NZ614205B2 - Fluoro-pyridinone derivatives useful as antibacterial agents - Google Patents

Fluoro-pyridinone derivatives useful as antibacterial agents Download PDF

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NZ614205B2
NZ614205B2 NZ614205A NZ61420512A NZ614205B2 NZ 614205 B2 NZ614205 B2 NZ 614205B2 NZ 614205 A NZ614205 A NZ 614205A NZ 61420512 A NZ61420512 A NZ 61420512A NZ 614205 B2 NZ614205 B2 NZ 614205B2
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New Zealand
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fluoro
methyl
butanamide
methylsulfonyl
mmol
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NZ614205A
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NZ614205A (en
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Matthew Frank Brown
Ye Che
Michael Joseph Melnick
Justin Ian Montgomery
Mark Stephen Plummer
Loren Michael Price
Usa Reilly
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Pfizer Inc
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Priority claimed from PCT/IB2012/050812 external-priority patent/WO2012120397A1/en
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Publication of NZ614205B2 publication Critical patent/NZ614205B2/en

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    • 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
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings
    • 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

Abstract

The disclosure relates to a class of fluoro-pyridinone derivatives of general structure I, wherein R1, R2, R3, T, D and E are as defined in the specification. The disclosure also relates to their use as LpxC inhibitors and to treat bacterial infections. Example compounds include: 4-{5-fluoro-4-[2-fluoro-3-(hydroxymethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, 4-[4-(3-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, 4-(5-chloro-5'-fluoro-2'-oxo-2,4'-bipyridin-1'(2'H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, 4-{4-[4-(1-cyano-1-methylethyl)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (2R)-4-(5-fluoro-2-oxo-4-quinoxalin-6-ylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyI}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide. fluoro-3-(hydroxymethyl)phenyl]-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, 4-[4-(3-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, 4-(5-chloro-5'-fluoro-2'-oxo-2,4'-bipyridin-1'(2'H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, 4-{4-[4-(1-cyano-1-methylethyl)phenyl]-5-fluoro-2-oxopyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (2R)-4-(5-fluoro-2-oxo-4-quinoxalin-6-ylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, (2R)-4-[5-fluoro-4-{4-[(trans-4-hydroxycyclohexyl)methoxy]phenyI}-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide.

Description

PCT/[82012/050812 FLUORO-PYRIDINONE DERIVATIVES USEFUL AS ANTIBACTERIAL AGENTS Field of the Invention This invention relates to novel amic acid tives. The ion also relates to methods of using such compounds in the treatment of ial infections (especially Gram-negative infections) and to pharmaceutical itions containing such nds.
Background of the Invention infection by Gram-negative bacteria such as Pseudomonas aeruginosa, Extended Spectrum B—lactamase producing (ESBL) Entgerobacteriaceae, and Acinetobacter baumannii is a major health problem, ally in the case of hospital- acquired infections. in addition, there is an sing level of ance to current antibiotic therapies, which severely limits treatment options. For example, in 2002, 33% of Pseudomonas aeruginosa ions from intensive care units were resistant to fluoroquinolones, while resistance to imipenem was 22% (ClD 42: 657-68, 2006). in addition, multi-drug resistant (MDR) infections are also sing; in the case of Pseudomonas aeruginosa, MDR increased from 4% in 1992 to 14% in 2002 (Biochem Pharm 71: 991, 2006).
Gram-negative bacteria are unique in that their outer membrane contains lipopolysaccharide (LPS), which is crucial for maintaining membrane integrity, and is ial for bacterial viability (reviewed in Ann. Rev. Biochem 76: 295-329, 2007). The major lipid component of LPS is Lipid A, and inhibition of Lipid A biosynthesis is lethal to bacteria. Lipid A is synthesized on the cytoplasmic surface of the bacterial inner membrane via a pathway that consists of nine different enzymes. These enzymes are highly conserved in most Gram-negative bacteria. LpXC [UDPO—(R—3— hydroxymyristoyl)— N-acetylglucosamine deacetylase] is the enzyme that catalyzes the first committed step in the Lipid A biosynthetic pathway, the removal of the N-acetyl group of UDPO-(R—3-hydroxymyristoyl)—N—acetylglucosamine. prC is a an” - dependent enzyme that has no mammalian homologue, making it a good target for the development of novel antibiotics. Several inhibitors of prC with low nM affinity have been reported (Biochemistry 45: 7940-48, 2006).
WO 20397 PCT/IBZOIZ/050812 Summary of the ion A new class of prC inhibitors has been discovered. These compounds, or their ceutically acceptable salts, can be represented by Formula I below: /T‘z_\ N ,...., H5715 in which: R1 is represented by 01-03 alkyl; R2 is represented by hydrogen or 01-03 alkyl; R3 is represented by hydrogen, halogen, hydroxy, cyano, C1-Csalkyl, C1-C3alkoxy, trifluoromethyl or trifluoromethoxy; T is represented by ethynyl, optionally substituted (Ce-C10)aryl or optionally substituted heteroaryl; D is absent, or is represented by —(CH2),-, -(CH2)n-O-(CH2)p-, 0r a bond; r is represented by the r 1, 2, or 3; n and p are each independently represented by the integer 0, 1, or 2; E is absent, or is represented by a substituent selected from the group consisting of: i) (CB_C1O)cycloalkyl, optionally substituted; ii) (Ce-C10)aryl optionally substituted; iii) heteroaryl, optionally tuted; and iv) heterocyclic, optionally substituted; with the proviso that: 1) if E is absent, then D is also absent; 2) T is not represented by unsubstituted phenyl; when E and D both are absent, R3 is hydrogen and R1 and R2 are each methyl.
The compounds of Formula | exhibit antibacterial activity, especially against Gram-negative sms. They may be used to treat bacterial infections in mammals, especially . The compounds may also be used for veterinary applications, such as treating infections in livestock and ion animals.
The compounds of Formula l are useful for treating a variety of infections; especially Gram-negative ions including nosocomial pneumonia, urinary tract ions, ic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intraabdominal infections, lung infections (including those in ts with cystic fibrosis), Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.), endocarditis, diabetic foot infections, yelitis, and central nervous system infections.
In order to simplify administration, the compounds will typically be admixed with at least one excipient and formulated into a pharmaceutical dosage form. Examples of such dosage forms include tablets, capsules, solutions/suspensions for injection, aerosols for tion, cream/ointments for topical, otic or ophthalmic use, and solutions/suspensions for oral ingestion.
Detailed Description of the Invention The headings within this document are only being utilized to expedite its review by the reader. They should not be construed as limiting the invention in any manner.
Definitions and Exemplification As used throughout this application, including the claims, the following terms have the meanings defined below, unless specifically indicated ise. The plural and ar should be treated as interchangeable, otherthan the indication of number: a. “C1- 03 alkyl” refers to a branched or straight chained alkyl group containing from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl, etc. b. “01- C3 alkoxy" refers to a straight or ed chain alkoxy group containing from 1 to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy, poxy, etc. c. "halogen” refers to a chlorine, fluorine, iodine, or bromine atom. d. “C1- 06 alkyl” refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, etc. e. “01- C6 alkyl, optionally substituted" refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, l, isobutyl, pentyl, etc. Such an alkyl group may be optionally substituted, in which up to 3 en atoms are replaced by a substituent selected from the group consisting of halogen, cyano, sulfonamide, imino, —OR4, -SR4, and —NR4R5 in which R4 and R5 are each independently represented by hydrogen or 01—03 alkyl. f. “01— 06 alkoxy" refers to a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, oxy, isopropoxy, n- , isobutoxy, pentoxy, etc. 9. “C1- C6 alkoxy, ally substituted” refers to a ht or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n- propoxy, isopropoxy, n—butoxy, isobutoxy, pentoxy, etc. Such an alkoxy group may be optionally substituted, in which up to 3 hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, sulfonamide, imino, -0R4, -SR4, and —NR4R5in which R4 and R5are each independently represented by en or C1—C3 alkyl . h. “(C6-C1O)aryl” means a cyclic, aromatic hydrocarbon containing from 6 to 10 carbon atoms. Examples of such aryl groups include phenyl, naphthyl, etc. i. “(Ce-C10)aryl optionally tuted” means a cyclic, aromatic hydrocarbon as defined above. Such an aryl moiety may be ally substituted with up to 4 non—hydrogen substituents, each substituent is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, (C1-C6)alkyl optionally substituted, (C1—Ca)alkoxy optionally substituted, trifluoromethyi, trifluromethoxy, phosphate, —SOgNR4R5, —(CH2)m-NR5—C(O)-R4, —(CH2)m-C(O)—N-R4R5, ~C(O)—R4,- C(O)—O—R4, ~SR4, -SOZR4 and -NR4R5, in which m, R4 and R5 are as defined above and each M independently represents an integer from 0-4. These substituents may be the same or different and may be located at any position of the ring, that is chemically permissible. “Phenyl ally substituted” refers to a phenyl ring substituted as described above. j. “heteroaryl” refers to an aromatic ring having one, or more, heteroatoms selected from oxygen, nitrogen and . More specifically, it refers to a 5- or 6- membered ring containing 1, 2, 3, or 4 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2 en atoms and 1 oxygen atom; or 2 nitrogen atoms and 1 sulfur atom. The —membered ring has 2 double bonds and the 6- membered ring has 3 double bonds (“hereinafter a “5— to 6-membered heteroaryl”). The term “heteroaryl” also PCT/[82012/050812 es bicyclic groups in which the heteroaryl ring is fused to a benzene ring, heterocyclic ring, a cycloalkyl ring, or another heteroaryl ring. es of such heteroaryl ring systems include, but are not limited to, pyrrolyl, furanyl, l, imidazolyl, oxazolyl, indolyl, thiazolyl, lyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, benzofuran, tetrazole, isoquinolinyl, oxadiazolyl, thiadiazolyl, azolyl, isoxazolyl, triazolyl, benzo[b]thienyl, 2-, 4—, 5-, 6-, or 7-benzoxazolyl, 7—benzimidazolyl, or benzothiazolyl. k. “heteroaryl, optionally substituted,” refers to a heteroaryl moiety as defined immediately above, in which up to 4 carbon atoms of the heteroaryl moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, (C1-Cs)alkyl ally substituted, (C1—Cs)alkoxy optionally substituted, trifluoromethyl, trifluromethoxy, phosphate, -sozNR4R5, -(CH2)m—N—C(O)-R4, -(CH2)m-C(O)-N-R4R5, -C(O)—R4, O-R4, -SR4, -SOzR4 and —NR4R5, in which m, R4 and R5 are as defined above. These substituents may be the same or different and may be located at any position of the ring, that is ally sible.
Any reference to an “optionally substituted 5- to 6— membered heteroaryl” refers to 5— to 6—membered heteroaryl ring as described in definition j, having the substitution pattern bed immediately above.
I. “(Cs-C10) cycloalkyl” refers to a saturated or partially saturated monocyclic, bicyclic, bridged bicyclic or tricyclic alkyl radical wherein each cyclic moiety has 3 to 10 carbon atoms. Examples of such cycloalkyl ls e cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. m. “(C3-C1o)cycloalkyl” optionally substituted refers to a (C3~C1o)cycloalkyl moiety as described above. Such a cycloalkyl group may be optionally tuted, in which up to 4 hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, nitro, hydroxy, (C1-CS)alkyl optionally substituted, (C1-Cs)alkoxy optionally substituted, trifluoromethyl, romethoxy, phosphate, oxo, —SOZNR4R5, -(CH2)m—NR5-C(O)—R4, —(CH2)m-C(O)-N-R4R5, - C(O)—R4, -C(O)—O-R4, -SR4, -SOzR4 and -NR4R5, in which M, R4 and R5 are as defined above. These substituents may be the same or different and may be located at any position of the ring, that is chemically permissible.
W0 2012/120397 PCT/[82012/050812 n. “(Cg-Ce) cycloalkyl” refers to a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl moiety, any of which may be optionally substituted as described above, if chemically permissible. o. “heterocycle” or “heterocyclic ring” refers to any 3- or 4—membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5—, 6—, 7—, 8-, 9-, or 10- membered ring containing 1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2 oxygen atoms in non—adjacent positions; 1 oxygen and 1 sulfur atom in non- adjacent positions; or 2 sulfur atoms in non-adjacent positions. The ered ring has 0 to 1 double bonds, the 6— and 7-membered rings have 0 to 2 double bonds, and the 8, 9, or 10 membered rings may have 0, 1, 2, or 3 double bonds.
The term “heterocyclic” also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring, a cyclohexane or cyclopentane ring or another heterocyclic ring (for example, indolyl, quinolyl, nolyl, tetrahydroquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). cyclics e: pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dinyl, zinyl, azepane, azocane, morpholinyl, isochromyl, quinolinyl, tetrahydrotriazine, tetrahydropyrazole, dihydro-oxathiol-4—yl, dihydro-1H— isoindole, tetrahydro—oxazolyl, ydro-oxazinyl, thiomorpholinyl, tetrahydropyrimidinyl, inyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. p. “heterocyclic, optionally substituted” refers to a heterocyclic moiety as defined immediately above, in which up to 4 carbon atoms of the heterocycle moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, (C1—Ca)alkyl ally substituted, (C1—Cs)alkoxy optionally tuted, oromethyl, trifluromethoxy, pentafluoro sulfonyl, phosphate, oxo, SOgNR4R5, -(CH2)m—N-C(O)-R4, —(CH2)m- C(O)—N—R4R5, -C(O)—R4, -c(0)-o-R4, —SR4, sogR“ and —NR4R5, in which m, R4 and R5 are as d above. These substituents may be the same or different and may be located at any position of the ring that is chemically sible. Any nitrogen atom within such a heterocyclic ring may optionally be substituted with (01-05) alkyl, or any other substituent listed above, if such a substitution is chemically permissible. Any sulfur atom in the ring may be further substituted with 1 or 2 oxygen atoms (if such a substitution is chemically permissible).
W0 2012/120397 PCT/IBZOIZ/050812 q. “therapeutically effective amount” refers to an amount of a compound of a l that, when administered to a patient, provides the desired effect; i.e., ing in the ty of the symptoms associated with a bacterial infection, decreasing the number of bacteria in the ed tissue, and/or preventing bacteria in the affected tissue from increasing in number( localized or systemic). r. nt” refers to warm blooded animals such as for example, ock, guinea pigs, mice, rats, s, cats, rabbits, dogs, monkeys, chimpanzees, and humans. 3. “treat” refers to the ability of the compounds to relieve, alleviate or slow the progression of the patient’s bacterial infection (or condition) or any tissue damage associated with the disease. t. “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/0r toxicologically, with the other ingredients comprising a ation, and/or the mammal being treated therewith. u. “isomer” means “stereoisomer’ and “geometric isomer” as defined below. v. “stereoisomer” means compounds that possess one or more chiral centers and each center may exist in the R or 8 configuration. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof. w. “geometric isomer” means compounds that may exist in cis, trans, anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof. x. Compounds of “Formula 1”, “formula l”, “formula (l)” and unds of the ion” are being used interchangeably throughout the application and should be treated as synonyms. y. The terms “pyridone” and “pyridinone” have been used interchangeably within this ation. No difference or distinction is meant, unless otherwise noted. One skilled in the art will readily tand this.
The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to e pharmaceutically acceptable acid addition salts of such basic compounds are those that form non—toxic acid on salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, W0 2012/120397 isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, rate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1’-methylene-bis-(2-hydroxy— 3-naphthoate)] salts. The compounds of the present ion that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in on to the acids mentioned above.
The invention also relates to base addition salts of the compounds of the invention. The chemical bases that may be used as reagents to prepare these ceutically acceptable base salts are those that form non—toxic base salts with such compounds. Such xic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and ) and alkaline earth metal cations (e.g., calcium and ium), ammonium or water—soluble amine addition salts such as N- methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. le base salts are formed from bases which form non-toxic salts. Non- limiting examples of suitable base salts include the um, arginine, benzathine, m, choline, diethylamine, ine, glycine, lysine, magnesium, ine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth —VCH, 2002). Methods for making pharmaceutically acceptable salts of nds of the invention are known to one of skill in the art.
Certain of the compounds of the formula (I) may exist as geometric isomers. The compounds of the formula (I) may possess one or more asymmetric centers, thus existing as two or more stereoisomeric forms. The present invention includes all the individual stereoisomers and geometric isomers of the compounds of formula (l) and mixtures thereof. individual enantiomers can be obtained by chiral tion or using the relevant enantiomer in the synthesis.
In addition, the compounds of the present invention can exist in ated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. The compounds may also W0 2012/120397 exist in one or more crystalline , i.e. polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the .
The invention also relates to prodrugs of the compounds of the ion. Thus certain derivatives of compounds of the ion which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into nds of the invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be found in Pro—drugs as Novel Delivery Systems, Vol. 14, A08 Symposium Series (T. i and W. Stella) and Bioreversible Carriers in Drug 1O Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
This invention also encompasses compounds of the ion containing protective groups. One skilled in the art will also appreciate that compounds of the invention can also be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient. The protection and deprotection of functional groups is described in “Protective Groups in Organic Chemistry”, edited by J.W.F. McOmie, Plenum Press (1973) and “Protective Groups in Organic Synthesis”, 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley- Interscience (1999).
The present invention also includes isotopically-labeled compounds, which are identical to those recited in formula l, but for the fact that one or more atoms are ed by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be orated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, ne and chlorine, such as, but not limited to, 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31F, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs f, and ceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically— labeled nds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for e increased in vivo half-life or W0 2012/120397 PCT/IBZOIZ/OSOSIZ reduced dosage requirements and, hence, may be preferred in some circumstances.
Isotopically-labeled compounds of this invention and gs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically-labeled reagent for a otopically—labeled reagent.
All of the compounds of Formula I contain a sulfonyl moiety as depicted below: oz-R1 H This sulfonyl moiety will always be substituted with a lower alkyl moiety.
Typically it will be methyl. The carbon atom nt to the sulfonyl may ally be substituted, as represented by R2. Typically both R1 and R2 will be methyl.
As is readily apparent to one skilled in the art, the carbon adjacent to the yl moiety is a chiral center. Therefore, the compounds can exist as the racemate, as the S—enantiomer, or as the R—enantiomer. In a further embodiment, the compounds may be prepared and administered as the R-enantiomer, as depicted below: Og—R1 H As is readily apparent to one skilled in the art, the compounds as synthesized will rarely be present exclusively as a single enantiomer. The opposite omer (i.e the S- enantiomer) may be t in minor amounts (i.e. “substantially pure”). This minor amount can be up to 10 w/w%, more typically no greater than 5 w/w%, in a further embodiment no greater than 1 w/w%, or more specifically, no greaterthan 0.5 w/w%.
All of the compounds of Formula | contain a pyridinone moiety as depicted below: 2012/050812 R3 o This pyridinone ring will be connected to the rest of the le via the 1— and 4- positions as depicted above. Position 3 will always be substituted with a fluoro moiety as depicted above. The pyridinone moiety may be optionally substituted, as depicted by the R3 moiety. R3 may ent one non-hydrogen substituent, as defined above. This non-hydrogen substituent may be located at either position 2 or 5 of the pyridinone ring.
Typically R3 will represent hydrogen.
T will always be present in the molecule. it will be represented by ethynyl, aryl or heteroaryl r ring system may be substituted as defined above.) Typically, T will be represented by phenyl, which may be optionally substituted. When T is heteroaryl, it will be linked to the pyridinone via a carbon-carbon bond (i.e. the heteroatom(s) will not be bonded to the pyridinone). If E is present, and D represents a bond, then it may represent any chemically permissible bond, i.e carbon-carbon, carbon-nitrogen, etc.
The presence of D and E are optional. if present, D will typically be a bond and E will be represented by either a 5- to 6-membered aryl or a (C3—Ce) cycloalkyl, either of which may be optionally substituted as defined above.
More specific embodiments of the invention include compounds of Formula | in which: a) R1 is methyl; b) R2 is ; 0) R3 is hydrogen; d) the compound is present as the R-enantiomer (Le. substantially pure); e) T is phenyl, which may be optionally substituted and D and E are both absent; f) T is phenyl, D is a bond and E is either C3-Cs cycloalkyl or a 5- to 6— membered aryl, either of which may be optionally substituted.
