.35 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.90 (t, J=7.28 Hz, 3 H) 1.30 (sxt, J=7.43 Hz, 2 H) 1.47 - 1.60 276 (m, 2 H) 3.41 (q, J=6.78 Hz, 2 H) 308.15 309 4.89, G 3.90 - 3.97 (m, 2 H) 4.09 - 4.13 (m, 2 H) 4.18 (q, 1:1.00 Hz, 2 H) 7.46 (s, 1 H) 7.49 (br. s., 1 H) 8.32 (t,J=5.9O Hz, 1 H) ' -1 1 1- M355 Exact LEE/:5 STRUCTURE Found 1H NMR Mass Time,_ .
[M+H] Method 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.87 (t, J=7.4 Hz, 3 H), 1.17 - / 1.35 (m, 2 H), 1.47 - 1.62 (m, 2 N5" H), 3.43 - 3.54 (m, 2 H), 4.19 — o 4.31 (m, 1 H), 5.39 (5,2 6 H), 7.55 277 IQ»:\N 304.16 305 0.5, 0 (br. s., 2 H), 7.65 (d, 1:4.0 Hz, 1 ””5 ”2 H), 7.85 (dd, 1:8.5, 5.0 Hz, 1 H), 8.00 (dd, 1:8.4, 1.5 Hz, 1 H), 8.07 (0!, J=8.8 Hz, 1 H), 9.27 (dd, 1:4.9, L 1.6 Hz, 1 H), 12.03 - 12.17 (m, 1 l H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (t,.|=7.0 Hz, 3 H), 1.14 - / 1.38 (m, 4 H), 1.45 - 1.71 (m, 2 \ H), 3.42 — 3.53 (m, 2 H), 4.23 (td, 278 I :Am, 318.18 319 0.58 D ;~§50(;45H221 in)”; 255(291E323H)’ (flew Hz, 1 H), 7.84 (dd, 1:8.4, 4.9 Hz, 1 H), 8.00 (dd, 1:8.5, 1.5 Hz, 1 H), 8.07 (d, J=8.8 Hz, 1 H), 9.27 (dd, 1:5.0, 1.8 Hz, 1 H), 12.10 (br. s., 1 1H NMR (400 MHz, 6) 5 ppm 0.87 (t,J=7.3 Hz, 3 H), 1.25 / (dq, 1:149, 7.4 Hz, 2 H), 1.45 - N5" 1.66 (m, 2 H), 1.66 - 1.83 (m, 2 279 n H), 3.43 (t, J=6.4 Hz, 2 6 H), 4.28 — 318.18 319 0.54.0 4.40 (m, 1 H), 5.39 (s, 2 H), 7.56 N“ "2 (br. s., 2 H), 7.66 (d, 1:4.0 Hz, 1 '7”“ H), 7.85 (dd, 1:8.5, 5.0 Hz, 1 H), 7.98 (dd, #85, 1.5 Hz, 1 H), 8.26 (d, J=9.0 Hz, 1 H), 9.27 (dd, 1:4.9, 1.6 Hz, 1 H), 12.13 (br. s., 1 H) _% T— __r 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (t,1=7.0 Hz, 3 H), 1.15 - / 1.35 (m, 4 H), 1.49 — 1.66 (m, 2 \ H), 1.68- 1.80 (m,2 H), 3.43 (t, \ J=6.4 Hz, 2 H), 4.26 — 6 4.39 (m, 1 280 I .1. (L1... 332.20 333 0.62, D H), 5.39 (s, 2 H), 7.55 (br. s., 2 H), 3.,»0, 7.66 (d, 1:4.3 Hz, 1 H), 7.85 (dd, 1:8.5, 5.0 Hz, 1 H), 7.97 (dd, 1:8.5, 1.5 Hz, 1 H), 8.26 (d, J=8.8 Hz, 1 H), 9.27 (dd, 1:5.0, 1.5 Hz, 1 H), 12.05 - 12.16 (m, 1 H) ""2 1H NMR (400 MHz, DMSO-ds) 5 “6.... ppm 0.89 (t,J=7.3 Hz, 3 H), 1.28 281 o i (dq,J=14.9, 7.3 Hz, 2 H), 1.49 2;? 302.17 303 0.71, D (quin, J=7.3 Hz, 2 H), 3.23 - 3.31 (m, 2 H), 4.49 (br. s., 2 6 H), 4.93 (5,2 H), 5.17 (br. s., 1 H), 5.47 (s, 0H 2 H), 6.37 (t, J=5.8 HZ, 1 H), 7.26 - 412— Exact STRUCTURE Mass 7.33 (m, 2 H), 7.33 - 7.42 (m, 3 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.84 (t, H0 H2, 3 H), 1.13 - 1.33 (m, 4 H), 1.42 - 1.56 (m, 2 H), 1.56 - 1.73 (m, 2 H), 3.40 (br. 282 s., 2 H), 4.06 - 4.20 6 (m, 1 H), 374.21 375 0.66, D 4.44 (br. s., 1 H), 5.10 (s, 2 H), .55 (s, 2 H), 6.28 (d, J=8.8 Hz, 1 H), 7.45 (s, 1 H), 7.67 (br. s., 1 H), 7.71 - 7.76 (m, 1 H), 7.93 - 8.03 (m, 2 H), 8.06 (br. s., 1 H) 1H NMR (400 MHz, DMSO—ds) 5 ppm 0.82 (t, 1:7.40 Hz, 3 H) 1.11 - 1.22 (m, 2 H) 1.43 - 1.55 (m, 2 H) 1.66 - 1.76 (m, 2 H) 2.25 - 2.34 (m, 1 H) 2.52 - 2.65 (m, 1 H) 2.88 283 - 2.97 (m, 1 H) 3.10 - 3.22 (m, 1 377.16 378 0.91, D H) 3.43 (t, J=6.4O Hz, 2 H) 4.24 — 4.34 (m, 1 H) 5.61 (dd, 1:7.40, 4.14 Hz, 1 H) 7.51 .60 Hz, 1 H) 7.53 (br. 5,2 H) 7.84 (s, 1 H) 8.17 (d, 1:8.78 Hz, 1 H) 8.44 (d, J=5.52 Hz, 1 H) 11.77 (br. s., l H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.82 (t, 1:7.40 Hz, 3 H) 1.11 - 1.22 (m, 2 H) 1.43 - 1.55 (m, 2 H) 1.66 - 1.76 (m, 2 H) 2.25 - 2.34 (m, 1 H) 2.52 - 2.65 (m, 1 H) 2.88 284 ”REQW - 2.97 (m, 1 H) 3.10 - 3.22 (m, 1 377.16 378 0.92,D 65811 H) 3.43 (t, J=6.40 Hz, 2 H) 4.24 - "AW 4.34 (m, 1 H) 5.61 (dd, 1:740, 4.14 Hz, 1 H) 7.51 (d, J=7.60 Hz, 1 H) 7.53 (br. s, 2 H) 7.84 (s, 1 H) 8.17 (d, J=8.78 Hz, 1 H) 8.44 (d, 1:5.52 Hz, 1 H) 11.77 (br. s., 1 H) 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.62 - 0.92 (m, 3 H) 1.14 - @— 7” 1.31 (m, 2 H) 1.42 - 1.63 (m, 2 H) Vk/o ”1,;an\N 