A further embodiment of the invention is directed to compounds of Formula I, substantially pure in which: a) R1 and R2 are each , R3 is hydrogen, and T, D and E are as defined; W0 2012/120397 PCT/IBZOIZIOSOSIZ b) R1 and R2 are each methyl, R3 is hydrogen, T is optionally substituted phenyl and both E and D are absent; 0) R1 and R2 are each methyl, R3 is hydrogen, T is optionally substituted phenyl, D is a bond and E is a 5- to 6-membered aryl, which may be optionally substituted; and d) R1 and R2 are each methyl, R3 is hydrogen, T is optionally substituted phenyl, D is a bond and E is C3-Ce cycloalkyl, which may be optionally substituted. in a further ment, the invention is directed to a subgenus represented by formula la below, in which the le is present as the R-enantiomer (i.e. the S~ omer may optionally be present in minor amounts). As depicted below, R1 and R2 are methyl, R3 is hydrogen, both E and D are absent and T is substituted phenyl. More ically R’3 is represented by one or more substituents selected from the group consisting of C1-03 alkyl, lkoxy, fluorine, chlorine, hydroxy, trifluoromethyl and trifluoromethoxy.
In a further embodiment, the invention is directed to a subgenus represented by formula lb below, in which the molecule is present as the R—enantiomer (i.e. the S- enantiomer may optionally be present as a minor impurity). As depicted below, R1 and R2 are methyl, R3 is hydrogen, T is phenyl, D is a bond and E is a 5- to ered heteroaryl, which may be optionally substituted.
W0 20397 — to 6-Membered Heteroaryl N Optionally Substituted \ Ib O In a more specific embodiment of the invention, the prC inhibitor is the following compound, or its pharmaceutically acceptable salt: In a more specific embodiment of the invention, the prC inhibitor is the following 1O compound, or its ceutically acceptable salt: Synthesis The compounds of Formula i can be prepared by a y of methods that are analogously known in the art. The reaction schemes presented below illustrate two alternative methods for preparing these compounds. Others, including modifications thereof, will be readily nt to one skilled in the art.
W0 2012/120397 PCT/IBZOIZIOSOSIZ The synthesis of the compounds of Formula | is depicted below in Scheme A.
The first step is to carry out the N-alkylation depicted in Step A. The pyridinone of structure 1 is reacted with the sulfonyl derivative of ure 2 generating the ediate of structure 3. Structure 3 can be further derivatized to generate the compounds of Formula i. Two alternative syntheses are depicted (Option A or B), but the reader wili y note they are variations of the same synthesis. The only difference is the order in which the steps are carried out. initially in Option A, the halide, depicted by X, at the 4-position of the pyridinone of structure 3 is displaced by the d terminal moiety E-D-T-M1, in which M1 is a metal species, such as a boron derivative suitable for undergoing a typical cross- coupling such as a Suzuki—Miyaura reaction. Hydrolysis, or l, of the ethyl protecting group (or other suitable protecting groups) in Step C affords the compound of structure 5. The terminal ylic acid of structure 5 is then converted to the protected hydroxamic acid derivative as depicted by structure 8. ection of the protected amic acid derivative of structure 8, as depicted in Step H, affords the final product of a I. While these reactions are well known to one skilled in the art, they are discussed in greater detail below.
Initially, in Option B of Scheme A, the ethyl protecting group (or other conventional protecting groups) is removed from the pyridinone of structure 3 generating the compound of structure 6 as depicted in Step E. in Step F, the terminal carboxylic acid of ure 6 is converted to the protected hydroxamic acid derivative of structure 7 via amidation conditions. In Step G, the halide function at the tion on the pyridinone moiety is then directly displaced by the desired terminal moiety, E-D-T— M1, via a coupling reaction to afford the protected hydroxamic acid derivatives of ure 8. As before, deprotection of the protected hydroxamic acid derivatives, as depicted in Step H, affords the compounds of Formula l.
WO 20397 PCT/IBZOIZIOSOSIZ SCHEME A o 0 Kim3 02M O -R1 3 I OH SW + Br KJkMoaR / R2 ——-————-—> l / O x o N-Alkylation x F 2 1 i Option A O9 Ion _t' B Step B Step E ng Hydrolysis 4 Step F Step C H2N-OPr Amidation Hydrolysis N-O-Pr \ I ED T , O x #23 F 7 Step0 , E StepG Amidation 02-R1 Coupling Reaction N-O—Pr l R2 X 0 E/D\T R3 F 8 StepH Deprotection o 02-R1 NH—OH I \3‘ R2 E/D\T ’ R3 The N—alkylation depicted above in Step A can be carried out using techniques well known to one skilled in the art. One of the starting materials is the 2-pyridinone derivative of structure 1. In this pyridinone, X will represented by a halide and R3 will be represented by the same moiety as is desired in the final product. Many of these none derivatives are known in the art and the remainder can be produced using synthetic techniques analogously known in the art. The reader’s attention is directed to Tet. Lett. (2005) Vol 46, 7917, for a description of such techniques. Preparation 2 infra, also illustrates their preparation.
The other reactant in the lation depicted in Step A is the protected alkyl sulfonate of structure 2, in which R1 and R2 are represented by the same moiety as is desired in the final product. An ethyl protecting group is yed, but any standard protecting group may be substituted. These alkyl sulfonates are also known in the art.
The reader’s attention is directed to Journal of Organic Chemistry, (1980) Vol 45, 8, 1486-1489 for a description of their preparation. Preparation 1 infra, also illustrates their preparation The N-alkylation can be carried out as is known in the art. Typically, equivalent amounts of the nds of structure 1 and 2 are contacted in a e of aprotic and protic solvents, such as ydrofuran and t-butanol, in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, etc. A transfer agent, such as utyl ammonium bromide, can be utilized, if desired.
The reactants are lly heated and the reaction is allowed to proceed to completion.
The desired product of structure 3 can be ed by methods known in the art. If desired, the product of structure 3 can be purified, or alternatively the crude can be used in the next step of the reaction. Preparation 2 infra, illustrates such an N- tion.
Scheme A illustrates how to incorporate the hydroxamic acid moiety into the molecules. Initialiy, the protecting group is removed from the carboxylic acid, thereby generating the ediate of structure 5 and 6, as ed in Step C (Option A) and Step E (Option B) respectively. The manner in which this is accomplished will vary with the identity of the actual protecting group and is well known to those skilled in the art.
The reader’s attention is directed to McOmie or Greene supra, for a discussion of ial protecting groups and methods for their removal. Preparation 2 infra describes how to remove an ethyl moiety as depicted in Scheme A. in Steps F and D, the hydroxamic acid moiety as depicted, is incorporated into the molecule. A protected hydroxylamine source may be used followed by a uent deprotection reaction (alternatively, hydroxylamine may be directly incorporated to eliminate the deprotection steps). in either case the hydroxamic acid is WO 20397 PCT/IBZOIZ/OSOSIZ incorporated into the molecule using rd amidation reactions. For example, the compound of structure 5 (Option A) or 6 (Option B) may be contacted with an excess of oxalyl chloride, in an aprotic solvent such as romethane for a sufficient period of time to allow the formation of the corresponding acid chloride, followed by the addition of an excess of either hydroxylamine or protected hydroxylamine. The reaction is then d to proceed to completion and the protected ediates of ure 7 (Option B) or 8 (Option A) is isolated from the reaction medium and purified as is known in the art. As mentioned above, any deprotection may be carried out as is known in the art (See Greene or McOmie supra). Alternatively, the amide can be formed using the ‘IO amide coupling reagent, 1,1‘-carbonyldiimidazole (CDl), 2-chloro—4,6-dimethoxy-1,3,5- triazine , or 1-ethyl—3-(3-dimethy|aminopropyl)carbodiimide (EDCl), as is known in the art.
Scheme A also depicts how to incorporate the terminal moiety, E-D-T, into the molecule. Regardless of whether Option A or Option B is chosen, a coupling reaction is ultimately carried out to attach the terminal moiety, E-D-T, to the 4—position of the pyridinone ediate. in Scheme A, the co—reactant is depicted as E-D-T—M1, where E-D-T—M1 represents the same moiety as desired in the final product, except that it will be substituted with a metal (or metalloid) such as ium, copper, boronic ester/acid, etc. at the desired point of attachment to the pyridinone intermediate of structure 3 or 7 (Le. the other reactant). The terminal groups encompassed by Formula l, i.e E-D-T, are either known in the art or can be prepared by methods analogously known in the art.
The coupling reaction can be d out by a variety of techniques. The Suzuki»- Miyaura strategy can be used to form the carbon—carbon bond. In such a reaction M1 will be represented by a c acid/ester. Equivalent molar amounts of the reactants will be contacted in a solvent such as tetrahydrofuran, 2—methyltetrahydrofuran, 1,4- e, water, toluene, or a mixture thereof in the presence of a transition metal catalyst such as a free or resin bound palladium or nickel species, together with a base such as sodium carbonate, potassium carbonate, cesium fluoride, cesium carbonate, etc. The on e can be heated by microwave or by other conventional techniques until adequate conversion is achieved. Once complete, the desired product may be isolated and recovered from the reaction and further purified as is known in the art. Analogously, the Castro—Stevens or Sonogashira-Hagihara strategy can be employed; the T moiety will be a suitable terminal acetylene species reacted in the presence of copper salt such as copper iodide. in such a reaction M1 can be 2012/050812 represented by the in situ generated cuprate s. Equivalent molar amounts of the reactants will be contacted in a t such as tetrahydrofuran, 2- methyltetrahydrofuran, dimethylformamide or a mixture thereof in the presence of a transition metal catalyst such as free or resin bound palladium or nickel, together with an appropriate base such as a suitable organic base for example N,N- diisopropylethylamine. The reaction mixture can be heated by microwave or by other conventional techniques until adequate conversion is achieved. Once complete, the desired product may be isolated and recovered from the reaction and further purified as is known in the art.
The reaction schemes depicted above for producing the compound of Formula 1, are merely illustrative. As is readily apparent to one skilled in the art, they may be modified depending upon the specific nd, availability of ts, etc.
Medical and Veterinary Uses The compounds may be used for the treatment or prevention of infectious disorders, especially those caused by susceptible and multi-drug resistant (MDR) Gram- negative bacteria. Examples of such Gram-negative bacteria include Acinetobacter baumannii, Acinetobacter spp., Achromobacter spp., Aeromonas spp., Bacteroides fragi/is, ella spp., Borrelia spp., la spp., Campy/obacter spp., acter diversus (koseri), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Francisella tularensis, Fusobacterium spp., hilus influenzae (B- Iactamase positive and ve), Helicobacter pylori, Klebsiel/a oxytoca, Klebsiella pneumoniae (including those ng ed—spectrum B-lactamases (hereinafter "ESBLs"), Legionel/a pneumophila, Moraxella catarrha/is (B-lactamase positive and negative), Morgana/la morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus vulgaris, Porphyromonas spp., Prevotella spp., Mannheimia haemolyticus, Pasteurella spp., Proteus lis, Providencia spp., Pseudomonas aeruginosa, Pseudomonas spp., Salmonella spp., Shigella spp., Serratia cens, Treponema spp., Burkho/deria cepacia, Vibrio spp., Yersinia spp., and Stenoz‘rophomonas mulophili‘a. Examples of other gram negative organisms include members of the Enterobacteriaceae that s ESBLs; KPCs, CTX—M, metallo-B—Iactamases (such as NDM-t, for example), and AmpC-type actamases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, and beta—lactam/beta- lactamase inhibitor combinations.
W0 2012/120397 PCT/132012/050812 In a more specific embodiment, the Gram—negative ia are selected from the group consisting of obacter baumannii, Acinetobacter spp.,Citrobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, K/ebsieI/a oxytoca, KIebsie/Ia pneumoniae, Serratia marcescens, Sfenofrophomonas maitophiiia, Pseudomonas aeruginosa and members of the Enterobacteriaceae and Pseudomonas that express ESBLs, KPCs, CTX—M, metallo—B-lactamases, and AmpC-type beta- ases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, and beta-Iactam/beta—lactamase inhibitor combinations.
Examples of infections that may be treated with the compounds of Formula I include mial pneumonia, urinary tract infections, systemic infections (bacteremia and ), skin and soft tissue infections, surgical infections, intraabdominal infections, lung infections in ts with cystic fibrosis, patients suffering from lung infections, endocarditis, diabetic foot infections, osteomyelitis, and l nervous system infections.
In addition, the nds can be used to treat bacter pylori infections in the GI tract of humans (and other mammals). ation of these bacteria is associated with improved health outcomes including fewer dyspeptic symptoms, reduced peptic ulcer recurrence and rebleeding, d risk of gastric cancer, etc. A more detailed discussion of eradicating H. pylori and its impact on gastrointestinal 2O illness may be found at: wwwinformaheatthcare.com, Expert Opin. Drug Saf. (2008) 7(3).
In order to exhibit this anti—infective activity, the compounds need to be stered in a eutically effective amount. A "therapeutically effective amount" is meant to be a sufficient quantity of the compound to treat the infection, at a reasonable benefit/risk ratio applicable to any such medical treatment. it will be understood, however, that the attending physician, within the scope of sound medical judgment, will decide the total daily dosage of the compound. The specific therapeutically effective dose level for any particular patient will depend upon a variety of s including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the ic compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. As a general guideline however, the total daily dose will typically range from about 0.1 mg/kg/day to about PCT/IBZOIZ/050812 5000mg/kg/day in single or in divided doses. Typically, s for humans will range from about 10 mg to about 3000 mg per day, in a single or multiple doses.
Any route typically used to treat infectious illnesses, including oral, parenteral, topical, rectal, transmucosal, and intestinal, can be used to administer the compounds.
Parenteral administrations include injections to generate a systemic effect or ions directly into to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, and intraocular, intranasal, intravetricular injections or infusions techniques. Topical strations include the treatment of areas readily accessible by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skin including the surface skin and the underneath dermal structures, or lower intestinal tract. Transmucosal stration includes nasal aerosol or inhalation applications.
Formulations Compounds of the ion can be formulated for stration in any way for use in human or veterinary medicine, by analogy with other bioactive agents such as antibiotics. Such methods are known in the art and are summarized below.
The composition can be formulated for administration by any route known in the art, such as mal, by-inhalation, oral, topical or parenteral. The compositions may be in any form known in the art, including but not limited to tablets, capsules, s, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, ophthalmic ointments/drops and otic drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as vatives, ts to assist drug penetration and emollients, etc.
Such topical formulations may also contain conventional carriers, such as cream or ointment bases and ethanol or oleyl l for lotions. Such carriers may be present, for e, from about 1% up to about 98% of the formulation.
Tablets and capsules for oral stration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example , n, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
PCT/IBZOIZIOSOSIZ The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl ose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non—aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a e e, water being typical. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before g into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after g into the vial and the water removed under vacuum. The dry lized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle d of being dissolved and ization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before ding in the sterile vehicle. Advantageously, a surfactant or g agent is included in the composition to facilitate uniform distribution of the nd.
The compositions may contain, for example, from about 0.1% by , to about 100% by weight, of the active material, ing on the method of administration.
Where the compositions comprise dosage units, each unit will contain, for example, from about 00 mg of the active ingredient. The dosage as employed for adult human treatment will range, for example, from about 10 to 3000 mg per day, depending on the route and frequency of administration.
If d, the nds of the invention may be administered in combination with one or more additional antibacterial agents (“the additional active agent”). Such use of compounds of the invention in combination with an additional active agent may be for simultaneous, separate or sequential use.
The Examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. it is to be understood that the scope of the present invention is not limited in any way by the scope of the following Examples and preparations. in the following Examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless othenNise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
EXAMPLES mental ures Experiments were generally carried out under an inert atmosphere (nitrogen or argon), particularly in cases where - or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification, including anhydrous ts where appropriate (generally Sure—SealTM products from the Aldrich Chemical Company, Milwaukee, Wisconsin).
Mass spectrometry data is reported from either liquid chromatography—mass spectrometry (LCMS) or atmospheric pressure chemical ionization (APCI). Chemical shifts for nuclear magnetic resonance (NMR) data are sed in parts per n (ppm, 6) referenced to residual peaks from the deuterated solvents employed. Melting points are uncorrected.
Low Resolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard 598%), ing chemical ionization (ammonium), or a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCl) platform which uses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as the ionizing agent. Room or ambient temperature refers to 20-25°C.
For syntheses referencing procedures in other es, reaction conditions (length of reaction and temperature) may vary. in general, ons were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate. cations may vary between ments: in general, solvents and the solvent ratios used for s/gradients were chosen to provide appropriate Rfs or retention times.
PCT/IBZOIZ/050812 In the discussion above and in the Examples below, the ing iations have the following meanings. if an abbreviation is not defined, it has its generally accepted meaning.
Ac acetate ACN acetonitrile AC20 acetic anhydride APCI atmospheric pressure chemical ionization Aq. aqueous 9—BBN 9—Borabicyclo[3.3.1]nonane bd broad t bm broad multiplet bs broad singlet BOC ten-butoxycarbonyl °C degrees celsius CBZ benzyloxycarbonyl CDl 1,1’-carbonyldiimidazole CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine cm centimeter doublet DCC 1,3—dicyclohexylcarbodiimide DCM dichloromethane dd doublet of doublets ddd doublet of doublets of doublets DIAD diisopropyl azodicarboxylate DME dimethyl ether DMF dimethylformamide DMA dimethylacetamide DMAP 4-dimethylaminopyridine DMSO dimethyl ide doublet of ts dt doublet of triplets EDCI 1-ethyl(3-dimethylaminopropyl)carbodiimide eq. equivalents EC ethoxy 320 diethyl ether EtOAc = ethyl acetate 9 = grams GCMS = gas chromatography mass spectromety h = hours 1H = proton HATU = (2-(7—aza—1 H-benzotriazole—1-yl)—1,1,3,3-tetramethyluronium hexafluorophosphate) HCI = hydrochloric acid H2N-OTHP = O—tetrahydro-2H—pyran—2~yl-hydroxylamine HOBT = Hydroxybenzotriazole HPLC = high pressure liquid chromatography Hz = hertz IPA = isopropanol J = coupling constant KOAc = ium acetate K3PO4 = potassium phosphate L = liter LCMS = liquid chromatography mass spectrometry LDA = lithium diisopropylamide LG = leaving group LiHMDS = lithium hexamethyldisilazide/ m bis(trimethylsilyl)amide m = multiplet M = molar M% = mole percent max = maximum mCPBA = meta-chloroperbenzoic acid MeOH = ol meq = milliequivalent MeTHF = yltetrahydrofuran mg = milligram M9804 = magnesium sulfate MHz = megahertz min = minutes mL = milliliter mm = millimeter PCT/132012/050812 mmol millimole MS mass spectrometry MTBE methyl tert-butyl ether m/z mass to charge ratio N normality NaH003 sodium bicarbonate : sodium sulfate NH4CI ammonium chloride NMM N-methylmorpholine 1O NMP 1-methyl—2—pyrrolidlnone NMR nuclear magnetic nce Pd palladium Pd EnCatTM palladium acetate and BINAP, microencapsulated in polyurea matrix 0.39mmollg Pd loading BINAP 0.25, Pd 1.0 Pd(dppf)C|2 bis(diphenylphosphino)ferrocenepalladium(ll) chloride Pd(dppf)C|2 dichloromethane complex Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) ppt precipitate p—TLC preparative thin layer chromatography PyBop benzotriazole-i-yl-oxy—trispyrrolidinophosphonium uorophosphate quartet retention factor room temperature singlet saturated tetrabutylammoinum bromide tert-butyldimethylsilyl 3O trifluoroacetic acid tetrahydrofuran tetrahyropyranyl thin layer chromatography trimethylsilyl triphenylphosphine WC 2012/120397 TPPO triphenylphosphine oxide uL = microliter PREPARATION OF STARTING MATERIALS Preparation 1 Synthesis of Template 1 (T1): Eth l4-bromo—2-meth l-2— meth lsulfon | butanoate and individual enantiomers (R) and (S).
Br/\)<n/ \/M9023 O 0 Step A) Eth l 2- meth lsulfon l ro anoate Sodium methanesulfinate (103 g, 937 mmol) was combined with ethyl 2- chloropropionate (109 g, 892 mmol) in ethanol (350 mL) in a 500 mL one neck round bottom flask. The reaction was heated to 77 0C for 20 h, and then allowed to cool to room temperature. The solids were removed by filtration through celite, and the filter pad was washed with ethanol. The combined tes were concentrated in vacuo. The crude t was suspended in diethyl ether (250 mL), and solids were removed by filtration. The filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil (51 g. 73%).1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.32 (t, J=7.05 Hz, 3 H) 1.67 (d, J=7.47 Hz, 3 H) 3.05 (s, 3 H) 3.83 - 3.92 (m, 1 H) 4.18 - 4.37 (m, 2 H).
Step B) Ethyl 4-bromo—2—methyl-2—imethylsulfonyl )butanoate Sodium hydride (60% dispersion in l oil, 2.33 g, 58.3 mmol) was washed with hexanes (2x10 mL) in a 100 mL two neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was d dropwise with ethyl 2- (methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The e was stirred 30 min at RT, cooled to 0 °C, and treated drop-wise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room temperature while stirring overnight. The mixture was quenched with saturated aq ammonium chloride (100 mL) and ted with l ether (4x50 mL). Combined organics were washed with 50% saturated sodium chloride (4x50 mL), dried (MgSO4), and concentrated in vacuo.
Crude material was purified via silica chromatography (350 9, 0 mesh) and an eluent of EtOAc in hexanes (10—20%) to afford the title compound as a pale yellow oil ZOlZ/OSOSIZ (7.9 g, 50%). 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 1.33 (t, J=7.05 Hz, 3 H) 1.64 (s, 3 H) 2.49 - 2.59 (m, 1 H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz,1 H) 3.05 (s, 3 H) 3.33 — 3.41 (m, 1 H) 3.46 — 3.54 (m, 1 H) 4.22 — 4.37 (m, 2 H).
Step C) Chiral separation of Ethyl 4-bromo—2—methyl-2—(methylsulfonyl)butanoate Crude ethyl 4—bromomethyl-2—(methylsulfonyl)butanoate (1.82 kg) was purified via flash chromatography using an LP-6OO column and toluene as the eluent to afford pure ethyl 4-bromo—2—methyI—2-(methylsulfonyl)butanoate (1.63 kg). The purified material was dissolved in ethanol (75 g/L) and resolved via chiral column chromatography (conditions listed in Table 1) on MCC-2 to afford enantiomer #1 (738.4 g, rt = 4.719 min, [01153920 = +14.1°) at 99% ee and enantiomer #2 (763.8 g, rt = 4.040 min) at 95% ee.
Purity of the enantiomers was determined via chiral HPLC, 4.6x250 mm Chiralpak AD, 10u column, 215 nm wavelength, mobile phase: ethanol, isocratic n at 1mL/min at t temperature. w Stationary Phase Column Dimension/Temp Feed Concentration 75 g/L in mobile phase Feed Rate 4.0 mL/min Eluent Rate 90.5 mL/min Recycling Rate 262 mL/min Period Time 1.0 min Enantiomer #1 was determined to be ethyl (2R)-4—bromo—2—methyl-2— (methylsulfonyl)butanoate, Template 1 (T1).
Preparation 2 Scheme B illustrates the ation of ethyl (2R)(5-fluoro~4~iodo—2- oxopyridin-1(2H)-y|)methyl(methylsulfonyl)butanoate (T2) and (2R)—4-(5-fluoro iodo—2—oxopyridin-1(2H)-yl)—2~methy|—2—(methylsulfonyl)-N—(tetrahydro—2H—pyran yloxy)butanamide (T3) and the corresponding racemic and diastereomeric mixtures ethyl 4-(5—fluoro—4-iodooxopyridin—1(2H)~yl)methyl(methylsulfonyl)butanoate W0 2012/120397 PCT/[82012/050812 (T4) and 4-(5-fluoroiodooxopyridin—1(2H)-y|)methyl(methylsulfonyl)—N- (tetrahydro-2H-pyranyloxy)butanamide (T5).
F BMBOZS \N T1OO\/ | MeOZS / —————-> ———_> M6023 MeOZS Synthesis of Template 3 (T3): 2R 5-Fluoro—4-iodo—2-oxo meth l—2- meth Isulfon l-N—tetrah dro-2H- ran lox butanamide I NWN‘O / O Step A) Com ound Ill: ro—4—iodo ridin—2 1H ~one Concentrated HCl (50 mL) was added to a mixture of 2,5-difluoroiodopyridine (2.0 g, 8.3 mmol) in 1,4-dioxane (350 mL) and water (100 mL). The mixture was heated to reflux and stirred at this temperature overnight. The on was concentrated to dryness and the residue was triturated in water (20 mL).The solids were collected via filtration and washed with water (2x30 mL) and hexanes (3x30 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (1.0 g, 50%). MS (LCMS) m/z 240.0 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 7.02 (d, J=5.07 Hz, 1 H) 7.68 (d, J=2.34 Hz, 1 H) 11.50 (br. 8., 1 H).
Step B) Tem |ate2 T2 : Eth l 2R roiodo-2—oxo methyl-Z-(methylsulfonyl )butanoate WO 20397 Cesium carbonate (1.77 g, 5.44 mmol) was added to a suspension of ro iodopyridln-2(1H)-one (1.00 g, 4.2 mmol) and ethyl (2R)bromomethyl (methylsulfonyl)butanoate (1.56 g, 5.44 mmol) in anhydrous THF (45 mL). The reaction was heated to 70 °C and stirred at this ature overnight. The reaction was quenched with water (100 mL) and extracted with EtOAc (2x100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24g column and an eluent of EtOAc in n-heptane (30-80%) to afford the title compound as a yellow residue (691 mg, 37%). MS (LCMS) m/z 446.0 (M+1). 1H NMR (400 MHZ, CHLOROFORM-d) 6 ppm 1.36 (t, 3 H) 1.75 (s, 3 H) 2.37 - 2.57 (m, 2 H) 3.10 (s, 3 H) 3.83 - 4.02 (m, 1 H) 4.16 — 4.37 (m, 3 H) 7.15 (d, 1 H) 7.20 (d, J=3.32 Hz, 1 H).
Step C) Com ound lV: 2R —4- 5—Fluoroiodo—2—oxo (methylsulfonyl)butanoic acid Potassium hydroxide (669 mg, 7.7 mmol) was added to a solution of ethyl (2R)—4-(5- fluoroiodooxopyridin-1(2H)-y|)methyl—2-(methylsulfonyl)butanoate (691 mg, 1.55 mmol) in 2-methyltetrahydrofuranzwater (2:1 22.5 mL) and the solution was stirred at 70°C for 2 h. The reaction was diluted with 1 N aq NaOH (50 mL). The organics were separated and the aqueous layer was washed with EtOAc (2x50 mL), and acidified to a pH of 3 using 3 M aqueous HCl. The s layer was extracted with EtOAc (3x60 mL), dried (MgSO4), filtered and concentrated to afford a yellow—white solid (290 mg, 44.8%). MS (LCMS) m/z 418.0. 1H NMR (400 MHz, 5) 5 ppm 1.53 (s, 3 H) 2.08 - 2.20 (m, 1 H) 2.36 — 2.48 (m, 1 H) 3.13 (s, 3 H) 3.79 — 4.02 (m, 2 H) 7.03 (d, J=6.05 Hz, 1 H) 7.96 (d, J=4.29 Hz, 1 H) 13.82 (br. s., 1 H).
Step D) Tem late 3 T3 : 2R 5-Fluoro-4—iodo-2—oxo 2— meth lsulfon l—N—tetrah dro-2H- ran lox butanamide ylmorpholine (120 uL, 1.1 mmol) was added to a solution of CDMT (178 mg, 3O 1.01 mmol) and (2R)—4—(5-fluoro—4—iodo—2-oxopyridin-1(2H)—yl)—2-methyl—2- (methylsulfonyl)butanoic acid (280 mg, 0.762 mmol) in 2-methyltetrahydrofuran (7.60 mL) and the reaction was stirred at rt for 1 h. THP-hydroxylamine (117 mg, 1.00 mmol) was added to the reaction and the reaction was d overnight at rt. The reaction was quenched with water (50 mL) and the aqueous layer was extracted with EtOAc (3x50 mL). The ed organics were washed with brine (50 mL), dried (MgSO4), filtered, W0 2012/120397 2012/050812 and concentrated to afford the title compound as an off-white solid (399.8 mg) MS (LCMS) 515.0 (M-1).
Example 1 —4— 5—Fluorooxo—4- 4- 2H-tetrazol meth lsulfon l-N- tetrah dro-2H- ran lox butanamide 2 .t / N/\)\n/NHOH \ O N” '21 Step A) 2- 4- 4 4 5 5-Tetrameth l—1 3 2-dioxaborolan | hen l -2H-tetrazo|e Pd(dppf)Cl2 (70.2 mg, 0.10 mmol) was added to a suspension of 4,4,4',4',5,5,5‘,5'- octamethyl-2,2'—bi—1,3,2-dioxaborolane (291 mg, 1.15 mmol), 2-(4-bromophenyl)-2H— tetrazole (215 mg, 0.96 mmol), and potassium acetate (191 mg, 1.91 mmol) in 1,4- dioxane (4.78 mL). The resulting suspension was heated to 80 °C and stirred at this temperature overnight. The reaction was allowed to cool, filtered through , and concentrated in vacuo. The crude product was ed via flash chromatography using a 409 silica gel Redisep column and an eluent of EtOAc in n-heptane (0—50%) to afford the title compound as a light yellow solid (258 mg, 99%). MS (LCMS) m/z 273.2 (M+1). 1H NMR (400 MHz, FORM-d) 5 ppm 1.36 (s, 12 H) 7.66 - 7.73 (m, 2 H) 7.96 - 8.02 (m, 2 H) 9.01 (s, 1 H).
Step B) 2R ~4- 5-Fluorooxo—4— 4- 2H-tetrazol methyl-Z—(methylsulfonyl)—N-(tetrahydro—2H—pyranyloxy)butanamide Pd EnCatTM (317 mg, 0.10 mmol) was added to a mixture of potassium ate (393 mg, 2.84 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2-yl)phenyl]—2H-tetrazole (258.4 mg, 0.95 mmol), and (2R)—4-(5-fluoro—4—iodooxopyridin—1(2H)—yl)—2-methyl—2- (methylsulfonyl)-N-(tetrahydro-2H-pyranyloxy)butanamide (490 mg, 0.95 mmol), T3, in 1,4-dioxanezwater (4:1, 10 mL). The reaction was heated to 80 °C and stirred at this temperature ght. The reaction was filtered through celite, and the filter pad was washed with methanol (250 mL). The ed filtrates were concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (20-100%) and methanol in W0 2012/120397 EtOAc (0-10%) to afford the title compound as a light tan solid (500 mg, 98%). MS (LCMS) m/z 534.4 (M-1). 0 Step C) 2R 5-FIuoro—2-oxo hydroxymethyI-2—gmethyisuifonyl)butanamide Hydrochloric acid (4.0 M in 1,4—dioxane, 1.7 mL, 6.63 mmol) was added to a solution of (2R){5—fluoro—2-oxo—4—[4—(2 H-tetrazol-2—yl)phenyl]pyridin-1 (2H)-yi}—2-methyl (methylsuIfonyl)—N—(tetrahydro—2H—pyran-2—yioxy)butanamide (500 mg, 0.94 mmol) in dichloromethanezmethanoi (5:1, 6 mL) at room ature. The reaction was stirred for 1 h then was concentrated under reduced re affording a residue, which was triturated in diethyl ether2pentane (1 :1) ght. The solid was collected via filtration and dried under reduced pressure to afford the title compound as a solid (340 mg, 76%). MS (LCMS) m/z 451.0 (M+1). 1H NMR (400 MHz, DMSO—de) 6 ppm 1.56 (s, 3 H) 2.09 — 2.21 (m, 1 H) 2.42 - 2.45 (m, 1 H) 3.09 (s, 3 H) 3.78 (m, J=11.80, 11.80, 5.20 Hz, 1 H) 3.97 — 4.10 (m, 1 H) 6.63 (d, J=7.61 Hz, 1 H) 7.84 (dd, J=8.68, 1.66 Hz, 2 H) 8.00 - 8.15 (m, 3 H) 10.16 (s, 1 H) 11.08 (br. s., 1 H).
Example2 2R 5—Fluoro—4— 2-fluoro—3—meth l hen l Step A) meth l meth Isulfon I-N- tetrah — ran on butanamide The title compound (470 mg, 48.7%) was obtained as a solid from (2-fluoro—3- methyiphenyl)boronic acid (388 mg, 2.52 mmol) using a procedure analogous to that described for (2R){5-f|uorooxo[4-(2H-tetrazolyl)phenyl]pyridin-1(2H)-yl} methyl(methylsuIfonyl)-N-(tetrahydro-2H-pyranyloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 499 (M + 1). 1H NMR (400 MHz, METHANOL-d4) 6 ppm 1.49 — 1.57 (m, 3 H) 1.59 (d, J = 3.71 Hz, 3 H) 1.64 - 1.74 (m, 3 H) 2.16 - 2.28 (m, 1 H) 2.27 - 2.31 (m, 3 H) 3.10 (d, J = 5.66 Hz, 3 H) 3.31 (s, 1 H) 3.47 - 3.55 (m, 1 H) 3.72 - 3.88 (m, 1 H) W0 20397 3.90 (s, 1 H) 3.99 - 4.15 (m, 2 H) 4.94 - 4.99 (m, 1 H) 5.47 (d, J = 7.22 Hz, 1 H) 7.20 - 7.26 (m, 1 H) 7.26 - 7.32 (m, 1 H) 7.40 - 7.47 (m, 1 H) 8.01 (dd, J = 11.90, 5.85 Hz, 1 H) 11.52 (d, J = 3.51 Hz, 1 H).
Step B) (2R -4— 5-FIuoro—4- 2—fluoro—3-meth l hen l hydroxy—Z-methyl-Z—lmethylsulfonyl)butanamide The title compound (185 mg, 46.6%) was obtained as a solid from (2R)—4-[5—fluoro—4—(2- fluoro-3—methylphenyl)—2-oxopyridin-1(2H)~yl]~2—methyl-2—(methylsulfonyl)—N—(tetrahydro- 2H~pyranyloxy)butanamide (477 mg, 0.957 mmol) using a procedure analogous to that described for (2R)—4-{5-fluoro-Z-oxo—4-[4-(2H—tetrazol-2—yl)phenyl]pyridin-1(2H)-yl}- N-hydroxy—2-methyl(methylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 415 (M + 1) 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.54 (s, 3 H) 2.13 (ddd, J = 13.03, 11.07, 4.78 Hz, 1 H) 2.40 - 2.45 (m, 1 H) 3.08 (s, 3 H) 3.76 (td, J = 11.81, 5.07 Hz, 1 H) 4.02 (td, J = 11.85, 5.17 Hz, 1 H) 6.53 (d, J = 7.61 Hz, 1 H) 7.45 - 7.64 (m, 4 H) 8.02 (d, J: 6.63 Hz, 1 H) 9.11 -‘ 9.26 (m, 1 H) 11.00— 11.13 (m, 1 H).
Example 3 4- ro hen |f|uorooxo ridin-1 2H meth n l~N~ tetrah dro—2H- ran lox butanamide The title compound (870 mg, 59.8%) was obtained as a solid from (4- chlorophenyl)boronic acid (610 mg, 4.36 mmol) using a procedure analogous to that described for (2R)-4—{5—fluoro—2-oxo[4-(2H-tetrazol-Z-yl)phenyl]pyridin-1(2H)—yl}-2— methyl(methylsu|fonyl)—N-(tetrahydro-2H—pyranyloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 502 (M+1). 1H NMR (400 MHz, DMSO-da) 6 ppm 1.17 - 1.28 (m, 2 H) 1.45 - 1.53 (m, 3 H) 1.56 (d, J = 3.71 Hz, 3 H) 1.60 — 1.72 (m, 3 H)2.08 - 2.23 (m, 1 H)3.07 (d, J = 6.44 Hz, 3 H) 3.48 (d, J = 11.12 Hz, 1 H) 3.67 - 3.85 (m, 1 H) 3.96 - 4.12 (m, 2 H) 4.88 — 4.97 (m, 1 H) 6.53 (d, J = 7.61 Hz, 1 H) 7.50 - 7.62 (m, 3 H) 8.00 (dd, J=13.07, 6.63 HZ, 1 H) 11.50 (s, 1 H).
WO 20397 Step B) 2R 4- 4-Chloro hen | f|uorooxo ridin-1 2H methyl-Z-(methylsulfonyl)butanamide The title nd (340 mg, 47.0%) was obtained as a solid from (2R)—4—[4—(4- phenyl)—5-f|uoro—2-oxopyridin-1(2H)~yl]-2—methyl(methylsulfonyl)—N—(tetrahydro— 2H—pyranyloxy)butanamide (870 mg, 1.74 mmol) using a procedure analogous to that described for (2R){5—fluoro—2—oxo-4—[4—(2H-tetrazol-2—yl)phenyl]pyridin—1 (2H)—y|}-N- hydroxy—Z-methyl-2—(methylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 417 (M +1).1H NMR (400 MHz, DMSO'de) 6 ppm 1.54 (s, 3 H) 2.13 (ddd, J: 13.12, 11.27, 5.07 Hz, 1 H) 2.37 - 2.45 (m, 1 H) 3.08 (s, 3 H) 3.76 (td, J = 11.90, 5.07 Hz, 1 H) 3.93 - 4.12 (m, 1 H) 6.53 (d, J = 7.61 Hz, 1 H) 7.49 - 7.66 (m, 4 H) 8.02 (d, J: 6.63 Hz, 1 H) 9.21 (s, 1 H) 10.95— 11.17 (m, 1 H).
Example 4 2R -4— 5—Fluoro-4— ridin-1 2H meth lsulfon |~N~ tetrah dro—2H- ran lox butanamide The title compound (230 mg, 81.7%) was ed as a solid from (2— fluorophenyl)boronic acid (122 mg, 0.871 mmol) using a procedure analogous to that described for (2R){5—fluoro—2-oxo—4—[4—(2H-tetrazolyl)phenyl]pyridin-1 (2H)-yl}—2~ methyl(methylsu|fonyl)—N~(tetrahydro-2H—pyranyloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 485 (M+1). 1H NMR (400 MHz, DMSO—de) 6 ppm 1.21 - 1.28 (m, 2 H) 1.48 - 1.56 (m, 3 H) 1.58 (d, J = 3.71 Hz, 3 H) 1.63 - 1.74 (m, 3 H) 2.15 - 2.26 (m, 1 H) 3.10 (d, J = 5.66 Hz, 3 H) 3.34 (br. s., 1 H) 3.51 (d, J: 10.73 Hz, 1 H) 3.71 - 3.88 (m, 1 H) 3.99 - 4.15 (m, 2 H) 4.94 - 4.99 (m, 1 H) 6.50 (d, J = 7.02 Hz, 1 H) 7.31 - 7.40 (m, 2 H) 7.46 - 7.53 (m, 1 H) 7.56 (m, J=7.76, 7.76, 5.56, 1.76 Hz, 1 H) 8.01 (dd, J: 11.90, 5.85 Hz, 1 H) 11.51 (d, J = 3.32 Hz, 1 H).