1.63 - 1.82 (m, 2 H) 3.40 (t, 285 J=6.40 Hz, 2 H) 4.25 - 4.36 (m, 1 383.21 384 0.8,D H) 5.22 (s, 2 H) 7.47 - 7.59 (m, 1 H) 7.47 - 7.59 (m, 2 H) 7.59 - 7.67 0H (m, 2 H) 7.72 (br. s., 1 H) 7.85 - 7.98 (m, 2 H) 8.08 (d, J=8.78 Hz, 1 H) 9.07 (s, 1 H) 12.16 (br. s., 1 H) W0 2012/‘136834 -’l 13- ‘ T LCMS M355 Exact 1 STRUCTURE Found 1H NMR Mass Tlme,, [NH-H] Method 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.84 (t, J=7.28 Hz, 3 H) 1.18 - 1.30 (m, 2 H) 1.50 - 1.64 (m, 2 H) 1.75 (dt,J=12.80, 6.40 Hz, 2 H) I TN» 2.14 (s, 3 H) 3.40 - 3.44 (m, 2 H) 286 ’ 4.31 (m,J=7.50 Hz, 1 H) 5.64 (5,2 A”, 38122‘ 382 089 0' H) 7.46 (br. s., 2 H) 7.78 - 7.85 (m, 1 H) 7.91 (t, J=7.65 Hz, 1 H) 8.00 (d, 1:6.02 H2, 1 H) 8.11 (d, J=8.28 Hz, 1 H) 8.37 (d, J=8.28 Hz, 1 H) 8.56 (d,J=S.77 Hz, 1 H) 9.30 (br. 5., 1 H) 12.20 (s, 1 H) l7 1H NMR (400 MHz, DMSO—ds) 5 kL ppm 0.90 (t,J=7.4O Hz, 3 H) 1.17 (d, J=6.52 Hz, 3 H) 1.23 - 1.38 (m, 287 2 H) 1.54 (quin, J=7.34 Hz, 2 H) NH 254.17 255 4.21, G 3.30 (s, 3 H) 3.41 (q, J=6.69 Hz, 2 H) 3.60 - 3.75 (m, 1 H) 3.78 - 3.98 H2 (m, 2 H) 7.32 - 7.58 (m, 3 H) 8.24 (t,J=S.77 H2,1 H) I 1H NMR (400 MHz, g) 5 kL ppm 0.90 (tt, 1:7.40, 3.50 Hz, 6 288 H) 1.23 - 1.36 (m, 2 H) 1.47 - 1.69 0 NH 268.19 269 0.86, 0 (m, 4 H) 3.33 (s, 3 H) 3.36 - 3.52 \/l\/° \N (m, 3 H) 3.92 (d, 1:4.77 Hz, 2 H) / 7.19 - 7.68 (m, 3 H) 8.21 (t, N ”2 P 1:602 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.85 (d, J=6.78 Hz, 6 H) 0.90 H (t, J=7.40 Hz, 3 H) 1.22 - 1.37 (m, 2 H) 1.54 (quin, 1:7.28 Hz, 2 H) 289 1.78 (m, 1:13.40, 6.70, 6.70 Hz, 1 NH 28221 283 545, G o H) 3.21 (d, 1:6.52 H2, 2 H) 3.40 YO’V \ I (q,J=6.69 Hz, 2 H) 3.56— 3.75 (m, N/ H: 2 H) 3.99 - 4.14 (m, 2 H) 7.32 - 7.60 (m, 3 H) 8.29 (t, 1:565 Hz, 1 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.91 (t, J=7.28 Hz, 3 H) 1.12 (d, J=6.52 Hz, 3 H) 1.31 (sxt, 9H 1:7.43 Hz, 2 H) 1.56 (quin, 1:7.34 H2, 2 H) 3.34 - 3.48 (m, 2 H) 3.61 290 A DI); 240.16 241 3.38, G (dd, 1:9.41, 7.40 Hz, 1 H) 3.83 (dd, 1:9.54, 3.51 Hz, 1 H) 3.90 — MN” Hz 4.02 (m, 1 H) 6.10 (br. s., 1 H) 7.40 (d, 1:5.27 Hz, 1 H) 7.48 (br. ., 2 H) 8.54 (t, 1:5.65 Hz, 1 H) ___J 12.02 (br. s., 1 H) —1 14- STRUCTURE Found 1H NMR Time, Method 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.90 (t, J=6.9 Hz, 3 H), 1.27 — 1.45 (m, 5 H), 1.47 - 1.69 (m, 2 H), 1.87 - 1.99 (m, 1 H), 3.49 - 3.58 (m, 1 H), 3.60 - 3.66 (m, 1 H), 4.17 (ddd,1=10.8, 5.5, 3.0 Hz, 1 H), .00 (s, 2 H), 5.15 (d, J=8.5 Hz, 1 H), 7.25 - 7.32 (m, 2 H), 7.39 (s, 1 H), 8.57 - 8.67 (m, 2 H) supports structure but don't see exchangables. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.82 — 0.93 (m, 3 H), 1.22 - 1.37 (m, 4 H), 1.40 - 1.51 (m, 1 H), 1.52 — 1.63 (m, 1 H), 2.20 — 2.39 (m, 2 H), 3.75 (5,3 H), 4.09 — 4.23 (m, 1 H), 4.72 (br. 5., 2 H), 5.04 (s, 1 H), .08 (d, J=4.8 Hz, 2 H), 5.70 - 5.87 W__L_ (m, 1 H), 7.30 (s, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.92 (t, 1:7.3 H2, 3 H), 1.31 - 1.50 (m, 3 / I" H), 1.55 - 1.67 (m, 2 H), 1.94 (m, 1=11.2, 11.2, 5.5, 2.6 Hz, 2 H), 293 Rum/LN,»M 3.42 - 3.54 (m, 1 H), 3.56— 3.69 317.19 318 155 F (m, 1 H), 4.17 (d, 1:7.3 Hz, 1 H), ; 4.53 (br. 5., 2 H), 5.04 (s, 2 H), I’ 6.05 (d,1=8.5 Hz, 1 H), 7.29 - 7.38 (m, 2 H), 7.54 (s, 1 H), 7.74 (td, I 1:7.7, 1.6 Hz, 1 H), 8.63 (d, 1:47 +_ Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM—d) 5 ppm 0.80 (t, J=6.9 Hz, 3 H), 1.13 - 1.39 (m, 5 1 H), 1.44 - 1.60 (m, 3 H), 1.80 - 1.95 (m, 1 H), 3.35 - 3.47 (m, 1 294 °ijI (Law. H) .59 (m 1 H) 4.08 331.20 332 1.76, F ’ km») ’ ’ (ddd,1=11.0, 5.5, 2.7 H2,1 H), S; 4.49 (s, 2 H), 4.97 (s, 2 H), 6.04 of (d, J=8.2 Hz, 1 H), 7.20 - 7.24 (m, 1 H), 7.27 (d, 1:7.7 Hz, 1 H), 7.45 (s, 1 H), 7.66 (td,1=7.7, 2.2 Hz, 1 H), 8.51 - 8.60 (m, 1 H) WO 36834 415- Mass E”3“ [‘ngat STRUCTURE Found 1H NMR Mass Time,.
[M+H] Method 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.88 (t, 1:7.0 Hz, 3 H), 1.17 - 1.45 (m, 4 , N H), 1.50- 1.81(m,4 H), 1.95 (tdd, \ 1:112, 11.2, 5.5, 2.6 Hz, 1 H), 295 o M, 2.59 (s, 3 H), 3.42~3.54(m, 1 H), I 345.22 346 1.7] F H37” , H, 3.56 - 3.66 (m, 1 H), 4.17 (m, 1:111, 5.6, 2.8 Hz, 1 H), 4.51 (br. s., 2 H), 5.00 (s, 2 H), 5.77 (d, J=8.7 Hz, 1 H), 7.14 (t, J=6.7 Hz, 2 L H), 7.53 (s, 1 H), 7.62 (t, 1:7.6 H2, l H) 1H NMR (400 MHz, DMSO-da) 5 /L ppm 0.85 (t,J=6.8 Hz, 3 H), 1.12 o/\/°I§N (01, 1:63 Hz, 6 H), 1.18 - 1.36 (m, 4 H), 1.41 - 1.73 (m, 4 H), 3.41 (t, 296 NH ( H2 326.23 327 0.84, D J=6.4 Hz, 2 H), 3.55 - 3.67 (m, 3 H), 3.82 - 3.90 (m, 2 H), 4.04 — 0H 4.18 (m, 1 H), 4.40 (br. s., 1 H), .58 (s, 2 H), 5.86 (d, 1:9.0 Hz, 1 H), 7.43 (s, 1 H) 1H NMR (400 MHz, DMSO—ds) 5 «"7: ppm 0.85 (t, 1:7.00 Hz, 3 H) 1.13 \NrK/o IN - 1.39 (m, 4 H) 1.51 - 1.65 (m, 2 NH (Aw H) 1.66 - 1.81 (m, 2 H) 3.36 - 3.45 322.19 323 0.48, 0 M (m, 2 H) 4.28 - 4.39 (m, 1 H) 5.46 (s, 2 H) 7.51 (br. s., 2 H) 7.62 (s, 1 OH H) 8.23 (d, 1:9.03 Hz, 1 H) 11.85 I (br. s., 1 H) PH NMR (400 MHz, DMSO-ds) 5 ppm 0.84 (t,J=7.15 Hz, 3 H) 1.09 - 1.34 (m, 4 H) 1.46 - 1.61 (m, 2 298 ,N\\N NH 5N" H) 1.61 - 1.77 (m, 2 H) 4.24 - 4.34 321.19 322 0.58, D 11%!) (m, 1 H) 5.17 (s, 2 H) 7.47 (br. s., I 2 H) 7.59 (d,J=5.52 Hz, 1 H) 8.05 H: (s, 1 H) 7.99 — 8.11 (m, 1 H) 11.89 (0!, 1:5.52 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 0,. ppm 0.87 (t, 1:7.40 Hz, 3 H) 1.16 - 1.32 (m, 2 H) 1.47 - 1.65 (m, 2 H) 1.67 - 1.80 (m, 2 H) 4.29 -4.40 299 [l 4 NH 5 /\ 313.13 319 0.58, 0 (m, 1 H) 5.03 - 5.20 (m, 2 H) 5.23 / ° \N (s, 2 H) 7.53 (br. s., 2 H) 7.63 (d, / J=5.27 Hz, 1 H) 8.18 (d, J=8.78 Hz, 1 H) 8.61 - 8.71 (m, 2 H) 8.94 (s, 1 H) 12.05 (6!, 1:5.02 Hz, 1 H) —’l 16- T7—__ Exa“ STRUCTURE 1H NMR Mass 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.89 (t, _N 1:7.0 Hz, 3 H), 1.16 (d, J=6.3 Hz, 3 H), 1.26 - 1.44 (m, 6 H), 1.51 (dd, 300 /°-§\:/)-“”2 268.19 269 4.13. B 1:87, 4.6 Hz, 1 H), 1.57 - 1.67 (m, 5111; 2 H), 3.63 - 3.75 (m, 1 H), 3.78 (s, 3 H), 4.07 ~ 4.24 (m, 1 H), 4.62 (br. s., 2 H), 5.07 (d, J=8.5 Hz, 1 H), 7.34 (s, 1 H) 1H NMR (400 MHz, s) 5 ppm 0.86 (t, J=7.3 Hz, 3 H), 1.12 (d, J=6.0 Hz, 6 H), 1.28 (dt, Wit”0 1:147, 7.5 Hz, 2 H), 1.48 (q, 1:74 Hz, 2 H), 1.54- 1.62 (m, 1 H), N H2 312.22 313 0.75, D 1.63 - 1.74 (m, 1 H), 3.38 - 3.46 fl (m, 2 H), 3.54 - 3.68 (m, 3 H), 3.86 (dd, 1:55, 4.0 Hz, 2 H), 4.14 °” (at, 1:48 Hz, 1 H), 4.34 - 4.48 (m, 1 H), 5.58 (s, 2 H), 5.86 (d, 1:9.0 H2,1 H), 7.43 (s, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 0.87 (t,J=7.4 H2, 3 H), 1.19 - \ 1.34 (m, 2 H), 1.41 - 1.60 (m, 2 ° H), 1.66 (5,2 H),3.44 (d,J=6.5 Hz, 302 / N 317.19 318 2 H), 4.09 — 4.26 (m, 1 H), 4.41 - NHm "2 4.50 (m, 1 H), 5.04 (s, 2 H), 5.61 (br. 5., 2 H), 6.36 (d, 1:8.5 Hz, 1 H), 7.39 (s, 1 H), 7.42 - 7.46 (m, 2 H), 8.52 - 8.61 (m, 2 H) Anal tical Methods.