Step B) 2R 5—Fluoro—4— methyl-Z-(methylsulfonyl )butanamide W0 2012/120397 PCT/132012/050812 The title compound (68 mg, 36.0%) was obtained as a solid from (2R)[5-fluoro(2- fluorophenyl)—2-oxopyridin-1(2H)-yl]—2-methyl—2-(methylsulfonyl)-N-(tetrahyd ro-2H- pyranyloxy)butanamide (230 mg, 0.475 mmol) using a procedure analogous to that described for (2R)—4-{5-fluorooxo-4—[4—(2H-tetrazolyl)phenyl]pyridin-1(2H)—yl}-N— hydroxy—2-methyl—2-(methylsulfonyl)butanamide,--Example 1, Step C. MS (LCMS) m/z 401 (M+1). 1H NMR (400 MHz, DMSO-dg) 5 ppm 1.58 (s, 3 H)2.18 (td, J = 12.15, 4.98 Hz, 1 H) 2.47 (m, 1 H) 3.12 (s, 3 H) 3.79 (td, J = 11.85, 5.17 Hz, 1 H) 4.07 (td, J= 11.81, 4.68 Hz, 1 H) 6.50 (d, J = 7.02 Hz, 1 H) 7.30 - 7.44 (m, 2 H) 7.46 - 7.64 (m, 2 H) 8.04 (d, J = 6.05 Hz, 1 H) 9.20 - 9.32 (m, 1 H) 10.99 - 11.17 (m, 1 H).
Example 5 2 3—Dih drobenzofuran l —5-fluoro-2—oxo 0 Step A) (2R 2-meth l-2— meth lsulfon l—N- tetrah dro-2H- ran lox mide The title compound (198 mg, 61.0%) was obtained as a solid from 2,3—dihydro—1- uran—5—ylboronic acid (153 mg, 0.871 mmol) using a procedure analogous to that bed for (2R)—4—{5-fluoro—2-oxo-4—[4-(2H-tetrazolyl)phenyl]pyridin—1(2H)~yl} methyl—2—(methylsulfonyl)—N-(tetrahydro—2H—pyran-2—yloxy)butanamide,«Example 1, Step B. MS (LCMS) m/z 509 (M+1). 1H NMR (400 MHz, DMSO-ds) 5 ppm 1.46 - 1.56 (m, 2 H) 1.58 (d, J = 4.10 Hz, 3 H) 1.63 - 1.76 (m, 3 H)2.12 - 2.27 (m, 1 H) 2.40 - 2.48 (m, 1 H) 3.10 (d, J = 6.05 Hz, 3 H) 3.23 (t, J=8.78 Hz, 2 H) 3.35 (br. s, 1 H) 3.51 (d, J = 12.10 Hz, 1 H) 3.67 - 3.88 (m, 1 H) 3.98 - 4.15 (m, 2 H) 4.59 (t, J = 8.78 Hz, 2 H) 4.96 (d, J = 2.73 Hz, 1 H) 6.46 (d, J = 7.81 Hz, 1 H) 6.81 - 6.92 (m, 1 H) 7.28 - 7.39 (m, 1 H) 7.47 (s, 1 H) 7.96 (dd, J=12.78, 6.73 Hz, 1 H) 11.55 (s, 1 H).
Step B) 2R -4— 4- 2 3-Dih dro—1-benzofuran—5— l -5—f|uorooxo N—hydroxy-Z-methyl( methylsulfonyl )butanam ide The title compound (165 mg, 53.0%) was obtained as a solid from (2R)—4—[4-(2,3- dihydro—1-benzofuran-5—yl)—5—fluoro—2-oxopyridin-1(2H)-yl]~2-methyl-2—(methylsulfonyl)— PCT/IBZOlZ/OSOSIZ N-(tetrahydro-ZH-pyran-2—yloxy)butanamide (198 mg, 0.389 mmol) using a procedure ous to that described for (2R)—4-{5-f|uorooxo[4-(2H-tetrazol-Z- yl)phenyl]pyridin-1(2H)—yi}-N—hydroxy—2—methyl—2—(methylsulfonyl)butanamide,vExample 1, Step C. MS (LCMS) m/z 425 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.57 (s, 3 H) 2.16 (dd, J = 5.56, 1.07 Hz, 1 H) 2.36 - 2.49 (m, 1 H) 3.11 (s, 3 H) 3.23 (t, J = 8.59 Hz, 2 H) 3.66 — 3.86 (m, 1 H) 4.04 (dd, J = 6.15, 0.88 Hz, 1 H) 4.59 (t, J: 8.78 Hz, 2 H) 6.45 (d, J = 7.81 Hz, 1 H) 6.87 (d, J = 8.39 Hz, 1 H) 7.34 (dd, J = 820,195 Hz, 1 H) 7.46 (s, 1 H) 7.98 (d, J: 6.83 Hz, 1 H) 9.15-9.31 (m, 1 H) 11.01 — 11.19 (m, 1 H).
Example 6 3 4-Difluoro hen l fluoro—2-oxo meth Isulfon trah dro—2H— ran lox butanamide The title compound (760 mg, 52.1%) was obtained as a solid from (3,4- difluorophenyl)boronic acid (596 mg, 3.78 mmol) using a procedure analogous to that described for (2R)—4—{5-fluoro—2-oxo—4—[4—(2H—tetrazoI-Z—yl)phenyl]pyridin-1 (2H)—yl} methyl-2—(methylsuIfonyl)—N-(tetrahydro~2H~pyranyloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 503 (M+1).
Step B) 2R 4- 3 4—Difluoro hen | ~5~fluorooxo ridin-1 2H methyl-21 methylsulfonyl )butanamide The title compound (350 mg, 55.0%) was obtained as a solid from (2R)—4—[4—(3,4- rophenyl)—5-f|uoro-Z—oxopyridin-1(2H)-y|]-2—methyl(methylsulfonyl)—N- (tetrahydro-2H-pyran—2-yloxy)butanamide (760 mg, 1.51 mmol) using a procedure ous to that described for (2R)—4-{5—f|uoro-2—oxo—4-[4-(2H-tetrazol yl)phenyl]pyridin—1(2H)-y|}—N-hydroxy—2-methyl-2—(methylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 419 (M+1). 1H NMR (400 MHz, DMSO-o‘s) 5 ppm 1.57 (s, 3 H) 2.06 —2.25 (m, 1 H) 2.38 —— 2.48 (m, 1 H) 3.11 (s, 3 H) 3.68 — 3.87 (m, 1 H) 3.96 ~— W0 2012/120397 PCT/[32012/050812 4.18 (m, 1 H) 6.60 (d, J = 7.61 Hz, 1 H) 7.37 — 7.52 (m, 1 H) 7.52 — 7.65 (m, 1 H) 7.65 — 7.84 (m, 1 H) 8.06 (d, J = 6.63 Hz, 1 H) 9.13 — 9.39 (m, 1 H) 11.06 (s, 1 H).
Example 7 2 2 2—trifluoroethox 2-meth l-2— meth lsulfon l —N— tetrah dro-2H- ran lox butanamide The title compound (860 mg, 78.6%) was obtained as a solid from [4-(2,2,2- trifluoroethoxy)phenyl]boronic acid (554 mg, 2.52 mmol) using a procedure analogous to that bed for (2 R){5-fluorooxo[4-(2H~tetrazolyl)phenyl]pyridin-1 (2H)- yl}—2-methyI-2—(methylsulfonyl)-N-(tetrahydro—2H-pyranyloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 565 (M+1).
Step B) 5—FIuorooxo—4— 4~ 2 2 2—trifluoroethox N—hydroxy—Z-methyl-Z—lmethylsulfonyl )butanamide The title compound (310 mg, 42.3%) was obtained as a solid from (2R)~4—{5—fluoro oxo[4—(2,2,2-trifluoroethoxy)phenyl}pyridin-1(2H)—y|}-2~methyI(methylsulfonyl)-N~ (tetrahydro-2H-pyran-2—yloxy)butanamide (860 mg, 1.52 mmol) using a procedure analogous to that described for (2R)—4-{5-fluorooxo—4-[4-(2H-tetrazol nyl]pyridin-1(2H)-y|}-N~hydr0xy—2—methyl(methylsulfonyl)butanamide, e 1, Step C. MS (LCMS) m/z 419 (M+1). 1H NMR (400 MHz, DMSO-de) 5 ppm 1.54 (s, 3 H) 2.06 - 2.22 (m, 1 H) 2.37 — 2.45 (m, 1 H) 3.08 (s, 3 H) 3.74 (td, J= 11.76, 4.98 Hz, 1 H) 3.93 - 4.10 (m, 1 H) 4.81 (q, J = 8.98 Hz, 2 H) 6.49 (d, J = 7.61 Hz, 1 H) 7.16 (d, J = 8.98 Hz, 2 H) 7.49 - 7.62 (m, 2 H) 7.98 (d, J = 6.63 Hz, 1 H) 9.21 (br. s., 1 H) 11.07 (s, W0 2012/120397 PCT/[82012/050812 Example 8 3 4-Dih dro-2H-chromen-6— —5—fluoro—2—oxo meth l meth Isulfon l -N- tetrah dro—2H- ran-2— on butanamide The title compound (500 mg, 82.3%) was obtained as a solid from hydro-2H- chromenylboronic acid (228 mg, 1.28 mmol) using a procedure analogous to that described for (2R)—4—{5-fluoro—2-oxo[4-(2H—tetrazolyl)phenyl]pyridin-1(2H)—y|} methyl—2-(methylsu|fonyl)-N-(tetrahydro—2H-pyranyloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 523 (M+1).
Step B) 3 4-Dih dro—2H-chromen lfluoro-2—oxo ridin-1 2H N-hydroxy-Z—methyl( methylsulfonyl )butanamide The title compound (240 mg, 57.1%) was ed as a solid from (2R)—4—[4—(3,4— dihydro—2H-Chromen—6—yl)fluorooxopyridin-1(2H)—yl}—2~methyl—2-(methylsulfonyl)—N- (tetrahydro-2H—pyranyloxy)butanamide (500 mg, 0.957 mmol) using a procedure ous to that bed for (2R)-4—{5-fluoro—2-oxo[4-(2H-tetrazol yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy—2-methyl-2—(methylsulfonyl)butanamide, Example 1, Step C. MS (LCMS) m/z 439 (M+1). 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.52 (s, 3 H) 1.83 — 1.97 (m, 2 H) 2.12 (ddd, J = 13.03, 11.27, 5.17 Hz, 1 H) 2.34 - 2.44 (m, 1 H) 2.75 (t, J = 6.34 Hz, 2 H) 3.07 (s, 3 H) 3.71 (td, J = 11.76, 5.17 Hz, 1 H) 3.92 - 4.07 (m, 1 H) 4.08 — 4.20 (m, 2 H) 6.42 (d, J = 7.61 Hz, 1 H) 6.79 (d, J = 8.39 Hz, 1 H) 7.20 ~ 7.32 (m, 2 H) 7.94 (d, J = 6.83 Hz, 1 H) 9.20 (br. s., 1 H) 11.07 (s, 1 H).
Example 9 2R 5-Fluoro—4- 4- meth Ithio hen |oxo ridin—1 2H (methylsulfonyl)butanamide W0 2012/120397 Step A) methyl-24 methylsulfonyl )butanoate 1,4-Dioxane (10 ml) and 3 M aq K3PO4 (1.12 mL, 3.3 mmol) was added to a flask ning [4-(methylthio)phenyl]boronic acid (0.283 g, 1.68 mmol), Pd(dppf)Cl2 (82 mg, 0.112 mmol) and ethyl (2R)—4-(5-fluoro—4-iodo—2—oxopyridin-1(2H)-yl)—2-methyl—2— (methylsulfonyl)butanoate, T2, (500 mg, 1.12 mmol) that was usly flushed with nitrogen. The mixture was heated to 60 °C and stirred at this temperature for 1h. The reaction mixture was d with EtOAc and washed with water. The organics were dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography on a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%) to afford the title compound as a gum (492 mg, 99%). MS (LCMS) m/z 442.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.17 - 1.27 (m, 3 H) 1.74 (s, 3 H) 2.38 - 2.61 (m, 5 H) 3.09 (s, 3 H) 3.88 - 4.02 (m, 1 H) 4.17 - 4.32 (m, 3 H) 6.57 (d, J=7.61 Hz, 1 H) 7.21 - 7.34 (m, 3 H) 7.37 - 7.48 (m, 2 H).
Step B) (2R —4— 5—Fluoro—4- 4- meth Ithio hen loxo ridin—1 2H 2— meth lsulfon | butanoic acid Lithium hydroxide monohydrate (165 mg, 6.68 mmol) was added to a solution of ethyl (2R){5-fluoro[4-(methylthio)phenyl]—2—oxopyrid in-1 (2H )-yl}—2-m ethyl—2- (methylsulfonyl)butanoate (0.492 g, 1.12mmol) in THszater (1:1, 14 mL) and the reaction was allowed to stir at rt for 18 h. The reaction mixture was acidified using 4 M aq HCI to afford a precipitate. The solid was collected via filtration and dried under vacuum to afford the title compound as a solid (339 mg, 73%). MS (LCMS) m/z 414.1 (M+1). 1H NMR (400 MHz, 6)6 ppm 1.54 (s, 3 H) 2.17 (ddd, 2, 10.00, .07 Hz, 1 H) 2.41 - 2.45 (m, 1 H) 2.49 (s, 3 H), 3.14 (s, 3 H) 3.78 - 4.15 (m, 2 H) 6.46 (d, J=7.81 Hz, 1 H) 7.28 - 7.39 (m, 2 H) 7.43 - 7.55 (m, 2 H) 8.01 (d, J=6.83 Hz, 1 H).
Step C) 2R 5-Fluoro-4— 4— meth lthio hen l 2— meth Isulfon trah dro—2H- ran on butanamide W0 2012/120397 PCT/IBZOIZ/OSOSIZ N,N-Diisopropylethylamine (450 uL, 2.45 mmol), O-(tetrahydro-ZH-pyran—Z— yl)hydr0xylamine (192 mg, 1.64 mmol) and HATU (447 mg, 1.23 mmol) were added to a solution of (2R){5—fluoro[4-(methylthio)phenyl]—2-oxopyridin-1(2H)—yl}-2—methyI-2— lsulfonyl)butanoic acid (339 mg, 0.82 mmol) in DMF (10 mL). The reaction was d to stir at rt for 18 h. The reaction mixture was diluted with EtOAc and washed with brine. The organics were dried ), filtered and concentrated. The crude residue was purified via flash chromatography using a 40 g silica column and an eluent of EtOAc in n—heptane (0-100%) to afford the title compound (420 mg, 100%). MS (LCMS) m/z 511.4 (M1).
Step D) 5-FIuoro 4— meth Ithio hen | hydroxv—Z-methvl—Z—gmethvlsulfonyl)butanamide Aqueous HCI (4 M, 3 mL) was added to a solution of 2R)—4-{5-f|uoro—4—[4- (methylthio)phenyl]—2~oxopyridin-1 (2H)—y|}—2-methyl(methylsulfonyl)-N-(tetrahydro— an—2-yloxy)butanamide (437 mg, 0.852 mmol) in THF (10 mL) and the reaction was allowed to stir at rt for 3 h. The reaction mixture was concentrated and then azeotroped with EtOAc and n—heptane several times to give the title compound as an ite solid (233 mg, 64%). MS (LCMS) m/z 429.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) 6 ppm 1.69 (s, 3 H) 2.37 (ddd, J=13.51, 10.59, 5.17 Hz, 1 H) 2.51 (8,3 H) 2.57 - 2.74 (m, 1 H) 2.82 (s, 3 H) 3.09 (s, 3 H) 3.97 (ddd, J=13.12, 10.59, 5.56 Hz, 1 H) 4.27 (ddd, J=13.03, 10.49, 5.17 Hz, 1 H) 6.68 (d, J=7.22 Hz, 1 H) 7.25 - 7.40 (m, 2 H) 7.47 - 7.59 (m, 2 H) 7.90 (d, J=6.05 Hz, 1 H).
Example 10 4~Ethox hen lfluorooxo (methylsulfonyl )butanamide MeOZS / NWNHOH \ o Step A) -4— 4- 4-ethox hen lfluoro—2-oxo ridin—1 2H - lmeth [- 2-(methylsulfonvl)butanoate The title compound (320 mg, 64%) was obtained as a gum from (4- ethoxyphenyl)boronic acid (280 mg, 1.68 mmol) using a procedure analogous to that described for ethyl (2R){5-fluoro-4—[4-(methylthio)phenyl]oxopyridin-1(2H)-y|} methyl(methylsuIfonyl)butanoate, Example 9, Step A. MS (LCMS) m/z 440.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 1.22 (t, J=7.12 Hz, 3 H) 1.40 (t, J=7.02 Hz, 3 H) 1.73 (s, 3 H) 2.36 — 2.61 (m, 2 H) 3.09 (s, 3 H) 3.85 - 3.98 (m, 1 H) 4.07 (dd, J=14.93, 7.12 Hz, 2 H) 4.25 (m, 3 H) 6.51 - 6.58 (m, 1 H) 6.93 (d, J=8.98 Hz, 3 H) 7.22 — 7.31 (m, 1 H) 7.44 (d, J=7.02 Hz, 1 H).
Step B) -5—fluoro—2-oxo ridin-‘l 2H (methylsulfonyl )butanoic acid Lithium hydroxide (108 mg, 4.37 mmol) was added to a solution of ethyl (2R)—4-[4—(4~ ethoxyphenyl)f|uoro-2—oxopyridin-1(2H)—yl]—2—methyl~2~(methylsulfonyl)butanoate (320 mg, 0.728 mmol) in tetrahydrofuranmater (1:1, 20 mL) and the reaction was allowed to stir at rt until te. The reaction mixture was acidified with 4 M aq HCI and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as a solid (220 mg, 73%). MS (LCMS) m/z 412.2 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.26 - 1.40 (m, 3 H) 1.54 (s, 3 H) 2.07 - 2.26 (m, 1 H) 2.43 (d, J=6.24 Hz, 1 H) 3.14 (s, 3 H) 3.83 - 4.15 (m, 4 H) 6.42 (d, J=7.81 Hz, 1 H) 6.93 - 7.07 (m, 2 H) 7.50 (dd, , 1.85 Hz, 2 H) 7.97 (d, J=6.83 Hz, 1 H).
Step C) -5—fluorooxo ridin-1 2H lsulfonyl etrahydro-2H—pyran—2-yloxy)butanamide The title compound (273 mg, 100%) was obtained from (2R)—4—[4-(4-ethoxyphenyl)—5— fluorooxopyridin-1(2H)-yl]—2-methyl(methylsulfonyl)butanoic acid (220 mg, 0.535 mmol) using a procedure ous to that described for —{5-fluoro—4-[4— (methylthio)pheny|}oxopyridin—1 (2H)-y|}methyl—2-(methylsulfonyl)—N-(tetrahydro- 2H-pyran-2—yloxy)butanamide, Example 9, Step C. MS (LCMS) m/z 509.4 (M+1).
Step D) 2R 4- 4-Ethox hen l fluoro-2—oxo methyl( methylsulfonyl )butanamide The title compound (205 mg, 83%) was obtained as a solid from (2R)—4-[4-(4- ethoxyphenyl)fluorooxopyridin-1(2H)-yl]methyl(methylsu|fony|)-N—(tetrahydro- 2H—pyranyloxy)butanamide (297 mg, 0.582 mmol) using a procedure analogous to that described for (2R)—4-{5-fluoro-4—[4-(methylthio)phenyl]—2-oxopyridin—1(2H)—yl}-N— hydroxy—2—methyl-2—(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z 427.2 (M+1). 1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.40 (t, J=6.93 Hz, 3 H) 1.69 (s, 3 H) 2.28 - 2.42 (m, 1 H) 2.54 - 2.69 (m, 1 H) 3.09 (s, 3 H) 3.86 - 3.99 (m, 1 H) 4.09 (q, J=7.02 Hz, 2 H) 4.18 — 4.32 (m, 1 H) 6.60 (d, J=7.42 Hz, 1 H) 7.01 (d, J=8.98 Hz, 2 H) 7.54 (dd, J=8.78, 1.56 Hz, 2 H) 7.82 (d, J=6.24 Hz, 1 H).