All compounds were characterized by LC-MS. The following LC-MS methods were used: Method A. Waters Aquity UPLC ed with a PDA detector (210—400 nm) and a Waters SQD with a dual mode ion source ES+/—. The column used was a Halo C18, 2.7 um, 2.1 x 50 mm, heated to 50°C. A gradient of 95% aqueous formic acid (0.1%)/5% acetonitrile to 100% acetonitrile was ramped over 1.5 minutes, held for 0.6 minutes, then returns to 100% aqueous formic acid (0.1%) for 0.5 minutes. The flow rate was 0.6 mL/min. -1 17- Method B. ,__________—_—_JJ_____Column YMC-PACK ODS-AC2, SOXZOmm 5 m A :H20 ( A) Mobile Phase Bzaoetonitrlle ( 0.05%TFA ) _____—_|_______.____ StogTime:10min PostTlme :OFF TIME min Gradient 8 100 0 LFlow Rate min Wavelength UV 220nm Column Temperture 50°C MS Eolarlty positive LCMS Agilent 1100 Method C.
Column YMC-PACK ODS—AQ, 50><2,0mm Shim A :H20 ( 0.1%TFA) Mob'le Phase' Bzaoetonitrile ( 0.05%TFA) StopTlme:10mln [Fost Time :OFF TIME(mln) A% o l 90 Gradient.
Flow Rate in Wavelength UV 220nm Oven Tem. 50°C ' Mgpolaritv gositive LCMS Agilent 1100‘ ~1 ’l 8- Method D. Reversed phase UPLC (Ultra mance Liquid Chromatography) was carried out on a d ethylsiloxane/silica hybrid (BEH) C18 column (1.7 pm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (10 mM ammonium acetate in HZO/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.7 minutes. An injection volume of 0.75 ul was used. Cone voltage was 30 V for ve tion mode and 30 V for negative ionization mode.
Method E. Using a Phenomenex Kinetex column(XB-C18 50 x 4.6 mm l.D. 2.6u) held at 35°C. MS detection: APl-ES Positive ionization mode, Mass range 00. PDA detection (A=190~400nm). The following gradient was used with a 2uL injection: Solvent A H20 + 0.1% Formic Acid Solvent B Acetonitrile Method F. Using a YMC ODS-AQ C—18;50 x 4.6 mm, ID = 3pm held at 35°C.
MS detection: APl—ES Positive ionization mode, Mass range 100-1400. PDA detection (A=190—400nm). The following gradient was used with a 2uL injection: Solvent A H20 + 0.1 % Formic Acid Solvent B Acetonitrile Flow ml/min 419— Method G. Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 °C). Flow from the column was split to a MS spectrometer. The MS or was configured with an electrospray ionization source. The capillary needle voltage was 3 kV and the source temperature was maintained at 140 °C. Nitrogen was used as the nebulizer gas. Xterra MS C18 column (3.5 pm, 4.6 x 100 mm) with a flow rate of 1.6 mL/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50 % B and 50 % C in 6.5 minutes, to 100 % B in 0.5 minute, 100 % B for 1 minute and re~equilibrate with 100 % A for 1.5 minutes. An injection volume of ul was used.
Method H. Reversed phase UPLC (Ultra Performance Liquid Chromato- graphy) was carried out on a bridged iloxane/silica hybrid (BEH) C18 column (1.7 pm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 mL/min.
Two mobile phases (mobile phase A: 10mM ammonium e in HZO/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient ion from 95 % A and 5 % B to 5 % A and 95 °/o B in 1.3 minutes and hold for 0.2 minutes. An ion volume of 0.5 ul was used. Cone voltage was V for positive tion mode and 20 V for negative ionization mode.
Biological Activity of compounds of formula (I) Description of Biological Assays Assessment of TLR7 and TLR8 activity The ability of compounds to activate human TLR7 and/or TLR8 was assessed in a cellular reporter assay using HEK293 cells transiently transfected with a TLR7 or TLR8 expression vector and NFKB-IUC reporter construct. In one instance the TLR expression uct expresses the respective wild type 3O sequence or a mutant sequence comprising a deletion in the second leucine- rich repeat of the TLR. Such mutant TLR proteins have previously been shown to be more tible to agonist activation (US 7498409).
Briefly, HEK293 cells were grown in e medium (DMEM mented with 10% FCS and 2 mM Glutamine). For transfection of cells in 10 cm dishes, cells were detached with Trypsin—EDTA, transfected with a mix of CMV-TLR7 W0 2012/136834 420- or TLR8 plasmid (750 ng), UC plasmid (375 ng) and a transfection reagent and incubated for 48 hours at 37°C in a humidified 5% C02 atmosphere. Transfected cells were then detached with Trypsin-EDTA, washed in PBS and resuspended in medium to a density of 1.67 x 105 cells/mL. Thirty microliters of cells were then dispensed into each well in 384-well plates, where uL of compound in 4% DMSO was already present. Following 6 hours incubation at 37°C, 5% C02, the luciferase activity was determined by adding ul of Steady Lite Plus ate (Perkin Elmer) to each well and readout performed on a ViewLux ultraHTS microplate imager (Perkin Elmer). Dose response curves were generated from measurements performed in quadruplicates. Lowest ive concentrations (LEC) values, defined as the concentration that induces an effect which is at least two fold above the standard deviation of the assay, were determined for each compound. nd toxicity was determined in parallel using a similar dilution series of compound with 30 pL per well of cells transfected with the CMV-TLR7 construct alone (1.67 x 105 cells/mL), in 384-well plates. Cell viability was measured after 6 hours incubation at 37°C, 5% C02 by adding 15 uL of ATP lite (Perkin Elmer) per well and reading on a ViewLux ultraHTS microplate imager n Elmer). Data was reported as CC5o.
Suppression of HCV replicon replication Activation of human TLR7 s in robust production of eron by plasmacytoid dendritic cells present in human blood. The potential of compounds to induce interferon was evaluated by looking at the antiviral activity in the HCV replicon system upon incubation with ioned media from peripheral blood mononuclear cells (PBMC). The HCV replicon assay is based on a bicistronic expression construct, as described by Lohmann et al.
(Science (1999) 285: 110—113; Journal of Virology (2003) 77: 3007-15 3019) with modifications bed by Krieger et al. (Journal of Virology (2001) 75: 4614-4624). The assay utilized the stably transfected cell line Huh-7 luc/neo harboring an RNA encoding a bicistronic expression construct comprising the wild type NSS—NS5B regions of HCV type 1b translated from an Internal Ribosome Entry Site (lRES) from encephalomyocarditis virus (EMCV), preceded by a er gene (Firefly-luciferase) and a selectable marker gene (neoR, neomycine phosphotransferase). The construct is d by 5’ and 3’ NTRs (non-translated regions) from HCV type 1b. Continued culture of the replicon cells in the presence of G418 (neoR) is ent on the replication of W0 2012/136834 —121— the HCV RNA. The stably transfected replicon cells that ate HCV RNA autonomously and to high levels, encoding inter a/ia rase, were used for profiling of the conditioned cell culture media.
Briefly, PBMCs were prepared from buffy coats of at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 105 cells/well were dispensed into 384—well plates containing compounds (70 uL total volume). After ght incubation, 10 uL of supernatant was transferred to 384—well plates containing 2.2 x 103 replicon cells/well in 30 uL (plated the day before). Following 24 hours of tion, replication was measured by assaying luciferase activity using 40 uL/well Steady Lite Plus substrate (Perkin Elmer) and ed with ViewLux ultraHTS microplate imager (Perkin .