Example 11 Step A) 2R 5-FIuoro—2—oxo—4- 4- ro meth Isulfon l-N- tetrah dro—2H- ran on butanamide The title compound (75.5 mg, 21%) was obtained as a solid from (2R)(5-fluoro iod opyridin—1 (2H)-y|)—2-methyl-2—(methylsulfonyl)—N-(tetrahyd pyran yloxy)butanamide, T3. (360 mg, 0.697 mmol) and (4-propylphenyl)boronic acid (171 mg, 1.04 mmol) using a procedure analogous to that described for ethyl (2R)—4-{5- fluoro[4-(methylthio)phenyl]—2~oxopyridin-1(2H)—yl}-2—methyl-2— (methylsulfonyl)butanoate, Example 9, Step A. MS (LCMS) m/z 507.4(M—1).
Step B) -Z-(methylsulfonyl)butanamide The title compound (58 mg, 94%) was obtained as a solid from (2R)[5-f|uoro—2-oxo (4-propylphenyl)pyridin-1(2H)-yl]—2-methyl(methylsulfonyI)—N—(tetrahydro-2H—pyran yloxy)butanamide (75 mg, 0.15 mmol) using a procedure analogous to that described for (2R)—4—{5-fluoro—4—{4—(methylthio)phenyl]-2—oxopyridin-1(2H)—yl}-N-hydroxy—2-methyl— 2-(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z 425.2 (M+1). 1H NMR (400 MHz, METHANOL—d4) 5 ppm 0.89 - 1.00 (m, 3 H) 1.57 - 1.76 (m, 5 H) 2.29 — 2.45 (m, 1 H) 2.55 - 2.69 (m, 3 H) 3.09 (s, 3 H) 3.86 - 4.04 (m, 1 H) 4.17 - 4.34 (m, 1 H) 6.63 (d, J=7.02 Hz. 1 H) 7.31 (d, J=8.00 Hz, 2 H) 7.44 - 7.55 (m, 2 H) 7.85 (d, J=5.85 Hz, 1 H).
W0 2012/120397 Example 12 uoro-GA-sulfan l Step A) 2R 5-Fluoro—2-oxo—4— 4— lmeth l—2- meth Isulfon l—N~ tetrah dro-2H— ran yloxy)butanamide 1,4-Dioxane was added to 1-bromo—4-(pentafluoro-6A-su|fanyl)benzene (500 mg, 1.77 mmol), 4,4,4',4',5,5,5',5'—octamethyl—2,2'-bi—1,3,2-dioxaborolane (628 mg, 2.47 mmol), potassium acetate (347 mg, 3.53 mmol) and Pd(dppf)Cl2 (130 mg, 0.177 mmol). The mixture was heated to 80 °C and stirred at this temperature for 3 h. (2R)(5-fluoro—4- iodo—2—oxopyridin—1(2H)—yI)—2-methyl(methylsulfonyl)-N—(tetrahydro—2H-pyran yloxy)butanamide, T3, (456 mg, 0.883 mmol) and aq Na2C03 (2.0 N, 1.77 mL, 3.53 mmol) were added and the reaction was d at 80 °C overnight. The mixture was diluted with EtOAc and washed with brine. The organics were dried (M9804), filtered, and trated. The crude residue was purified via flash chromatography using a 40 g silica column and an eluent of EtOAc in n-heptane (0—100%) to afford the title compound (205 mg, 39.2%). MS(LCMS) m/z 591.4 (M-1).
Step B) 5-Fluoro—2—oxo~4- 4- entafluoro-BA—sulfan l vi t—N-hyd roxv—Z—methyI-Z-i methylsulfonyl )butanamide Aqueous HCl (1.0 M) was added to a solution of (2R)—4—{5-fluorooxo-4—[4— fluoro-6A-su|fany|)phenyl]pyridin~1(2H)—yl}-2—methyl(methylsulfonyl)—N- (tetrahydro-2H—pyran—2—yloxy)butanamide (81 mg, 0.14 mmol) and the reaction was stirred at rt overnight. The reaction was concentrated in vacuo to afford the title compound as a solid (70 mg, 100%). MS(LCMS) m/z 509.1 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.58 (s, 3 H) 2.06 — 2.26 (m, 1 H) 3.11 (8,3 H) 3.70 — 3.89 (m, 1 H) 3.97 - 4.14 (m, 1 H) 6.64 (d, J=7.41 Hz, 1 H) 7.81 (d, 2 H) 8.04 (d, J=8.78 Hz, 2 H) 8.11 (d, J=6.44 Hz, 1 H).
PCT/IBZOlZ/050812 Example 13 5-Fluoro 3-meth l hen | ridin-1 2H meth lsulfon l-N- tetrah dro-2H- ran-2— lox butanamide The title compound (510 mg, 55%) was obtained as a gum from (3— methylphenyl)boronic acid (384 mg, 2.82 mmol) using a procedure analogous to that bed for (2R)—4-{5-fluorooxo[4-(2H-tetrazol—2-yl)phenyl]pyridin-1(2H)—yl} methyl-2—(methylsulfonyl)—N-(tetrahydro—2H-pyran-2—yloxy)butanamide, e 1, Step B. MS (LCMS) m/z 479.4 (M1).
Step B) —Z-(methylsulfonyl)butanamide The title compound (255 mg, 61%) was obtained as a solid from (2R)—4—[5—fluoro(3- methylphenyl)—2—oxopyridin-1(2H)-yl]methyl-2—(methylsulfonyl)-N-(tetrahydro—2H— pyranyloxy)butanamide (510 mg, 1.06 mmol) using a procedure analogous to that described for (2R)~4-{5-fluoro—4-[4-(methylthio)phenyl]oxopyridin—1(2H)—yl}-N— hydroxy-2—methyI(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z 397.1 (M+1). 1H NMR (400 MHz, METHANOL—d4) 5 ppm 1.70 (s, 3 H) 2.28 - 2.44 (m, 4 H) 2.62 (dd, J=10.44, 5.37 Hz, 1 H) 3.09 (s, 3 H) 3.96 (ddd, J=12.98, 10.63, 5.46 Hz, 1 H) 4.19 — 4.35 (m, 1 H) 6.64 (d, J=7.22 Hz, 1 H) 7.27 - 7.45 (m, 4 H) 7.88 (d, J=5.85 Hz, 1 H).
Example 14 5-FIuoro—4- 4-quorometh l hen I—2—oxo ridin-1 2H 2-{methylsulfonyl )butanamide M9028 0‘ / NWNHOH Step A) (2R 5-Fluoro—4— meth l meth lsulfon l-N- tetrah — ran—2- lox mide The title compound (360 mg, 38%) was obtained as a gum from (4-flu0ro—3— methylphenyl)boronic acid (434 mg, 2.82 mmol) using a procedure analogous to that described for (2R){5-fluoro—2-oxo-4—[4-(2H—tetrazolyl)phenyl]pyridin—1(2H)—yl} methyl(methylsulfonyl)—N-(tetrahydro-2H-pyranyloxy)butanamide, Example 1, Step B. MS (LCMS) m/z 497.0 (M-1).
Step B) 2R ~4- 5-Fluoro-4— 4-fluoro—3—meth l hen l oxo ridin-1 2H hydroxy-Z-methyl-2—lmethylsulfonyl )butanamide The title nd (271 mg, 91%) was obtained as a white solid from (2R)—4-[5-fluoro— 4-(4-fluor0methylpheny|)oxopyridin-1(2H)-yl]methyl(methylsulfonyl)—N- (tetrahydro—ZH—pyran—2—yloxy)butanamide (360 mg, 0.722 mmol) using a procedure analogous to that described for (2R)—4—{5-fluoro—4-[4-(methylthio)phenyl]oxopyridin- 1(2H)—yl}—N-hydroxy—2-methyl—2-(methylsulfonyl)butanamide, Example 9, Step D. MS (LCMS) m/z 415.1 (M+1). 1H NMR (400 MHz, DMSO—ds) 6 ppm 1.54 (s, 3 H) 2.13 (ddd, 2, 11.17, 4.98 Hz, 1 H) 2.26 (s, 3 H) 2.40 — 2.45 (m, 1 H) 3.08 (s, 3 H) 3.75 (td, J=11.85, 5.17 Hz, 1 H) 4.02 (td, J=11.85, 4.98 Hz, 1 H) 6.49 (d, J=7.61 Hz, 1 H) 7.20 - 7.28 (m, 1 H) 7.38 — 7.45 (m, 1 H) 7.50 (d, J=7.41 Hz, 1 H) 8.01 (d, J=6.63 Hz, 1 H).
Example 15 -Fluoro—1- ' meth Isulfon l but l 4- oxetan—3- lox hen l ridin-21H -one M8028 “‘x‘ / NWNHOH \ O Step A) 3-(4-Bromoghenoxy)oxetane W0 2012/120397 4-Bromophenol (2.59, 14.5 mmol) and K2C03 (5.459, 39.4 mmol) were added to a solution of oxetanyl 4-methylbenzenesulfonate (3.009, 13.1 mmol) in DMF (10 mL) in a sealed tube. The reaction was heated to 100 °C and stirred at this temperature for 24 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried (M9804), filtered and concentrated to afford the title compound. MS (GCMS) m/z 228. This material was used in subsequent steps without r purification.
Step B) 4,4,5,5—Tetramethy|—2~|4-(oxetan—3-yloxylphenyll—1,3,2—dioxaborolane The title compound (3.11 g, 86%) was obtained from 3-(4—bromophenoxy)oxetane (3.00 g, 13.1 mmol) using a procedure ous to that bed for 2—[4-(4,4,5,5— tetramethyl-1,3,2-dioxaborolan—2—yl)phenyI]—2H-tetrazole, Example 1, Step A. MS (GCMS) m/z 276. 1H NMR (400 MHz, FORM-d) 6 ppm 1.31 (s, 12 H) 4.70 - 4.79 (m, 2 H) 4.91 - 5.00 (m, 2 H) 5.18 ~ 5.27 (m, 1 H) 6.67 (d, J=8.78 Hz, 2 H) 7.73 (d, J=8.78 Hz, 2 H).
Step C) 5-Fluoro5(3R)—3-(methylsulfonyl11(tetrahydro-ZH—pyran-Z- lox amino but I 4- oxetan-S- on hen | ridin-2 1H -one 1,4—Dioxane (20 mL) and water (5 mL) were added to a flask containing (2R)—4-(5— fluoroiodo—2-oxopyridin—1 (2H)—yl)methyl-2—(methylsulfonyl)—N-(tetrahydro—2H- pyran-2~yloxy)butanamide, T3 (287 mg, 0.56 mmol), 4,4,5,5—tetramethyl—2—[4-(oxetan-3— yloxy)phenyl]-1,3,2—dioxaborolane (301 mg, 1.09 mmol), Pd(PPh3)4 (65 mg, 0.06 mmol), and potassium carbonate (230 mg, 1.67 mmoi), which was previously flushed with N2.
The mixture was heated to 80 °C and stirred at that ature overnight. The on was concentrated and purified via flash chromatography using two 12 g silica gel columns. The first column was eluted with methanol in romethane (0-20%). The second column was eluted with EtOAc in n-heptane (0-100%) ed by methanol in dichloromethane (0-20%) to afford the title compound as a solid (164 mg, 54%). MS (LCMS) m/z 537.4 (M-1).
Step D) 5-Fluoro oxetan—3— yloxy)phenyligyridin-2( 1 H z-one Trifluoroacetic acid (1 mL) was added to a solution of 5-fluoro{(3R)—3- (methylsulfonyl)—3-[(tetrahydro-2H-pyran—2-yloxy)amino]butyl}[4—(oxetan yloxy)phenyl]pyridin-2(1H)—one (164 mg, 0.304 mmol) in DCM (10 mL). The reaction was allowed to stir at rt overnight and then concentrated under vacuum. The residue W0 2012/120397 was re-dissolved in dichloromethane and n—heptane and concentrated again to afford the title compound as a solid. (113 mg, 82%). MS (LCMS) m/z 455.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.69 (s, 3 H) 2.35 (ddd, 6, 10.63, 5.17 Hz, 1 H) 2.53 - 2.67 (m, 1 H) 3.09 (s, 3 H) 3.91 (ddd, J=12.98, 10.63, 5.27 Hz, 1 H) 4.16 - 4.30 (m, 1 H) 4.69 (dd, J=7.51, 4.78 Hz, 2 H) 5.02 (t, J=6.73 Hz, 2 H) 5.33 (t, J=5.46 Hz, 1 H) 6.58 (d, J=7.42 Hz, 1 H) 6.85 - 6.91 (m, 2 H) 7.55 (dd, J=8.68, 1.85 Hz, 2 H) 7.80 (d, J=6.24 Hz, 1 H).
Example 16 4—Chloro-2—fluoro hen l -5—fluoro—2—oxo ridin—1 2H methyl-Z-(methylsulfonyl)butanoic acid To a 3 L flask with mechanical stirring was added ethyl (2R)(5-fluoro-4—iodo—2- oxopyridin-1(2H)-yl)—2-methyl(methylsulfonyl)butanoate, T2 (100 g, 225 mmol), (4— chloro—2-fluorophenyl)boronic acid (25.5 g, 146 mmol) and Pd(dppf)2C12 (4.93 g, 6.74 mmol). The flask was purged with N2, then degassed 2-methyltetrahydrofuran (1 L) and 3 M aq K3PO4 (225 mL, 674 mmol) were added. The reaction mixture was heated to 75 °C and d at this temperature for 30 min. Additional (4—chloro—2— fluorophenyl)boronic acid (25.5 g, 146 mmol) was added and the reaction was allowed to heat for 1.5 h. The e was allowed to cool to rt and the aqueous layer was separated. The organic layer was passed through a celite pad and placed back in the reaction vessel. Lithium hydroxide (28 g, 667 mmol) in water (700 mL) was added and the mixture was heated to 50 °C and stirred at this temperature for 1 h. The mixture was allowed to cool and the aqueous layer separated. Celite was added to the s layer and the mixture was filtered through a plug of celite. The filtrate was placed in a flask with ad stirrer and carefully acidified with 4 M aq HCI and heated to 50 0C with ng until a precipitate formed. The solid was collected via filtration and dried under vacuum to afford the title compound as a tan solid (68.7 g, 74%). MS (LCMS) m/z 2012/050812 420.5 (M+1). 1H NMR (400 MHz, DMSO-de) 5 ppm 1.54 (s, 3 H) 2.18 (ddd, J=13.17, .24, 5.07 Hz, 1 H) 2.41 - 2.45 (m, 1 H) 3.10 - 3.19 (s, 3 H) 3.87 - 4.08 (m, 2 H) 6.47 (d, J=7.02 Hz, 1 H) 7.42 (dd, J=8.39, 1.95 Hz, 1 H) 7.48 - 7.55 (m, 1 H) 7.30 (dd, J=9.95, 1.95 Hz, 1 H) 8.06 (d, J=6.05 Hz, 1 H).
Step B) 2R 4- 4—Chlorofluoro hen | -5—fluoro—2-oxo ridin—1 2H methyl—2—( methylsulfonyl )—N-(tetrahyd ro-2H—pyra nyloxy )butanam ide N—Methylmorpholine (54 mL, 491 mmol) and 2-chioro-4,6~dimethoxy—1,3,5—triazine (43.1 g, 245 mmol) were added to a solution of (2R)—4—[4-(4—chloro—2-fluoropheny|) 1O fluoro~2~oxopyridin-1(2H)—yl}—2-methyl—2-(methylsulfonyl)butanoic acid (68.7 g, 164 mmol) in 2-methyltetrahydrofuran (1 L) and the reaction was stirred at rt for 2 h. 0- (Tetrahydro-ZH—pyranyl)hydroxylamine (28.8 g, 245 mmol) was added and the reaction was d to stir at rt for 1 h. The mixture was filtered and the filtrate was concentrated. The crude e was purified via column chromatography using silica gel and eluting with 40% EtOAc in n-heptane (4L) and EtOAc (6L). The desired fractions were combined and concentrated to afford the title compound as a white gummy solid. (74.829, 88%). MS (LCMS) m/z 517.9 (M-1).
Step C) 2R -4— 4- 4-Chlorofluoro hen | —5-fluorooxo ridin-1 2H v-Z-methyI-Z—i methylsulfonyl amide Water (312 mL) and 1 N aq HCl (23.9 mL, 23.9 mmol) were added to a solution of (2R)— 4-[4-(4-chloro-2—fluorophenyl)fluoro—2—oxopyridin—1(2H)—yl]-2—methyl (methylsu|fonyl)—N-(tetrahydro—2H-pyran-2~yloxy)butanamide (74.7 9,144.1 mmol) in l (126 mL). The reaction was heated to 70 °C and stirred at this temperature overnight. The reaction was allowed to cool and the solid was collected via filtration and washed with water until the filtrate had a pH of ~5. The solid was dried under vacuum to afford the title compound as a white solid (46.48 g, 74%). MS (LCMS) m/z 435.6 (M+1). 1H NMR (400 MHz, DMSO-de) 5 ppm 1.56 (s, 3 H) 2.09 - 2.21 (m, 1 H) 2.44 (d, J=5.27 Hz, 1 H) 3.10 (s, 3 H) 3.77 (td, J=11.90, 5.07 Hz, 1 H) 4.04 (td, 5, 4.98 Hz, 1 H) 6.51 (d, J=7.02 Hz, 1 H) 7.44 (dd, J=8.29, 2.05 Hz, 1 H) 7.50 - 7.56 (m, 1 H) 7.62 (dd, J=9.95, 1.95 Hz, 1 H) 8.04 (d, J=5.85 Hz, 1 H) 9.22 (s, 1 H) 11.05 (s, 1 H).
Example 17 -fluoro 2-fluoro—3—methox hen | oxo methyl-21 methylsulfonyl )butanamide PCT/IBZOlZ/050812 Step A) methyl-Z-(methylsulfonyl oic acid 1,1'-Bis(diphenylphosphino)ferrocene-palladium(ll)dich|oride dichloromethane complex (5.90 g, 7.22 mmol) was added to a mixture of ethyl (2R)(5-fluoro-4—iodo-2— oxopyridin—1(2H)-yl)—2-methyl—2-(methylsulfonyl)butanoate, T2 (29.63 g, 66.55 mmol), (2—fluoro—3—methoxyphenyl)boronic acid (18.50 g, 108.9 mmol) and ium phosphate tribasic (54.5 g, 205 mmol) in 2~methyltetrahydrofuran (450 mL) and deionized water (225 mL). The mixture was heated to 60 °C and stirred at this temperature overnight. The reaction was allowed to cool to rt. The aqueous layer was separated from the organics and the organics were washed with water (200 mL) and brine (200 mL), dried ), and filtered. Darco® G-60 —100 mesh, powder was added to the filtrate and was stirred for 1 h. Solids were removed via filtration over celite and the filtered pad was washed with EtOAc (~300 mL). The combined tes were concentrated to afford a red oil (30.62 g). The oil was dissolved in 2- methyltetrahydrofuran (450 mL) and deionized water (225 mL). ium hydroxide (26.1 g, 465 mmol) was added to the mixture and the reaction was heated to 50 °C and stirred at this temperature overnight. The reaction was allowed to cool to rt. The 2O s layer was separated and washed with diethyl ether (2x200 mL). The aqueous layer was slowly acidified while stirring using concentrated HCl to a pH of 1 and the suspension was stirred for 1 h. The suspension was filtered and the solids were washed with water (3x100 mL) and hexanes (3x300 mL). The solids were dried in vacuo to afford the title compound as a tan solid (26.49 g, 94.54%). MS (LCMS) m/z 416.0 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.57 (s, 3 H) 2.14 — 2.28 (m, 0 H) 2.42 - 2.54 (m, 1 H) 3.18 (s, 3 H) 3.88 (s, 3 H) 3.90 — 4.09 (m, 2 H) 6.44 (d, J=7.03 Hz, 1 H) 6.92 - 7.04 (m, 1 H) 7.20 - 7.36 (m, 2 H) 8.06 (d, J=5.95 Hz, 1 H) 13.90 (br. s., 1 H).