The inhibitory activity of each compound on the Huh7—luc/neo cells were reported as E050 values, defined as the compound concentration applied to the PBMCs resulting in a 50% reduction of luciferase activity which in turn indicates the degree of replication of the replicon RNA on transfer of a defined amount of PBMC culture medium. Recombinant interferon a—2a (Roferon-A) was used as a standard control compound.
Biological ty of compounds of formula (I) . All compounds showed C050 of >24uM in the HEK 293 TOX assay described above.
Activation of ISRE promoter elements The potential of compounds to induce lFN—l was also evaluated by measuring the activation of interferon-stimulated responsive elements (ISRE) by conditioned media from PBMC. The ISRE t of sequence GAAACTGAAACT is highly responsive to the STAT1—STAT2-IRF9 transcription factor, activated upon binding of lFN-i to their receptor lFNAR (Clontech, PT3372—5W). The plasmid plSRE-Luc from Clontech (ref. 631913) contains 5 copies of this ISRE element, ed by the firefly luciferase ORF. A HEK293 celi line stably transfected with plSRE-Luc (HEK-ISREluc) was ished to profile of the conditioned PBMC cell culture media.
Briefly, PBMCs were prepared from buffy coats of at least two donors using a standard Ficoll fugatlon protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 105 cells/well were sed into 384—well plates containing compounds (70 uL total ). After ght incubation, 10 pL of supernatant was transferred to 422— 384-well plates containing 5 x 103 HEK—lSREluc well in 30 uL (plated the day ). Following 24 hours of incubation, activation of the ISRE ts was measured by assaying luciferase activity using 40 uL/well Steady Lite Plus substrate (Perkin Elmer) and measured with ViewLux ultraHTS microplate imager (Perkin Elmer). The stimulating activity of each compound on the HEK- lSREluc cells was reported as LEC value, defined as the compound concentration applied to the PBMCs resulting in a luciferase activity at least two fold above the standard deviation of the assay. The LEC in turn indicates the degree of ISRE activation on transfer of a defined amount of PBMC culture medium. Recombinant interferon a—2a (Roferon-A) was used as a standard l compound.
For a given compound, the LEC value obtained from this assay were in the same range as the E050 values obtained from the “suppression of HCV replication assay.” Thus, it is le to compare the potential of compounds to induce IFN-l by PBMC, measured by either of the 2 assays.
TABLE II BIOLOGICAL ACTIVITY OF THE COMPOUNDS.
TLR7- TLR8- STRUCTURE -leR2_LEC wt_LEC dIRR2_LEC HUH7_EC50 4.91 —123- TLR7— TLR7- TLR8- TLR8- PBMC- wt_LEC leR2_LEC wt_LEC leR2_|.EC HUH7_EC50 6.71 1.17 2.56 1.10 1.14 6.18 1.69 4.53 2.30 2.65 0.01 0.16 0.10 0.02 3.11 0.37 9.72 TLR7- TLR7— STRUCTURE l-EC wt_LEC dIRR2_LEC HUH7_EC50 ~125- TLR7— TLR7- TLR8- TLR8- PBMCSTRUCTURE Wt__LEC leR2_LEC wt_LEC EC HUH7_EC50 .. L\= 16 0.49 2.68 0.59 0.79 N<—>——\NH 17 \ go 0.34 2.03 0.67 0.71 __l—_——_—_ 18 o \ 0.83 1.87 0.85 0.63 0.43 1.33 3.08 426- - TLR7- TLR8- STRUCTURE wt_LEC leR2__LEC wt_LEC LEC HUH7_EC50 427- TLR7- TLR7- TLR8- TLR8- PBMC— STRUCTURE wt_LEC 0"“me wt_LEC EC HUH7_EC59 2.47 9.18 6.99 1.75 29 1.32 2.86 1.19 2.97 —_—r————_———— >25 6.44 1.16 9.07 31 —0 i >24.59 5-27 17.53 6.46 10.36 32 10.60 1.35 9.97 4.43 1.06 33 ..\ 0.36 1.78 1.17 1.48 428— PBMCSTRUCTURE wt_LEC leR2__LEC wt_LEC dIRR2_LEC C50 0.05 1.50 0.70 N<—2—NH\/\/ 37 o 0.04 9.22 5.69 0.12 38 — 21.97 2.46 >50 22.88 11.28 39 3.01 14.41 7.10 o L\_ ~129— I TLR7- TLR7- TLR8- TLR8- PBMCSTRUCTURE wt_LEC LEC wt_LEC leR2_LEC HUH7_EC50 0.10 0.04 0.79 0.59 45 o O\—\7 0.17 0.58 0.40 0.17 / J_ - LECTLR7- TLR7- TLR8- TLR8- PBMC- STRUCTURE wt__LEC dIRR2_LEC HUH7_EC50 46 0.19 3.85 1.96 2.51 / O / O 47 NQNH o \o—\7 0.20 1.87 0.66 0.33 N>—.N\ NH 48 O 0.28 1.75 0.60 0.64 0.55 0.78 0.50 TLR7- TLR7- TLR8- TLR8- PBMC- wt_LEC leR2_LEC wt_LEC dIRR2_LEC HUH7_EC50 52 0.63 3.61 1.65 0.26 53 0.64 3.06 2.15 0.60 54 0.68 1.40 0.69 0.75 / n 55 \E\/ 0.72 0.16 0.12 0.41 12.02 0.84 5.55 1.47 0.80 0.88 1.80 0.74 0.80 TLR7- TLR7- TLR8- TLR8- PBMC- STRUCTURE wt_LEC leR2_LEC wt_LEC leR2_LEC C50 58 6.48 0.99 3.84 2.17 2.99 NHZ M w 1. 59 NLéiu‘“ 1.20 0.36 0.13 0.40 N/>_N\ NH 60 ~— \——\_ 5.58 1.38 2.08 0.65 1.91 Ngwi 61 g 1.38 3.59 1.56 1.91 >—-N N/ \ NH 62 21.26 1.76 0.55 0.15 0.74 / 0H N/ \ /4/—/ 63 2.78 1.79 6.35 1.94 2.69 W 1:21;. m 8.47 2.03 18.43 7.65 4.29 21.59 2.04 3.68 1.13 2.30 2.29 9.03 1.89 2.27 2.31 >24.59 >24.59 2.43 2.54 0.56 0.43 1.17 2.22 6.16 I TLR7- TLR7- TLR8- TLR8- PBMC- STRUCTURE wt_LEC leR2__LEC wt_LEC dIRR2_LEC HUH7_EC50 N>_\/ NH 70 — \—\_L 15.84 4.96 >24.59 >24.59 >23.81 "3%N 71 w >24.59 >24.59 >24.59 4.96 O \_\_ ”mNH 72 >25 5.57 6.24 17.50 73 NQ” >25 0.80 0.47 1.39 l 0 HEK- Structure -1 35— HEK- Structure 436— PBMC HEK- TLR7 TLR8 HUH-7 c Strucmre thEC wt LEC Ecso LEC I0 b 3.090 6.960 ND 0.050 N 3% NH \N 88 l ~137- Structure 1.670 6.670 ND 0.526 NH 5”W 89 I: ‘i——‘———— -—— >25 8.460 6.950 ND 7—4 \401N 90 NHz N43,. >25 20.850 7.650 ND <{_/ ~_</ ”Pg?” >25 14.570 20.160 ND S N Mum!»° / >25 15.880 9.050 ND 1.590 3. 170 0.696 N D 94 !NA”: F : 1 2.730 2.010 0.726 ND 95 NMOr}:«km: wo 36834 ~138- PBMC HEK- TLR7 TLRS HUH7- ISREI Structure uc wt LEC wt LEC ecso LEC m“:\N >25 6.340 4.310 ND 96 H) of}. 21.810 5.070 2.640 ND FWNH \NJNHZ Mira”:o \N I >25 10.100 21.960 ND MIA“:° \N 8.980 1.820 1.280 ND 99 j OW0 18.950 6.160 5.120 ND 100 /\/\NH NAHZ ”Hz _._ N>/~ NH 0.277 0.597 0.055 0 L\_ ND 101 / \ NHz T "—*_ N>l— NH _ L\_ 0.141 5.690 0.012 ND 102 PG .__l__.
WO 36834 -1 39- PBMC HEK— TLR 7 TLR 8 HUH 7- ISREIuc Structure wt LEC wt LEC Ecso LEC I I n ‘I 1.190 1.270 0.725 ND 0 01A“ 103 /\/\NH NAN!» BS0H >25 12.390 >23.81 ND Orr! 104 /\/\NH NAHZ >25 22.020 19.050 ND 105 MNH NAHz /\°:L°I/\N 16.100 5.940 3.150 ND NH \N/JNHz L106 J— 2.460 3.940 1.590 ND 6.580 >25 6.770 ND 0.790 2.230 0.393 ND 109 /\/\NHOr}!NAHZ wo 2012/136834 2012/056388 440- 2.380 3.780 0.740 ND )1l§/—_N BEH—NH 0.257 ND 0.096 ND m 3.960 5.560 3.350 ND 112 INA“2 .8 5f ‘0 0.433 2.240 0.251 ND 113 8 mi”. 2.020 >25 2.000 ND 114 / "s 0H m 5 N 6.180 6.510 3.730 ND 115 om/N H2 N>/\:N?—NH 0.652 1.610 0.066 ND (”‘0 l_ 7 .1 441- PBMC HEK- TLR 7 TLR 8 HUH-7 c Structure wt LEC wt LEC ECso LEC 0.008 0.143 0.002 ND 123 \ ,{ WO 36834 442- PBMC HEK- TLR7 TLR8 HUH-7 ISREluc Structure wt LEC wt LEC 13c50 LEC N (sz 15.610 13.650 >23.81 ND 04"“N 5 1.630 0.598 0.336 ND 125 N/ H2 ——r—-_ ~—I \Q HM“ 1.000 1.020 0.264 ND W0 \N 126 I ”A“, 1__ J \o H G 1.030 2.050 NH 0.256 ND o/\/0 \N 127 l ____‘ .1 @Hm 2.430 3.740 0.284 ND 123 (\kaNAHZ \O KL Q 2.090 3.250 NH 0.432 ND 0 o/\/0 \N 129 | I __1_ F— __T _,_ _.__ (EEO| 0.676 NH 6.560 0.103 ND ON \N 130 l l— __1 2012/056388 ~143- |—_ PBMC HEK- TLR7 TLR8 HUH7 lSREluc Structure wt LEC wt LEC Ecso LEC 1.700 >25 0.806 ND ON \N 131 / o H 1.470 >25 0.634 ND 132 Work»:I / flfi kL 1.500 3.090 0.585 NH ND D o/\/0 \ 133 l I N H2 \% 2.010 2.110 NH 0.935 ND o/\/° \N 134 IA“: r H m 3.230 1.970 NH 3.190 ND ON \N 135 I __i___ g“ \ Hm. 2.000 2.030 0.275 ND / ONO 136 I \—_\—NH '\ ,{>_N 0.757 1.760 22.760 ND 137 9° ° 2012/056388 ~144- TLR 7 Structure wt LEC wt LEC _._N \ ,HH: 1.040 1.050 0.570 ND NH, ‘1‘ fi- N/ \ NH 0 L\— 0.025 0.286 0.009 ND / \ 139 "E3” F r ‘_ ”é kL 0.617 NH 2.250 0.175 ND E,/\/ \ 140 I L_ N Hz l_ L 4.360 0.704 0.733 ND / o/VD 141 I\N *—“ *l— N/ \ O HO >25 2.370 19.680 / K)” ND 142 /_/‘"” 1'... ~'—T‘ .-_I \ {\LNH 1.810 0.880 0.443 ND / o/Vo 143 I N/ Hz \ /" ‘J" g“ 13.010 20.790 1.320 ND W0 2012/136834 2012/056388 ~145~ Structure WO 36834 446- PBMC HEK- TL“ “Rs HUH7- ISREI Structure LI c thec thEC lac50 LEC c. 5.410 >25 3.350 ND /\/\NX7”\ H2 .640 ND 3.430 ND 153 / myH [ 3.710 2.960 3.020 ND 154 N/ Hz J, 2.660 4.560 3.440 ND ._._ g N ’i NH £L\— 0.828 2.060 0.697 ND "‘ V 1_ 1_ 0.333 1.110 0.162 ND __\_\ o 157 \N /N I— NH2 ...___.1 .J .1.— N o—CPW 3.080 >25 3.310 ND 0 _ 158 /——/— WO 36834 ~147— PBMC HEK- TLR 7 TLR 8 HUH-7 ISREluc Structure wt LEC wt LEC ECso LEC 0.573 2.500 0.728 ND /0 0 0.606 23.030 0.769 ND MNlK/k‘fiz0 164 / N NQNN 5b— 0.683 1.800 0.187 ND -1 48- PBMC HEK- TLR 7 TLR 8 HUH-7 ISREIuc ure wt LEC wt LEC Ecso LEC 0.128 0.980 0.046 .110 >25 3.130 ND 169 a / lN Vo \ 0.319 1.750 2.630 ND 170 /\/\NHKb\NJNHZ 0.396 1.060 0.158 ND 171 MM”ofj\NJNHz 6— 1 Ch" /“\I 0.187 2.000 o 0.045 ND MT!\/Lqu 449- PBMC HEK- TLR 7 TLR 8 HUH 7 ISREIuc Structure wt LEC wt LEC ECso LEC Q / \ 0.222 2.550 0.086 ND . 1* <10 \0 / 0.447 2.610 0.052 ND v/\D \ 0.367 2.480 0.167 ND M0fNJ... 0 “Hz \ 0.868 0.463 0.173 ND 176 of: MNH \NJNHZ 0.795 0.819 0.197 ND MNH \ _.._!______. >~§N 3% 0.810 0.410 0.302 ND 178 A»...or\N/‘LNH. _.