Step B) 2R 5-Fluoro—4— 2-fluoromethox hen | methyl( sulfonyl z-N—(tetrahydro—2H—pyran-2—yloxy )butanamide N—Methylmorpholine (11 mL, 96.2 mmol) was added to a solution of CDMT (13.5 g, 116 mmol) and (2R)—4-[5-fluoro—4—(2-fluoromethoxyphenyl)—2-oxopyridin—1(2H)—yl]-2— PCT/IBZOIZ/OSOSIZ methyl(methylsulfonyl)butanoic acid (26.49 g, 63.77 mmol) in 2- methyltetrahydrofuran (640 mL) and the reaction was stirred for 2 h. THP- hydroxylamine (13.5 g. 116 mmol) was added to the reaction and the reaction was stirred overnight at rt. The reaction was quenched with saturated aqueous sodium bicarbonate (500 mL). The organic layer was separated and washed with water (300 mL) and brine (300 mL), then dried (M9804), and filtered. Darco G-60,-100 mesh, powder was added to the filtrate and the sion was d for 1 h. The charcoal was removed via tion through a celite pad and the filter pad was washed with EtOAc (1 L). The filtrate was concentrated to afford the title compound as a yellowish- 1O white solid (30.49, 92.93%). MS (LCMS) m/z 513.9 (M-1).
Step C) 2R ro-4— 2—fluoro—3—methox hen l hydroxy-Z—methyl( methvlsulfonyl )b uta namide Pyridinium p—toluenesulfonate (190 mg, 0.76 mmol) was added to a solution of (2R)—4— [5-fluoro-4—(2—fluoromethoxyphenyl)oxopyridin-1 (2H )-yl]methyl (methylsulfonyl)-N-(tetrahydro—2H-pyranyloxy)butanamide (777 mg, 1.51 mmol) in ethanol (15 mL). The reaction was heated to 50 °C and stirred at this ature overnight. Additional pyridinium p—toluenesulfonate (118 mg, 0.47 mmol) was added to the solution and the reaction was heated at 60 °C for 3 h. The reaction was allowed to cool to rt and the precipitate was collected via filtration. The solid was washed with ethanol (15 mL) and hexanes (15 mL) and dried in vacuo to afford the title compound as a white solid (413 mg, 63.5%). MS (LCMS) m/z 431.0 (M+1). 1H NMR (400 MHz, s) 6 ppm 1.57 (s, 1 H) 2.08 — 2.25 (m, 0 H) 2.41 — 2.56 (m, 1 H) 3.02 ~ 3.19 (m, 3 H) 3.71 - 3.85 (m, 1 H) 3.88 (s, 3 H) 3.98 - 4.13 (m, 1 H) 6.47 (d, J=7.02 Hz, 1 H) 6.93 - 7.08 (m, 1 H) 7.19 ~ 7.36 (m, 2 H) 8.04 (d, J=5.66 Hz, 1 H) 9.24 (d, J=1.56 Hz, 1 H) 11.07 (d, J=1.56 Hz, 1 H).
Example 18 W0 2012/120397 PCT/IBZOlZ/050812 Step A) Eth | 4- tetrah dro—2H- ran lox c clohexanecarbox late Pyridinium-4—toluenesulfonate (2.57 g, 10.2 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxyiate (8.8 g, 51.10 mmol) and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL) and the reaction was stirred at rt for 16 h. The reaction was quenched with saturated aq NaHCOs. The layers were separated and the organic layer was washed with water. The organic layer was dried (Na2804), ed, and concentrated. Purification via flash tography on a 200 g silica column using an eluent of EtOAc in hexanes (5-10%) afforded the title compound as a clear oil (11.1 g, 85%).
Step B) -(Tetrahydro-2H-gyranyloxy)cyclohexyllmethanol and (+l-Htrans- 4- tetrah dro-2H- ran lox c clohex | methanol Sodium borohydride (3.69 g, 97.5 mmol) was added to a solution of ethyl 4-(tetrahydro— 2H-pyranyloxy)cyclohexanecarboxylate (2.50 g, 9.75 mmol) in ethanol (100 mL) at 0 °C. The reaction was allowed to warm to rt as the ice bath expired. After 2 days the reaction was cooled to 0 °C and quenched by the addition of 1 N aq HCl until the effervescence ceased, pH 5—6. The reaction was concentrated and the resulting residue was ioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried (M9804), filtered, and concentrated. Purification on a silica gel 100g column and an eluent of EtOAc in hexanes (10—40%) afforded the two sets of enantiomers as clear oils. +/- — cis-4— tetrah dro—2H- ran—2- on c clohex nol (387 mg, 18%). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.30 — 1.65 (m, 12 H) 1.64 — 1.76 (m, 1 H) 1.76 ~ 1.94 (m, 3 H) 3.33 - 3.64 (m, 3 H) 3.80 - 4.01 (m, 2 H) 4.59 - 4.75 (m, 1 H). +/- -trans tetrah - ran-2— lox c clohex nol (824, 39.4%) 1H NMR (400 MHz, CHLOROFORM—d) 6 ppm 0.86 -1.11 (m, 2 H) 1.16 - 1.31 (m, 1 H) 1.31 - 1.64 (m, 7 H) 1.64 — 1.77 (m, 1 H) 1.78 - 1.93 (m, 3 H) 1.99 - 2.14 (m, 2 H) 3.35 - 3.67 (m, 4 H) 3.80 — 4.04 (m, 1 H) 4.63 - 4.79 (m, 1 H).
Step C) 2—|(trans§l4-(4,4,5,5-Tetramethyl-1,3,2—dioxaborolan—2— yl )ph en oxylmethyltcycloh exyl )oxyltetra hyd ro-2H-eran W0 2012/120397 Diisopropyl azodicarboxylate (2.1 mL, 10.5 mmol) was added to a solution of [trans (tetrahydro-2H-pyran-2—yloxy)cyclohexyl]methanol (2.05 g, 9.57 mmol), 4-(4,4,5,5- tetramethyl—1,3,2-dioxaborolanyl)phenol (2.3 g, 10.7 mmol), triphenylphosphine (2.76 g, 10.5 mmol), and triethylamine (1.5 mL,10.5 mmol) in THF (150 mL) at 0°C. The reaction was allowed to warm to rt and stirred overnight. Water (200 mL) was added and the reaction was extracted with EtOAc (600 mL). The organics were washed with 1 M aq NaOH (4x100 mL), brine, then dried (Na2804), filtered and concentrated under reduced re. The crude residue was purified via flash chromatography using an eluent of 20% EtOAc in hexanes to afford the title compound as a white solid (1.9 g, 1O 48%). MS (APCI) m/z 417.3 (M+1).
Step D) Eth l 2R —4— 5-fluoro-2—oxo 4— trans-4— tetrah dro-2H- lox c clohex lmethox hen | ridin-1 2H - l—2—meth l (methylsulfonyl )butanoate Pd(dppf)Cl2 (350 mg, 0.431 mmol) was added to a solution of ethyl (2R)—4—(5—fluoro iodooxopyridin-1(2H)-y|)methy|—2—(methylsuIfonyl)butanoate (1.6 g, 3.6 mmol), 2— [(trans{[4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2— yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (1.9 g, 4.49 mmol), and ium phosphate tribasic (2.9 g, 10.8 mmol) in 2-methyl tetrahydrofuran/water (5:1, 240 mL). The reaction mixture was heated to 80 °C and d at this temperature for 16 h. The reaction was allowed to cool to rt, and water (50 mL) was added. The mixture was ted with EtOAc (3x150 mL). The ed organic phases were dried (Na2804), filtered, and concentrated under reduced pressure to afford the title compound as a light tan solid (1.4 g, 64%). MS (LCMS) m/z 608.2 (M+1). lox c clohex l methox - hen l ridin—1 2H - l -2—meth l (methylsulfonyl )butanoic acid Aqueous lithium hydroxide (2.0 M, 5.8 mL, 2.3 mmol) was added to a solution of ethyl (2R)[5-fluoro—2-oxo-4—(4-{[trans—4—(tetrahydro—2H-pyran—2—yloxy)cyclohexyl]methoxy}— phenyl)pyridin-1(2H)-y|]methyl(methylsulfonyl)butanoate (1.4 g, 2.3 mmol) in ethanol (40 mL). The reaction was heated to 50 °C for 3 h. The reaction was allowed to cool to ambient temperature and then acidified to a pH of ~3 with 1.0 N aq. HCl. The mixture was ted with EtOAc (3x150 mL). The ed organic phases were W0 2012/120397 PCT/IBZOIZIOSOSIZ dried 4), filtered, and concentrated under reduced pressure to afford the title compound as a white solid (1.28 g, 98%). MS (LCMS) m/z 580.3 (M+1).
Step F) 2R 5-Fluoro—2-oxo-4— 4- lox c clohex Imethox — hen I ridin—1 2H - lmeth l-2— (methylsulfonyl)—N-§tetrahvdro—2H-pvran-2—vloxy)butanamide N—Methyl line (340 uL, 3.09 mmol) was added to a suspension of (2R)—4-[5- fluoro—2~oxo~4-(4—{[trans—4—(tetrahyd ro—2H-pyran-2—yloxy)cyclohexyl]methoxy}- phenyl)pyridin—1(2H)-yl]—2-methyl—2—(methylsulfonyl)butanoic acid (1.28 g, 2.21 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (510 mg, 2.87 mmol) in yltetrahydrofuran (30 mL) and the reaction was stirred for 1 h at rt. O-(Tetrahydro-2H-pyran—2— yl)hydroxylamine (61 mg, 0.52 mmol) was added, and the reaction was stirred overnight at rt. Water (50 mL) was added, and the mixture was extracted with EtOAc (3x150 mL).
The combined organic phases were dried (NaZSO4), ed, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane 0%) to afford the title compound as a light brown residue (700 mg, 46%). MS (LCMS) m/z 677.4 (M+1).
Step (3) (2R )|5—fluoro—4-§4-l (transhyd roxycyclohexyl )methoxvlghenylt-Z- oxopyridin—1(2H)-vli-N-hydroxy—Z-methyl-Z-gmethylsulfonyl)butanamide Hydrochloric acid (4.0 M in 1,4-dioxane, 1.7 mL, 6.63 mmol) was added to a solution of (2R)—4—[5-fluoro—2—oxo—4-(4—{[trans—4-(tetrahydro-2H-pyran~2- yloxy)cyclohexyl]methoxy}phenyl)—pyridin—1 (2H )~y|]~2-methyl—2—(methylsulfonyl)—N- (tetrahydro—2H-pyranyloxy)butanamide (450 mg, 0.66 mmol) in 1,4- dioxane:DCM:water (22:1, 5 mL) at room ature. After 1 h, the reaction was concentrated under reduced re. The crude residue was triturated in ethanol (10 mL) overnight. The solid was collected via filtration, washed with ethanol (5 mL), and dried under reduced pressure to afford the title compound as a white solid (110 mg, 33%). MS (LCMS) m/z 511.1 (M+1). 1H NMR (400 MHz, DMSO-ds) 6 ppm 0.97 - 1.19 (m, 4 H) 1.54 (s, 3 H) 1.58 - 1.72 (m, 1 H) 1.72 - 1.89 (m, 4 H) 2.04 - 2.23 (m, 1 H) 2.41 (m, 1 H) 3.08 (s, 3 H) 3.18 - 3.40 (m, 1 H) 3.65 - 3.84 (m, 3 H) 4.01 (td, J=11.61, 4.88 Hz, 1 H) 4.49 (br. s., 1 H) 6.45 (d, J=7.81 Hz, 1 H) 6.94 - 7.06 (m, 2 H) 7.36 - 7.54 (m, 2 H) 7.96 (d, J=6.83 Hz, 1 H) 9.21 (s, 1 H) 11.07 (s, 1 H) 11.12 (s, 1 H). 2012/050812 Example 19 -Fluoro—4- ro—4-methox hen | meth l—2— meth lsulfon l—N- tetrah dro-2H- ran—2— lox butanamide Pd M (580 mg, 0.17 mmol) was added to a mixture of potassium ate (723 mg, 5.2 mmol), romethoxyphenyl)boronic acid (318 mg, 2.1 mmol), and (2R)—4- (5-fluoro—4—iodooxopyridin-1(2H)-yl)methyl—2-(methylsulfonyl)-N—(tetrahydro—2H- pyranyloxy)butanamide, T3, (900 mg, 1.7 mmol) in 1,4-dioxanezwater (5:1, 24 mL).
The reaction was heated to 80 °C and allowed to stir at this temperature overnight. The reaction was filtered through a pad of celite, which was washed with methanol (250 mL).
The filtrate was concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in heptanes 0%), then 10% methanol in EtOAc to provide the title compound as a light tan residue (800 mg, 99%). MS (LCMS) m/z 495.1 (M1).
Step B) 2R 5—Fluoro 3-fluoromethox hen | hydroxy—Z—methyl-Z—l methylsulfonyl )butanamide The title compound (400 mg, 58%) was obtained as a solid from (2R)—4-[5-fluoro(3- fluoromethoxyphenyl)—2-oxopyridin-1 (2H)-yl}methyl(methylsulfonyl)—N- (tetrahydr0—2H-pyranyloxy)butanamide (800 mg, 1.65 mmol) using a procedure analogous to that described for the preparation of (2R)-4—[5-fluoro—4-{4—[(trans hyd roxycyclohexyl)methoxy]phenyl}-2—oxopyridin-1 (2H)—yl]—N—hydroxy-2—methyl-2— (methylsulfonyl)butanamide, Example 18, Step G. M8 (LCMS) m/z 413.1 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.54 (s, 3 H) 2.06 - 2.18 (m, 1 H) 2.38 - 2.47 (m, 1 H) 3.08 (s, 3 H) 3.74 (td, J=12.00, 4.88 Hz, 1 H) 3.87 (s, 3 H) 4.02 (td, J=11.85, 4.98 Hz, 1 H) 6.52 (d, J=7.81 Hz, 1 H) 7.21 — 7.31 (m, 1 H) 7.34 — 7.51 (m, 2 H) 7.99 (d, J=6.83 Hz, 1 H) 9.20 (s, 1 H)11.06 (br. s, 1 H).
W0 2012/120397 e 20 rimidin—2- Step A) 2— 4— 4 4 5 5—Tetrameth M 3 2-dioxaborolan-2— | hen l rimidine A degassed solution of 2-bromopyrimidine (1.5 g, 9.4 mmol), 2,2'—(1,4— phenylene)bis(4,4,5,5-tetramethyI—1,3,2-dioxaborolane) (5.1 g, 16.0 mmol), 1.0 M aq K3PO4 (28.3 mL, 28.3 mmol), and Pd(PPh3)4 (330 mg, 0.31 mmol) in DMF (140 mL) was heated to 80 °C and stirred at this temperature for 16 h. Water (100 mL) was added to the reaction mixture and was extracted with EtOAc (3x200 mL). The ed organic phases were dried (Na2S04), filtered, and trated under reduced pressure. The crude al was purified via flash chromatography using an eluent of 17% EtOAc in n—heptane to afford the title compound as a white solid (0.7 g, 28%). MS (LCMS) m/z 283.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.36 (s, 12 H) 7.19 (t, J=4.68 Hz, 1 H) 7.93 (d, J=8.00 Hz, 2 H) 8.43 (d, J=7.81 Hz, 2 H) 8.81 (d, J=4.68 Hz, 2 H).
Step B) Eth I 2R 5-Fluoro—2-oxo—4- methyl—2-( methylsulfonyl )butanoate The title compound (278 mg, 87%) was obtained as a light tan solid from 2—[4—(4,4,5,5— tetramethyl-1,3,2—dioxaborolan—2-yl)phenyl]pyrimidine (270 mg, 0.94 mmol) and ethyl (2R)—4-(5-fluoroiodo—2—oxopyridin-1(2H)-yl)—2—methyl-2—(methy|sulfonyl)butanoate, T2, (300 mg, 0.67 mmol) using a procedure analogous to that described for the ation of ethyl (2R)—4—[5-fluoro-2—oxo—4-(4-{[trans(tetrahydro-2H—pyran—2— yloxy)cyclohexyl]methoxy}phenyl)pyridin-1 (2H)—yl]—2-methyl-2— (methylsulfonyl)butanoate, Example 18, Step D. MS (LCMS) m/z 474.2 (M+1).
Step C) 2R —4— 5-FIuoro—2-oxo-4— methyl-Z-(methylsulfonyl)butanoic acid W0 2012/120397 The title compound (250 mg, 98%) was ed as a light brown gum from ethyl (2R)- 4-[5-fluor0oxo-4—(4-pyrimidinylphenyl)pyridin-1(2H)~yl]-2—methyl (methylsulfonyl)butanoate (270 mg, 0.57 mmol) using a procedure analogous to that described for the ation of -[5-fluoro—2—oxo-4—(4—{[trans(tetrahydro-2H- pyran—2-yloxy)cyclohexy|]methoxy}-phenyl)pyridin-1(2H)—yl]—2—methyl—2- (methylsulfonyl)butanoic acid, Example 18, Step E. MS (LCMS) m/z 446.1 (M+1). 1H NMR (400 MHz, OL-d4) 6 ppm 1.73 (s, 3 H) 2.39 - 2.51 (m, 1 H) 2.62 - 2.75 (m, 1 H) 3.17 (s, 3 H) 4.20 - 4.46 (m, 2 H) 6.86 (d, J=7.02 Hz, 1 H) 7.65 (t, J=5.07 Hz, 1 H) 7.83 (d, J=7.02 Hz, 2 H) 8.09 (d, J=5.85 Hz, 1 H) 8.53 (d, J=8.39 Hz, 2 H) 9.06 (d, 1O J=4.88 Hz, 2 H).
Step D) 2R 5-Fluoro—2—oxo-4— methyl—24 methylsulfonyl )—N-(tetrahyd ro-2H—gyranyloxy)butanamide The title compound (290 mg, 94%) was obtained as a light brown gum from (2R)[5- fluoro-2—oxo—4—(4-pyrim idinylphenyl )pyridin—1 (2H )—yl]m ethyl (methylsulfonyl)butanoic acid (250 mg, 0.56 mmol) and O-(tetrahydro-2H—pyran yl)hydroxylamine (87 mg, 0.74 mmol) using a procedure analogous to that described for the preparation of (2R)—4—[5-f|uoro—2—oxo—4—(4-{{trans(tetrahydro—2H—pyran y|oxy)cyclohexyl]methoxy}—phenyl)pyridin-1(2H)-yl]methyl(methylsulfonyl)-N- hydro-2H-pyran-Z—yloxy)butanamide, Example 18, Step F. MS (LCMS) m/z 543.0 (M+1).
Step E) 2R 5-Fluorooxo 4- ‘ ' ' ridin-1 2H hydroxy—2-methyIgmethylsulfonyl)butanamide The title compound (80 mg, 30%) was obtained as a tan solid from (2R)—4-[5—fluoro—2- oxo(4—pyrimidinylpheny|)pyridin-1(2H)-yl]—2-methyl—2—(methylsu|fonyl)-N- (tetrahydro-2H—pyranyloxy)butanamide (312 mg, 0.57 mmol) using a procedure analogous to that described for the preparation of (2R)[5-f|uoro—4-{4—[(trans hyd roxycyclohexyl)methoxyiphenyl}oxopyridin-1 (2H)—yl]—N-hydroxy—2—methyI 3O (methylsulfonyl)butanamide, Example 18, Step G. M8 (LCMS) m/z 461.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) 6 ppm 1.70 (s, 3 H) 2.31 - 2.45 (m, 1 H) 2.56 - 2.71 (m, 1 H) 3.10 (s, 3 H) 3.87 -4.01 (m, 1 H)4.19 - 4.33 (m, 1 H) 6.70 (d, J=7.42 Hz, 1 H) 7.38 (t, J=4.88 Hz, 1 H) 7.73 (dd, J=8.59, 1.76 Hz, 2 H) 7.87 (d, J=6.05 Hz, 1 H) 8.53 (d, J=8.59 Hz, 2 H) 8.87 (d, J=4.88 Hz, 2 H).
W0 2012/120397 PCT/[32012/050812 Step A) 5—Methox 4- 4 4 5 5-tetrameth M 3 2-dioxaborolan—2— | hen I rimidine The title compound (700 mg, 17%) was obtained as a white solid from 2-chloro methoxypyrimidine (1.85 g, 12.8 mmol) and 2,2‘—(1,4—phenylene)bis(4,4,5,5—tetramethyl- 1,3,2-dioxaborolane) (6.9 g, 21.0 mmol) using a procedure analogous to that described for the preparation of 2-[4-(4,4,5,5-tetramethyl—1,3,2—dioxaborolan yl)phenyl]pyrimidine, Example 20, Step A. MS (LCMS) m/z 313.1 (M+1). 1H NMR (400 MHz, CHLOROFORM—d) 6 ppm 1.33 (s, 12 H) 3.93 (s, 3 H) 7.83 - 7.90 (m, 2 H) 8.28 — 8.34 (m, 2 H) 8.45 (s, 2 H).