____..x—__ mo 0.078 0.142 0021 ND MNHDrNANHz wo 2012/136834 ~150- PBMC HEK- TL“ “Rs HUH7- ISREIUC Structure wt LEC thEC 15c50 LEC N/ \ 0.135 0.524 0.047 ND 0 LL 180 N/ \ \~~~ H 0.146 1.210 0.096 ND 181 F 0%\‘N 0.014 0.178 0.007 ND MNH \ __'_ —_L_ l__4 \N kL /\N 0.056 1.580 0.023 ND 0.157 1.650 0.053 ND 184 /\/\0?[/an \I Dr 0.743 2.340 0.488 ND r\ 0.122 0.680 0.065 ND NA“: 186 \A/lg'm, wo 2012/136834 2012/056388 ~151- PBMC HEKTLR7 HUH7' ISREI"c Structure thEC thEC 6c50 LEC Q—NH 0.286 0.743 0.066 ND 191 EH“5)\ ._i_ \_/ OH\-—-:5 D g,” 0.080 0.220 0.044 ND 2/ \:N 192 ~=( J—___ (1H ” ”” £34”:/ \ 0.032 0.654 0.017 ND 193 /_/_ PBMC HEK- TLR 7 TLR 8 HUH-7 c Structure wt LEC wt LEC Ecso LEC 0.076 0.511 0.089 ND m "H, OH 0.512 2.280 0.218 ND 0.253 0.181 0.200 ND wo 2012/136834 453- PBMC HEKTL“ HUH7- lSREIu Structure C thec thEC ecso LEC 0.566 0.647 0.758 ND r— 4— 13%\N 0.164 0.089 0.049 ND 202 K; NH 4 S_N L/J N/ \ Nfi - 0.124 0.160 0.054 ND 203 / ’{ . 0.791 0.791 0.493 ND 0 Sin 204 fix\" 0.369 1.110 0.047 ND \\ H2 205 " N/ \ NH "‘0 \—\_ >25 9.450 >23.81 ND 206 5‘ / N/\>—\ \ \N 0 /_N)—N\ H2 N2 0.177 1.450 0.063 ND wo 20121136834 PBMC TLR7 TLR8 HUH-7 ure wt LEC wt LEC EC50 \ Nsz 0.001 0.093 0.000 ND 208 f "A“ / N:>>_\ \ “QR—””2/ \ 0.074 0.667 0.076 ND 209 /—/_ N>/_\—_N\2~NHL\— 0.686 0.896 0.237 ND m1° /_N>‘""‘’{ 0.203 1.040 0.097 ND 211 /_/_ \I 0.007 0.148 0.005 ND is MNH N/J‘NHZ N>/_N\ NH "—0 L\__ 0.225 0.207 ND 0.032 213 N/ \ \I 0.134 0.593 ND 0.027 N1 .,~\ 5 NH “2 W0 2012/136834 2012/056388 -1 55- Structure 2012/056388 -1 56— Structure WO 36834 -1 57- Structure wo 2012/136834 -158— PBMC HEK— TLR7 “RS HUH7 lSREluc ure thEC thec EC50 LEC \— .— N \N/ 0.241 0.333 ND 0.031 236 \N /N 014 4— .41 £511 a?” 0.156 1.830 ND 0.051 237 $0 b 0.234 1.920 ND 0.091 N W5 4“H2 238 1.. 0H SNHIN:\~ 0.464 0.247 ND 0.145 \N,N\C?“ H“NN "2‘. 0.008 0.442 ND 0.005 ..__.__._r._.._._.___._.
N... M .. 0.008 0.304 ND 0.004 241 N/ \ on —“I““ l‘ .>r“\ ziJJ EX 5.400 3.010 ND 0.006 wo 2012/136834 2012/056388 459- HEK- ISREIuc Structure — 0.343 0.103 ND 0.190 243 /”x t—v @; L- EM 0.202 1.400 ND 0.104 W: éLNHz 244 ‘ on _‘7 NH .45 Q 0.040 0.507 ND 0.011 245 N/ \ \ SJ) N 0.157 NH A 1.150 ND 0.043 \1 D 246 I‘“MAW viva 1011:)‘4‘02\N 12.390 8.240 ND 3.200 247 JR NH / \ o \——-—: NH 2.120 0.654 ND 0.529 248 é \ NHsjjA 0.039 0.172 ND 0.036 ’ 10 249 A”: -160~ PBMC HEKTLR 7 TLR 8 HUH-7 ISREIuc ure wt LEC wt LEC Ecso LEC \ \N 12.760 >25 ND 6.230 253 A/RLNHOf”N/ ”2 \N 1.770 0.467 ND 0.364 NH ”2 254 flvx of" 0.552 0.515 ND 0.315 NH H2 255 OHKIVV5 1.630 0.100 ND 0.039 m.\N 256 Hsv\ WO 36834 461— PBMC HEK- TLR7 TLR8 HUH-7 ISREIuc Structure thEC thEC EC50 LEC “~11 or" 0.697 0.444 ND 0.304 NH NéLNHz M5 257 J— u____ [\N 0.074 0.153 ND 0.060 NH H2 258 Hi/\ 0 0 / IN 6.980 3.150 ND 1.250 259 (fix/vS __l_ ., 5L —1 / IN 4.850 2.830 ND >8.14 260 ”(RA5 “mm/k 10.790 2.300 ND 7.460 /O \N » 261 I N142 MGM"0 0.658 0.168 ND 0.363 262 / \ \o —1 \I 0.049 0.159 ND 0056 MNH MAW wo 2012/136834 462- TLR7 TLR8 Structure wt LEC thEC 43‘; or 0.215 0.489 ND 0.087 I ”/LNHZ 264 ”“5 \/0° I“ 0.752 3.700 ND 0.591 NH NAHZ 255 M ”ISA“,o \N 1.070 1.890 ND 0.557 266 [ —L——— \/\) / VH2 4.880 0.719 ND 1.710 267 /)rNH’“ r NH ma”:\N 2.100 1.800 ND 1.170 /\/SL 268 4..
(I 24.550 8.280 ND 9.750 269 or" /:-/NH\NH NA”: / I” 0.109 0.131 ND 0.006 270 fKA 2012/056388 —1 63— Structu re WO 36834 -1 64- HEK- ISREIuc Structure wo 2012/136834 465- *]— PBMC HEK- TL“ TLRS HUH7- ISREI Structure UC thEC thEC Ecso LEC 0.036 0.266 0.530 ND N A» °” L. i_ [I i .6 pr: 0.620 7.660 ND 0.128 NH Hz 286 S RM” 15.530 5.380 ND 3.560 \05 o 287 I\N N/ H2 ”’T— \ Hm >25 10.200 ND 14.890 \i/O \N 288 I ._ 1_ L Hm” 0.875 0.930 ND 0.647 289 \I/\W0 | >25 9.110 ND 12.460 290 MNHOFN(LNHz ——: _,_ m“:/ N 0.120 0.407 ND 0.106 291 A wo 2012/136834 466— TLRS Structure wt LEC wt LEC \O \—>—NHZ N 0.913 3.082 ND ND N: ' Wr____._ \N 0.197 0.530 ND 0.088 \/\‘ I N “2 293 of H°I§~ 0.133 0.521 ND 0.042 294 ' 0f 0.047 0.430 ND 0.034 295 ? /l\o/\/°I§N/ ””3 “2 0.664 2.540 ND 0.310 295 o f wk," j NH“K/°jf§~ NH NA“ 2.810 >25 ND 2.540 NH,»§N NEW 0.394 2.840 ND 0.058 \ék/O \N 298 I A” 2 _L TIP 249 PCT PBMC HEK- TLR 7 TLR 8 HUH7 c Structure wt LEC wt LEC ADA/orb;/ NH N H2 0.664 2.540 ND 0.310 ND = Not done.

Claims (15)

Claims 1.
1. A compound of formula (I) R2 N N N NH2 ?? or a ceutically acceptable salt, tautomer(s), solvate or polymorph thereof, wherein R1 is en, C1-4alkyl, cyclopropyl or C1-6alkoxy, halogen, hydroxyl, trifluoromethyl. R2 is C1-8alkyl, (C1-4)alkoxy-(C1-4)alkyl, C3-7cycloalkyl, C4-7heterocycle, aryl, ??? bicyclic heterocycle, alkylaryl, heteroaryl and alkylheteroaryl, each of which is optionally substituted by one or more substituents independently selected from: • halogen; • hydroxyl; ??? • amino; • C1-6alkyl; • di-(C1-6)alkylamino; • C1-6alkylamino; • koxy; ??? • C3-6cycloalkyl; • carboxylic acid; • carboxylic ester; • carboxylic amide; • heterocycle optionally substituted by one or more groups independently ??? selected from C1-6alkyl, C1-6alkoxy, carboxylic ester and amide; • aryl optionally substituted by one or more groups ndently selected from: halogen; C1-6alkyl ally tuted by one or more groups independently selected from hydroxyl and aryl; C1-6alkoxy optionally substituted by one or more halogen; carboxylic acid; carboxylic ester; ??? amide; and aryl optionally substituted by one or more groups independently selected from halogen, kyl and C1-6alkoxy; • alkenyl; • alkynyl; • alkylaryl; • heteroaryl optionally substituted by one or more groups independently selected from: halogen; hydroxyl; C1-6 alkyl optionally substituted by one or more groups independently selected from hydroxyl, C1-6 alkyl, C1- 6alkoxy, heterocycle, carboxylic ester, aryl and nitrile; C1-6 alkoxy ?? optionally substituted by one or more groups independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, heterocycle, carboxylic ester and nitrile; carboxylic acid; carboxylic ester; amide; aryl ally tuted by one or more groups ndently selected from halogen, C1-6 alkyl and C1-6 alkoxy; heterocycle; and nitrile; ??? • alkylheteroaryl; and • nitrile; and R3 is C4-8 alkyl, C4-8 alkoxy, C2-6 alkenyl or C2-6 alkynyl, each of which is optionally substituted by one or more tuents independently selected from halogen, hydroxyl, amino, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl or ??? nitrile; with the proviso that: 2-amino(4-chlorophenoxy)(5-hydroxypentylamino)pyrimidine, 2-amino(4-chlorophenoxy)(4-hydroxybutylamino)pyrimidine, o(4-chlorophenoxy)(6-hydroxyhexylamino)pyrimidine, ??? 2-amino(4-chlorophenoxy) (tris(hydroxymethyl)methylamino)pyrimidine; 2-amino (4-chlorophenoxy)(3,4-dihydroxybutylamino)pyrimindine; o(4-chlorophenoxy)(2-hydroxymethylethylamino )pyrimindine; ??? 2-amino(4-chlorophenoxy)(1,1-dimethyl hydroxyethylamino)pyrimindine; and 2-amino(4-chlorophenoxy)(1-ethylhydroxyethylamino)pyrimindine; are excluded.
??? 2. A compound of formula (I) according to claim 1 wherein R3 is butyl or pentyl.
3. A nd of formula (I) according to claim 1 wherein R3 is C4-8 alkyl substituted with yl.
4. A compound of formula (I) according to claim 3 wherein R3, when being C4-8 alkyl substituted with hydroxyl, is one of the following (S) (S) (S) (S) ??
5. A nd of formula (I) according to any one of claims 1 to 4, wherein R1 is en or -CH3.
6. A compound of formula (I) according to any one of claims 1 to 5, wherein wherein R2 is alkylaryl or alkylheteroaryl, substituted with C1-3alkyl, hydroxyl, alkoxy, nitrile, heterocycle or ester.
??? 7. A compound of formula (I) according to any one of claims 1 to 5, wherein R2 is C1-3alkyl substituted by aryl, heterocycle, or aryl which is further substituted by C1-3alkyl, alkoxy, carboxylic ester or carboxylic amide.
8. A compound of formula (I) according to any one of claims 1 to 5, wherein ??? R2 is N N N N O O each of which can be optionally further substituted with C1-6alkyl, hydroxyl, koxy, nitrile, heterocycle or ester.
??? 9. A compound according to claim 1 having the formula: , or ?
10. A pharmaceutical composition comprising a compound of formula (I) or a ceutically acceptable salt, tautomer(s), solvate or polymorph f according to any one of claims 1-9 together with one or more ceutically acceptable ents, diluents or carriers.
11. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof according to any one of claims 1-9, or a pharmaceutical composition ing to claim 10, for use as a medicament.
12. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof according to any one of claims 1- 9, or a pharmaceutical composition according to claim 10, for use in the treatment of a disorder or disease in which the tion of TLR7 and /or ??? TLR8 is involved.
13. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof, in the production of a medicament for use in the treatment of a ??? disorder or disease in which the modulation of TLR7 and/or TLR8 is involved.
14. A compound according to claim 1, substantially as herein described with reference to any one of the accompanying examples thereof.
15. Use according to claim 13, substantially as herein described with reference to any one of the accompanying examples thereof.
NZ615301A 2011-04-08 2012-04-10 Pyrimidine derivatives for the treatment of viral infections NZ615301B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP11161595 2011-04-08
EP11161595.1 2011-04-08
PCT/EP2012/056388 WO2012136834A1 (en) 2011-04-08 2012-04-10 Pyrimidine derivatives for the treatment of viral infections

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NZ615301A NZ615301A (en) 2016-03-31
NZ615301B2 true NZ615301B2 (en) 2016-07-01

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