Step B) 2R —4— 5-Fluoro 4— 5—methox 1 2H — lmeth l—2— meth lsulfon l—N- tetrah dro—2H- ran—2— yloxy)butanamide The title compound (900 mg, 95%) was obtained as a tan solid from oxy-2—[4- (4,4,5,5—tetramethyl—1,3,2-dioxaborolan—2—yl)phenyl]pyrimidine (719 mg, 2.3 mmol) and (2R)—4-(5—fluoro—4-iodo-2—oxopyridin-1 (2H )-y|)—2-m ethyl-2—(methylsu|fonyl)-N-(tetrahydro- an-2—yloxy)butanamide, T3, (850 mg, 1.65 mmol) using a procedure analogous to that described for the preparation of (2R)—4—[5-fluoro(3-fluoro—4-methoxyphenyl)—2- oxopyridin-1(2H)-yl]methyl—2—(methylsulfonyl)-N—(tetrahydro-2H-pyran yloxy)butanamide, Example 19 Step A. MS (LCMS) m/z 573.2 (M+1).
Step C) 1(2H )-yl t-N-hydroxy—Z-methyl-M methylsulfonyl )butanamide The title nd (50 mg, 6%) was obtained as a light brown solid from -{5— fluoro—4—[4—(5—methoxypyrimidinyl)phenyl]—2—oxopyridin-1(2H)-yl}methyl—2— PCT/IBZOlZ/050812 (methylsulfonyl)-N-(tetrahydro—2H-pyranyloxy)butanamide (900 mg, 1.57 mmol) using a procedure analogous to that described for the preparation of (2R)—4—[5—fluoro{4- [(trans-4—hydroxycyclohexyl)methoxy]phenyl}oxopyridin—1(2H)—yl]-N-hydroxy—2— methyl(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 491.1 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.53 (s, 3 H) 2.08 - 2.19 (m, 1 H) 2.39 — 2.48 (m, 1 H) 3.07 (s, 3 H) 3.69 - 3.78 (m, 1 H) 3.92 (s, 3 H) 3.96 - 4.08 (m, 1 H) 6.56 (d, J=7.71 Hz, 1 H) 7.67 (m, J=8.70, 2.00 Hz, 2 H) 8.01 (d, J=6.54 Hz, 1 H) 8.34 - 8.38 (m, 2 H) 8.64 (s, 2 H) 9.19 (br. d, J=1.80 Hz, 1 H) 11.04 (br. d, J=1.90 Hz, 1 H). e 22 h drox ~2-meth l meth lsulfon lbutanamide Step A) 2— 4-Bromo hen I -4—methox -2H—1 2 3-triazole Cesium carbonate (4.5 g, 13.7 mmol) was added to a solution of 2-(4-bromophenyl)—2H- 1,2,3-triazoI—4-ol (1.1 g, 4.6 mmol) and methyl iodide (0.36 mL, 5.7 mmol) in THF (50 mL). The on was heated to 60 °C and stirred at this temperature for 16 h. Water (20 mL) was added to the reaction, and the resulting mixture was extracted with EtOAc (2x150 mL). The combined organic phases were dried over potassium carbonate, filtered, and trated under reduced re to afford the title compound as a tan solid (1.1 g, 95%). 1H NMR (400 MHz, METHANOL-d4) 5 ppm 3.98 (s, 3 H) 7.39 (s, 1 H) 7.55 - 7.62 (m, 2 H) 7.79 - 7.86 (m, 2 H).
Step B) 4—Methoxy—2-l4—(4,4,5,5-tetramethyI-1,3,2-dioxaborolan-2—yl)phenyll-ZH- 1 2 3-triazole Pd(dppf)C|2 (0.71 g, 0.87 mmol) was added to a mixture of 2-(4-bromophenyi) methoxy-2H-1,2,3-triazole (1.1 g, 2.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl—2,2’-bi-1,3,2- orolane (1.3 g, 5.2 mmol), potassium acetate (1.3 g, 13.0 mmol), in 2-methyl tetrahydrofuran2water (5:1, 60 mL). The reaction was heated to 80 °C and stirred at this temperature for 16 h. The reaction was allowed to cool to rt, and water (50 mL) was PCT/IBZOIZ/OSOSIZ added. The on was filtered through celite, which was washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure, and the resulting crude material was purified by flash chromatography using an eluent of EtOAc in n—heptane (10—60%) to afford the title compound as a light tan solid (1.2 g, 92%). MS (LCMS) m/z 302.3 (M+1). 1H NMR (400 MHz, METHANOL—d4) 5 ppm 1.33 (s, 12 H) 4.01 (s, 3 H) 7.40 (s, 1 H) 7.78 — 7.84 (m, 2 H) 7.88 - 7.95 (m, 2 H).
Step C) 1O 2-yloxy)butanamide The title nd (1.15 mg, 88%) was obtained as tan solid from 4-methoxy—2—[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyll-2H—1,2,3-triazole (0.98 g, 1.4 mmol) and (2R)—4-(5-fluoro—4—iodo-2—oxopyridin-1(2H)-y|)—2-methyl(methylsulfonyl)-N— (tetrahydro—2H-pyran-2—yloxy)butanamide, T3, (1.2 g, 2.3 mmol) using a procedure ous to that described for the preparation of (2R)—4—[5-fluoro(3-fluoro—4- methoxyphenyl)oxopyridin-1(2H)—yl]—2-methyl-2—(methylsulfonyl)-N-(tetrahydro-2H- pyranyloxy)butanamide, Example 19 Step A. MS (LCMS) m/z 562.0 (M+1).
Step D) 2O oxopyridin—1 (2H )—yl t—N—hydroxy—Z—methyl-Z-g methylsulfonyl )butanamide The title compound (700 mg, 70%) was obtained as a light tan solid from (2R)—4-{5— fluoro[4-(4-methoxy-2H-1,2,3-triazol—2-yl)phenyl]oxopyridin-1(2H)—yl}-2—methyl (methylsulfonyl)-N—(tetrahydro-2H—pyran-2—yloxy)butanamide (1.15 g, 2.04 mmol) using a procedure analogous to that described for the preparation of (2R)~4-[5-fluoro{4- [(trans—4-hydroxycyclohexyl)methoxy]phenyl}oxopyridin—1(2H)—yl]—N-hydroxy—2— methyl(methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 480.2 (M+1). 1H NMR (400 MHz, 5) 6 ppm 1.53 (s, 3 H) 2.07 - 2.18 (m, 1 H) 2.39 - 2.48 (m, 1 H) 3.06 (s, 3 H) 3.69 — 3.77 (m, 1 H) 3.95 (s, 3 H) 3.97 - 4.08 (m, 1 H) 6.54 (d, J=7.62 Hz, 1 H) 7.65 - 7.73 (m, 2 H) 7.75 (s, 1 H) 7.90 - 7.98 (m, 2 H) 8.03 (d, J=6.64 3O Hz, 1 H) 11.06 (br. s., 1 H).
Example 23 2R 5—Flu0ro—4- 4— 4-meth l—2H-1 2 3-triazol-2— hyd roxy-Z-methyl( methylsulfonyl )butanamide PCT/132012/050812 M8028 ‘0 / NWNHOH \ o ‘U‘’N Step A) 4—Meth l—2— 4- 4 4 5 5-tetrameth H 3 2-dioxaborolan-2~ I hen l —2H- 1 2 3-triazole Pd(dppf)C|2 ( 592 mg, 0.718 mmol) was added to a solution of ium acetate (705 mg, 7.18 mmol), 2-(4—bromophenyl)methyl-2H—1,2,3-triazole ( 600 mg, 2.52 mmol), and 4,4,4‘,4',5,5,5‘,5'-octamethyl-2,2'—bi-1,3,2-dioxaborolane (729 mg, 2.87 mmol) in 1,4-dioxane (20 mL). The on was heated to 80 °C and stirred at this temperature for 16 h. The reaction was filtered through celite, and the filter pad was washed with to EtOAc (150 mL). The combined filtrates were concentrated under reduced pressure, and the crude material was purified via flash chromatography using EtOAc in n—heptane (10-60%) to afford the title compound as a light tan solid (720 mg, 98%). MS (LCMS) m/z 286.2 (M+1). 1H NMR (400 MHz, OL-d4) 6 ppm 1.32 (s, 12 H) 2.36 (s, 3 H) 7.66 (s, 1 H) 7.77 - 7.84 (m, 2 H) 7.92 - 8.00 (m, 2 H).
Step B) 1(2 H )—yl i—2—methyl—2—g methylsulfonyl )—N-(tetra hyd ro—2H—pyran yloxy)butanamide The title compound (0.99 g, 98%) was obtained as a tan gum from 4-methyl(4— (4,4,5,5~tetramethyl—1,3,2-dioxaborolanyl)phenyl)—2H-1,2,3-triazole (0.70 g, 2.4 mmol) and (2R)—4-(5-f|uoroiodo—2-oxopyridin-1(2H)-yl)—2-methyl(methylsulfonyl)—N- (tetrahydro—2H-pyran-2—yloxy)butanamide, T3, (0.90 g, 2.0 mmol) using a procedure analogous to that bed for the ation of (2R)[5~fluoro(3—fluoro—4- methoxyphenyl )—2-oxopyridin-1 (2H )-yl]—2—methyl(methylsulfonyl)-N-(tetrahydro-2H- pyran—2—yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 546.5 (M+1).
Step C) 1(2H )—yl t-N-hydroxy—Z-methyl-Zl methylsulfonyl )butanamide The title compound (450 mg, 53%) was ed as a tan solid from (2R){5-fluoro [4-(4-methyl-2H—1,2,3-triazol—2-yl)phenyl}-2—oxopyridin-1(2H)—yl}—2-methyl-2— (methylsulfonyl)—N—(tetrahydro—2H—pyranyloxy)butanamide (0.99 g, 1.81 mmol) using a procedure analogous to that described for the preparation of (2R)-4—[5—fluoro—4-{4— PCT/IBZOIZ/050812 [(transhydroxycyclohexyl)methoxy]phenyl}oxopyridin-1(2H)-yl]-N-hydroxy methyl(methylsulfonyl)butanamide, Example 18, Step G. M8 (LCMS) m/z 464.2 (M+1). 1H NMR (400 MHz, DMSO—de) 5 ppm 1.53 (s, 3 H) 2.06 - 2.20 (m, 1 H) 2.33 (br. s, 3 H) 2.38 - 2.49 (m, 1 H) 3.06 (s, 3 H) 3.68 - 3.80 (m, 1 H) 3.90 - 4.11 (m, 1 H) 6.55 (d, J=7.61 Hz, 1 H) 7.65 - 7.76 (m, 2 H) 7.90 (br. s, 1 H) 7.96 - 8.10 (m, 2 H) 11.05 (br. s., 1 H).
Example 24 ~4~ 5-Fluoro—2-oxo-4— uinoxalin | (methylsulfonyl)butanamide M9028 ‘0 / NWNHOH N \ o L\ o meth Isulfon l-N— tetrah dro—2H- ran-2— on butanamide The title compound (480 mg, 95%) was obtained as a light brown gum from 6-(4,4,5,5- tetramethyl—1,3,2-dioxaborolanyl)quinoxaline (347 mg, 1.36 mmol) and (2R)(5- fluoro-4—i0do-2—0X0pyridin—1 (2H)-yl)methyl(methylsu|fonyl)-N-(tetrahydro—2H- pyranyloxy)butanamide, T3, (500 mg, 0.97 mmol) using a ure analogous to that described for the ation of (2R)—4—[5-fluoro—4-(3-fluoro—4-methoxyphenyl)-2— oxopyridin—1(2H)-yl]methyl(methylsulfonyl)-N-(tetrahyd ro-2H-pyran yloxy)butanamide, Example 19 Step A. MS (LCMS) m/z 517.1 (M+1).
Step B) 5-Fluoro—2-oxo uinoxalin l ridin-1 2H methyl-Z-(methylsulfonyl)butanamide The title compound (110 mg, 28%) was obtained as a light tan solid from (2R)(5— oxoquinoxalinylpyridin—1(2H)-yl)-2—methyl-2—(methylsulfonyl)-N- (tetrahydro—2H—pyran—2-yloxy)butanamide (0.48 g, 0.93 mmol) using a ure analogous to that described for the preparation of (2R)[5-fluoro{4-[(trans hydroxycyclohexyl)methoxy]phenyl}—2-oxopyridin—1(2H)—yl]—N-hydroxymethyI (methylsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 433.2 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.54 (s, 3 H) 2.09 - 2.19 (m, 1 H) 2.44 — 2.52 (m, 1 H) 3.07 (s, 3 H) 3.73— 3.84 (m, 1 H)4.04 (m, 1 H) 6.71 (d, J=7.61 Hz, 1 H) 7.99 (dt, , 1.96 Hz, 1 H) 8.06 - 8.10 (m, 1 H) 8.17 (d, J=8.78 Hz, 1 H) 8.28 (t, J=1.71 Hz, 1 H) 8.89 - 9.05 (m, 2 H) 9.20 (br. s., 1 H) 11.03 (br. s., 1 H).
Example 25 —4— 5—Fluoro—4— 3-methox hen l meth lsulfon l-N—tetrah dro—2H- ran lox butanamide The title compound (800 mg, 99%) was otained as a light tan gum from (3- methoxyphenyl)boronic acid (318 mg, 2.09 mmol) and (2R)(5-fluoro—4—iodo—2— oxopyridin—1(2H)-yl)methyl(methylsulfonyI)-N-(tetrahydro—2H-pyran yloxy)butanamide, T3, (900 mg, 1.74 mmol) using a procedure analogous to that bed for the preparation of (2R)—4-[5-fluoro-4—(3-fluoro—4-methoxyphenyl) oxopyridin—1(2H)-y|]methyl—2-(methylsulfonyl)-N-(tetrahyd ro—2H-pyran-2— yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 495.1 (M+1).
Step B) 2R -4— 5-Fluoro—4- 3—methox hen I ridin-1 2H methyl-Z—(methylsulfonyl )butanamide The title compound (400 mg, 58%) was obtained as a tan solid from (2R)—4-[5—fluoro—4— (3—methoxyphenyI)—2—oxopyridin—1 (2H )-yl}-2—methyl(methylsu |fonyl)-N—(tetrahyd ro—2H- 2-yloxy)butanamide (0.82 g, 1.65 mmol) using a procedure analogous to that described for the preparation of (2R)[5-fluoro—4—{4—{(trans hydroxycyclohexy|)methoxy]phenyl}-2—oxopyridin-1 (2H)-yl]-N-hydroxy—2-m ethyl lsulfonyl)butanamide, Example 18, Step G. MS (LCMS) m/z 413.1 (M+1). 1H NMR (400 MHZ, DMSO-de) 6 ppm 1.52 (s, 3 H) 2.05 — 2.18 (m, 1 H) 2.36 - 2.50 (m, 1 H) 3.06 (s, 3 H) 3.66 — 3.78 (m, 4 H) 3.95 - 4.08 (m, 1 H) 6.50 (d, J=7.61 Hz, 1 H) 6.98 - 7.11 (m, 3 H) 7.32 - 7.40 (m, 1 H) 7.98 (d, J=6.54 Hz, 1 H) 9.18 (br. s., 1 H) 11.04 (s, 1 PCT/IBZOIZ/OSOSIZ Example 26 2H-1 2 3-triazol {1:31 Step A) 2— 4- 4 4 5 5—Tetrameth H 3 2-dioxaborolan—2— l hen l —2H-1 2 3-triazole Pd(dppf)Cl2 (280 mg, 0.343 mmol) was added to a mixture of 2-(4-bromophenyl)—2H- 1,2,3-triazole (255 mg, 1.14 mmol), 4,4,4‘,4',5,5,5',5‘-octamethy|—2,2'—bi-1,3,2— 1O dioxaborolane (350 mg, 1.38 mmol), and potassium acetate (340 mg, 3.46 mmol) in 1,4— dioxane (10 mL). The reaction was heated to 80 °C and stirred at this temperature overnight. The reaction was d to cool to rt and was diluted with EtOAc (30 mL) and brine (30 mL). The mixture was filtered through celite, and the organic layer was separated from the filtrate. The aqueous layer was extracted with EtOAc (2x30 mL) and the organics were combined, dried (M9804), filtered and concentrated. The crude material was ed via flash tography using an Analogix 29 column and an eluent of EtOAc in n-heptane (O-10%) to afford the title compound as an orange solid (240.6 mg, 78.0%). MS (LCMS) m/z 272.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.37 (s, 12 H) 7.83 (s, 2 H) 7.94 (d, 2 H) 8.10 (d, J=8.59 Hz, 2 H).
Step B) —4~ 5-fluorooxo—4— 4— 2H—1 2 3~triazol-2— | 1 (2H 2-yl tmethyI-2—g sulfonyl )butanoate Pd(dppf)C|2 (484 mg, 0.59 mmol) was added to a mixture of ethyl (2R)—4-(5-fluoro iodo—2-oxopyridin-1(2H)—y|)—2-methyl-2—(methylsulfonyl)butanoate, T2, (2.20 g, 4.94 mmol), 2—[4-(4,4,5,5-tetramethyl—1,3,2—dioxaborolan—2-yl)phenyl]—2H-1,2,3-triazole (2.01 g, 7.41 mmol), and potassium phosphate (3.95 g, 14.8 mmol) in 2- methyltetrahydrofuran (200 mL) and deionized water (40 mL). The reaction was heated to 60 °C and was vigorously stirred at this temperature overnight. The on was diluted with EtOAc (100 mL) and water (100 mL) and was ed through a celite pad (~1 inch). The filter pad was washed with EtOAc (100 mL) and the filtrates were combined. The aqueous layer was separated and was extracted with EtOAc (2x100 W0 2012/120397 PCT/132012/050812 mL). The combined organics were washed with brine (100 mL), dried (M9804), filtered and concentrated. The crude material was purified via flash chromatography using a Varian SF25-40g column and an eluent of EtOAc in hexanes (30-100%) to afford the title compound as a yellow solid (1.54 g, 67.4%). MS (LCMS) m/z 463.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 5 ppm 1.23 (t, 3 H) 1.62 (s, 3 H) 2.18 - 2.32 (m, 1 H) 2.52 — 2.66 (m, 1 H) 3.16 (s, 3 H) 3.92 ~ 4.07 (m, 2 H) 4.08 - 4.24 (m, 2 H) 6.59 (d, J=7.81 Hz, 1 H) 7.72 - 7.84 (m, 2 H) 8.10 (d, J=6.63 Hz, 1 H) 8.12 — 8.17 (m, 2 H) 8.18 (s, 2 H).
Step C) 5-Fluoro—2-oxo ' ridin-1 2H 1O 2-meth l-2— meth lsulfon l ic acid Potassium hydroxide (1.30 g, 23.2 mmol) was added to a solution of ethyl (2R)—4-{5— fluorooxo—4—[4-(2H-1 ,2,3-triazol—2-yl)phenylipyridin—1(2H)-y|}methyl-2— lsulfonyl)butanoate (1.54 g, 3.33 mmol) in 2-methyltetrahydrofuranzwater (2::1 42.5 mL) and the solution was d at rt overnight. Methanol (5 mL) was added and the reaction was heated to 60 °C. The reaction mixture was stirred at this temperature for 2 h. The reaction was trated and triturated in 3 M aq HCI. The solid was collected via tion and washed with water (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.39 g, 96.1%).
MS (LCMS) m/z 435.0 (M+1). 1H NMR (400 MHz, DMSO-de) 5 ppm 1.58 (s, 3 H) 2.13 - 2.30 (m, 0 H) 2.41 - 2.61 (m, 1 H) 3.17 (s, 3 H) 3.89 — 4.13 (m, 2 H) 6.59 (d, J=7.81 Hz, 1 H) 6.56 - 6.63 (m, 1 H) 7.79 (dd, J=8.78, 1.76 Hz, 3 H) 8.09 (d, J=6.83 Hz, 1 H) 8.12 — 8.17 (m, 2 H) 8.19 (s, 2 H).
Step D) 2R —4- 5-Fluoro—2-oxo-4— 2—meth l—2- meth lsulfon l -N— tetrah dro—2H- ran—2- lox butanamide N-Methylmorpholine (540 uL, 4.9 mmol) was added to a solution of CDMT (750 mg, 4.27 mmol) and (2R)—4-{5—fluoro—2-oxo~4-[4—(2H-1 ,2,3-triazol-2—yl)phenyl]pyridin-1(2H)- yl}—N—hydroxy-2—methyl(methylsulfonyl)butanoic acid (1.39 g, 3.20 mmol) in 2- methyltetrahydrofuran (30 mL) and the reaction was stirred for 1 h at rt. rahydro— 2H-pyranyl)hydroxylamine (670 mg, 5.72 mmol) was added to the reaction and the reaction was stirred overnight at rt. The reaction was quenched with saturated aq NaHCO3 (100 mL) and the aqueous layer was extracted with EtOAc (3x100 mL). The combined cs were washed with brine (100 mL), dried (M9804), filtered and concentrated. The crude product was purified via flash chromatography using a Varian W0 2012/120397 SF25-409 column and eluent of EtOAc in hexanes (30-100%) to afford the title nd as a white solid (1.53 g, 89.6%). MS (LCMS) m/z 532.2(M-1).
Step E) 5-FIuoro—2—oxo 4- 2H-1 2 3—triazol | ridin—1 2H N-hydroxymethyl—2—( methylsulfonyl )butanamide Pyridinium p—toluenesulfonate (360 mg, 0.50 mmol) was added to a solution of (2R)—4— {5-fluoro—2—oxo—4-[4-(2H-1,2,3-triazol-2—yl)phenyl]pyridin-1(2H)—yl}methyl—2— lsu|fony|)—N-(tetrahydro—2H-pyran—2-yloxy)butanamide (1.53 g, 2.87 mmol) in l (60 mL). The solution was heated to 70 °C and was stirred at this temperature for 3 h. The reaction was allowed to cool and was d at rt for three days. The solid was collected via filtration, washed with ethanol (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.05 g, 81.5%). MS (LCMS) m/z 450.0 (M+1), 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.58 (s, 3 H) 2.08 - 2.27 (m, 0 H) 2.38 - 2.59 (m, 1 H) 3.12 (s, 3 H) 3.72 — 3.90 (m, 1 H) 4.00 — 4.17 (m, 1 H) 6.62 (d, J=7.61 Hz, 1 H) 7.70 - 7.88 (m, 2 H) 8.08 (d, J=6.63 Hz, 1 H) 8.12 - 8.18 (m, 2 H) 8.19 (s, 2 H) 9.25 (d, J=1.95 Hz, 1 H) 11.09 (d, J=1.76 Hz, 1 H).
Example 27 —Fluoro 2-fluoro—4—methox hen | meth | meth lsulfon I-N- tetrah dro—2H- ran on butanamide The title compound (1.5 g, 94%) was obtained from oro—4—methoxypheny|)boronic acid (737 mg, 4.34 mmol) and (2R)(5-f|uoro—4—iodo—2-oxopyridin-1(2H)~y|)methyl (methylsulfonyl)-N-(tetrahydro—2H-pyranyloxy)butanamide, T3, (1.6 g, 3.1 mmol) using a procedure analogous to that described for the preparation of (2R)[5-fluoro (3—fluoro—4-meth0xyphenyl)oxopyridin-1(2H)-y|]-2—methyl(methylsulfonyl)—N- (tetrahydro-2H—pyranyloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 513.3 (M+1).
WC 20397 -Fluoro omethox hen | 1 2H hydroxy-Z-methyl-Z-g methylsulfonyl )butanamide A solution of HCI (4 M in 1,4-dioxane, 4.4 mL, 17.5 mmol) was added to a solution of (2 R)—4—[5-fluoro—4-(2-fluoro—4-m ethoxyphenyl)—2-oxopyridin—1 (2H)—yl]-2—methyl—2- (methylsu|fonyl)—N-(tetrahydro—2H—pyran-2—yloxy)butanamide (1.5 g, 2.9 mmol) in 1,4- dioxane (20 mL), DCM (20 mL), and water (5 mL) and the reaction was stirred for 20 min at rt. The reaction was concentrated under reduced pressure, isopropyl alcohol (10 mL) was added to the residue and the mixture was trated. lsopropyl l (30 mL) was added to the residue and the solution was stirred overnight at rt to afford a precipitate. The precipitate was collected via filtration, washed with isopropyl alcohol, and dried under vacuum to afford the title nd as a light brown solid (725 mg, 58%) MS (LCMS) m/z 431.0 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.57 (s, 3 H) 2.07 - 2.25 (m, 1 H) 2.42 - 2.48 (m, 1 H) 3.11 (s, 3 H) 3.71 - 3.81 (m, 1 H) 3.83 (s, 3 H) 4.00 - 4.11 (m, 1 H) 6.44 (d, J=7.02 Hz, 1 H) 6.92 (dd, J=8.59, 2.54 Hz, 1 H) 7.00 (dd, J=12.39, 2.44 Hz, 1 H) 7.42 (t, J=8.49 Hz, 1 H) 8.03 (d, J=5.85 Hz, 1 H) 9.25 (br. s., 1 H) 11.10 (s, 1 H).
Example 28 —4- 5—FIuoro—4- 4—methox hen l meth lsulfon l-N- tetrah dro—2H~ ran-2— lox butanamide The title compound (1.90 g, 98.8%) was obtained as a yellow solid from (4— methoxyphenyl)boronic acid (902 mg, 5.94 mmol) and (2R)-4—(5-fluoro—4-iodo—2— oxopyridin-1(2H)-yl)methyl—2-(methylsuIfonyl)—N-(tetrahydro—2H-pyran-2— yloxy)butanamide, T3, (2.0 g, 3.87 mmol) using a procedure analogous to that described for the preparation of (2R)—4-[5—fluoro(3-fluoro—4—methoxyphenyl)-2— oxopyridin-1(2H)-y|]methyl(methylsulfonyl)-N-(tetrahydro-2H-pyran yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 495.4 (M-1). methyl(methylsulfonyl)butanamide The title compound (651 mg, 41.3%) was ed as a white solid from (2R)—4-[5- fluoro(4-methoxyphenyl)-2—oxopyridin-1 (2H)-yl]—2—methyl—2-(methylsu|fonyl)-N- (tetrahydro-2H—pyran—2—yloxy)butanamide (1.90 g, 3.83 mmol) using a procedure analogous to that described for the preparation of (2R){5—fluoro—2—oxo[4—(2H-1,2,3- triazoIyl)phenyl]pyridin—1(2H)-yl}-N-hydroxy—2-methyI(methylsu|fonyl)butanamide Example 26, Step E. MS (LCMS) m/z 413.0 (M+1). 1H NMR (400 MHz, DMSO—ds) 6 ppm 1.57 (s, 3 H) 2.08 - 2.23 (m, 1 H) 2.41 - 2.48 (m, 1 H) 3.11 (s, 3 H) 3.72 — 3.80 (m, 1O 1 H) 3.81 (s, 3 H) 3.97 — 4.13 (m, 1 H) 6.49 (d, J=7.81 Hz, 1 H) 6.95 — 7.15 (m, 2 H) 7.46 — 7.67 (m, 2 H) 7.99 (d, J=6.63 Hz, 1 H) 9.24 (s, 1 H) 11.11 (s, 1 H). e 29 5-Fluoro 4-meth l hen | Step A) 2-(methylsulfonyl)butanoate The title compound (484 mg) was obtained as a brown gum from (4- 2O methylpheny|)boronic acid (229 mg, 1.68 mmol) and ethyl (2R)-4—(5-fluoro—4—iodo—2- oxopyridin-1(2H)~yl)methyl—2—(methylsulfonyl)butanoate ,T2, (500 mg, 1.12 mmol) using a procedure analogous to that described for the preparation of ethyl (2R)—4—{5- fluoro—2-oxo—4-[4-(2 H—1 ,2,3-triazoIyl)phenyl]pyridin-1(2H)—yl}—2—methyl (methylsulfonyl)butanoate, Example 27, Step B. MS (LCMS) m/z 410.1 (M+1).
Step B) 1 2H - Imeth l—2- (methylsulfonyl)butanoic acid The title compound (294 mg, 65.2%) was obtained as a white solid from ethyl (2R)—4-[5-fluoro—4-(4-methylphenyl)oxopyridin-1(2H)-yl]methyI (methylsulfonyl)butanoate (484 mg, 1.18 mmol) using a procedure ous to that described for the preparation of (2R)—4-{5—fluoro—2-oxo[4—(2H—1,2,3-triazol-2— yl)phenyl]pyridin-1(2H)-y|}—2—methyl-2—(methylsu|fony|)butanoic acid, Example 26, Step W0 2012/120397 PCT/IBZOIZ/OSOSIZ 0. MS (LCMS) m/z 332.0 (M+1). 1H NMR (400 MHz, s) 5 ppm 1.57 (s, 3 H) 2.14 - 2.25 (m, o H) 2.33 (s, 3 H) 2.43 - 2.54 (m, 1 H) 3.17 (s, 3 H) 3.89 - 4.07 (m, 2 H) 3.43 (d, J=7.81 Hz, 1 H) 7.31 (d, J=8.00 Hz, 2 H) 7.42 — 7.52 (m, 2 H) 8.03 (d, J=6.83 Hz, 1 H).
Step C) 2R 5-Fluoro 4-meth l hen l (methylsulfonyl )-N-(tetrahydro—2H-pyran—2~yloxy)butanamide The title compound (331 mg, 89.3%) was obtained as a white solid from (2R)[5- fluoro(4-methylphenyl)~2~oxopyridin-1(2H)-yl}-2—methyl-2~(methylsulfonyi)butanoic acid (294 mg, 0.77 mmol) using a ure analogous to that described for the preparation of 2R)-4—{5—f|uoro-2—oxo—4—[4-(2H-1,2,3-triazol-2—yl)phenyl]pyridin-1 (2H)-y|}- 2-methyl-2—(methylsuifonyl)-N—(tetrahydro-2H-pyran—2—yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 479.3 (M-1).
Step D) 2R 5-Fluoro 4-meth | hen i methyl(methylsulfonyl)butanamide The title compound (96 mg, 34%) was ed as a white solid from (2R)—4-[5-fluoro (4-methylphenyl)oxopyridin—1(2H)—yl]—2-methyl-2—(methylsuIfonyl)-N—(tetrahydro-2H- pyran-2—yloxy)butanamide (331 mg, 0.69 mmol) using a procedure analogous to that described for the preparation of 2R)—4-{5-f|uoro—2-oxo[4-(2H—1,2,3-triazol yl)phenyl]pyridin-1(2H)-yl}-2—methyl(methylsulfonyl)butanamide, Example 26, Step E.
MS (LCMS) m/z 397.0 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.58 (s, 3 H) 2.10 — 2.25 (m, 1 H) 2.37 (s, 3 H) 2.42 - 2.49 (m, 1 H) 3.12 (s, 3 H) 3.71 - 3.84 (m, 1 H) 4.00 - 4.12 (m, 1 H) 6.51 (d, J=7.81 Hz, 1 H) 7.32 (d, J=7.81 Hz, 2 H) 7.48 (dd, J=8.20, 1.76 Hz, 2 H) 8.02 (d, J=6.83 Hz, 1 H) 9.24 (d, J=1.76 Hz, 1 H) 11.11 (d, J=1.95 Hz, 1 H).
Example 30 W0 2012/120397 Step A) 5—Fluorooxo 4- trifluoromethox methyl-Z—(methylsulfonyl)-N-(tetrahydro-ZH-pyran-Z-yloxy)butanamide The title compound (69.7 mg, 49.1%) was obtained as a yellow-white solid from [4— (trifluoromethoxy)phenyl]boronic acid (82.3 mg, 0.47 mmol) and (2R)—4—(5-fluoroiodo- 2—oxopyridin-1 (2H )—yl)—2-methyl—2-(methylsulfonyl)—N-(tetrahyd ro-2H—pyran—2- yloxy)butanamide, T3, (133 mg, 0.26 mmol) using a ure analogous to that bed for the preparation of (2R)—4—[5-f|uoro-4—(3-fluoro—4—methoxyphenyl)—2- oxopyridin—1(2H)—yI}-2~methyl(methylsulfonyl)-N—(tetrahydro-2H-pyran—2- yloxy)butanamide, Example 20, Step A. MS (LCMS) m/z 551.1 (M—1).
Step B) hydroxy-Z-methyI( methylsulfonyl )butanamide The title compound (12.2 mg, 20.9%) was obtained as a white solid from (2R){5- fluorooxo—4-[4-(trifluoromethoxy)ph enyl}pyridin-1 (2H)-yl}methyl-2—(methylsulfonyl)- N—(tetrahydro—ZH-pyranyloxy)butanamide (68.9 mg, 0.13 mmol) using a procedure analogous to that described for the preparation of (2R){5-fluorooxo[4-(2H-1,2,3- triazolyl)phenyl]pyridin-1(2H)-y|}-N-hydroxymethyi(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 467.0(M+1). 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.57 (s, 3 H) 2.07 — 2.25 (m, 0 H) 2.39 — 2.55 (m, 1 H) 3.11 (8,3 H) 3.72 — 3.86 (m, 1 H) 3.97 — 4.13 (m, 1 H) 6.58 (d, 1 H) 7.50 (d, J=8.00 Hz, 2 H) 7.65 — 7.77 (m, 2 H) 8.06 (d, J=6.44 Hz, 1 H) 9.23 (d, J=1.17 Hz, 1 H) 11.08 (s, 1 H).
Example 31 ridin—1 2H Step A) 2R 5-Fluoro-4— meth Isulfon l-N- tetrah - ran lox butanamide The title nd (67 mg, 54%) was obtained as a white solid from (4- phenyl)b0ronic acid (66.2 mg, 0.47 mmol) and (2R)(5-fluoro-4—iodo—2- oxopyridin-1(2H)-yl)methyi(methylsu|fonyl)-N-(tetrahydro—2H—pyran—2— yloxy)butanamide, T3, (133 mg, 0.26 mmol) using a procedure analogous to that described for the preparation of (2R)[5-fluoro(3-fluoromethoxyphenyl)—2- oxopyridin—1(2H)-yl]methyl(methylsulfonyl)-N-(tetrahydro—2H-pyran—2— butanamide, Example 19, Step A. MS (LCMS) m/z 483.1 (M-1).
Step B) 2R -4— ro—4- 4—fluoro hen l oxo ridin-1 2H methyl—Z-(methylsulfonyl)butanamide The title compound (7.9 mg, 14%) was obtained as a white solid from (2R)[5-fluoro (4-fluorophenyl)oxopyridin-1 (2H)—yl]—2—methyl-2—(methylsu|fonyl)-N-(tetrahyd ro-2H— pyranyloxy)butanamide (67 mg, 0.14 mmol) using a procedure analogous to that described for the preparation of (2R)—4~{5~f|uoro—2-oxo—4-{4—(2H-1,2,3—triazol yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy—2—methyl(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 401.0 (M+1). 1H NMR (400 MHZ, DMSO-de) 6 ppm 1.58 (s, 3 H) 2.10 —2.24 (m, 1 H) 2.42 — 2.50 (m, 1 H) 3.12 (s, 3 H) 3.71 — 3.88 (m, 1 H) 3.99 — 4.14 (m, 1 H) 6.55 (d, J=7.61 Hz, 1 H) 7.25 —7.45 (m, 2 H) 7.58 — 7.72 (m, 2 H) 8.05 (d, J=6.83 Hz, 1 H) 9.24 (s, 1 H) 11.10 (s, 1 H).
Example 32 2R -4— 5—Fluoro—4— 4- \o N/ Step A) 2-Methox 4— 4 4 5 5-tetrameth M 3 2—dioxaborolan | hen l ridine The title compound (1.40 g) was obtained as a white solid from 5-(4-bromophenyl)—2— methoxypyridine (1.0 g, 3.8 mmol) using a procedure analogous to that bed for the ation of 2-[4-(4,4,5,5-tetramethyl-1,3,2—dioxaborolanyl)phenyl]-2H-1,2,3- triazole, Example 26, Step A. MS (LCMS) m/z 312.1 (M+1).
W0 2012/120397 lmeth l meth lsulfon l-N- tetrah dro-2H- ran-2— yloxylbutanamide The title compound (273 mg, 61.4%) was obtained as a yellow solid from 2-methoxy-5— [4-(4,4,5,5—tetramethyl-1,3,2—dioxaborolan—2-yl)phenyl]pyridine (362 mg, 1.16 mmol) and (2R)—4-(5—fluoro—4—iodo—2—oxopyridin—1(2H)—yl)-2—methyl-2—(methylsuIfonyI)—N-(tetrahydro- 2H—pyran-2—yloxy)butanamide, T3, (400 mg, 0.78 mmol) using a procedure analogous to that described for the preparation of (2R)—4-[5—f|uoro—4-(3—fluoro-4—methoxyphenyI) oxopyridin—1(2H)~yl]-2~methyI(methylsuifonyl)—N—(tetrahydro~2H—pyran-2~ yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 574.0 (M+1).
Step C) 2R 5-Fluoro—4- 4- 6-methox yl {-N-hyd roxy—2-methyli methylsulfonyl )butanamide The title compound (156 mg, 67%) was obtained as a white solid from (2R)—4-{5-fluoro- 4-[4-(6-methoxypyridin—3—yl)phenyi]—2-oxopyridin-1 (2H)—yl}methyl—2—(methylsulfonyl)— N-(tetrahydro—ZH-pyranyloxy)butanamide (273 mg, 0.48 mmol) using a procedure analogous to that described for the preparation of (2R){5-fluorooxo[4-(2H-1,2,3- triazol-2—yl)phenyl]pyridin—1(2H)-yl}-N-hydroxy—2—methyI—2-(methylsu|fonyl)butanamide, e 26, Step E. MS (LCMS) m/z 490.0 (M+1). 1H NMR (400 MHz, e) 6 ppm 1.58 (s, 3 H) 2.09 — 2.27 (m, 0 H) 2.43 — 2.57 (m, 1 H) 3.12 (s, 3 H) 3.73 —- 3.86 (m, 1 H) 3.91 (s, 3 H) 4.00 —4.14 (m, 1 H) 6.59 (d, J=7.61 Hz, 1 H) 6.94 (d, J=8.59 Hz, 1 H) 7.60 — 7.73 (m, 2 H) 7.75 — 7.86 (m, 2 H) 7.98 — 8.19 (m, 2 H) 8.57 (d, J=2.54 Hz, 1 H) 9.25 (br. 8., 1 H) 11.10 (s, 1 H).
Example 33 hen lfluorooxo 1 2H -Z-(methylsulfonyl )butanamide MeOZS / NWNHOH \ 0 F o Step A) hen Ifluorooxo ridin—1 2H meth l—2- meth Isulfon i-N- tetrah dro—2H- ran lox butanamide WO 20397 ZOlZ/OSOSIZ The title compound (69.7 mg, 49.1%) was obtained as a yellow solid from 2-[ - (difluoromethoxy)phenyl]—4,4,5,5-tetramethyi-1,3,2-dioxaborolane (82.3 mg, 0.47 mmol) and (2R)—4—(5-fluoroiodo—2—oxopyridin—1(2H)—yl)—2-methyl-2—(methylsulfonyl)—N- (tetrahydro-2H-pyran-2—yloxy)butanamide, T3, (133 mg, 0.26 mmol) using a procedure analogous to that described for the preparation of (2R)[5-fluoro—4—(3—fluoro—4- methoxyphenyl)oxopyridin—1 (2H )-yl]methyl(methylsulfonyl)—N-(tetrahydro—2H- pyran—2-yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 531.2 (M—1).
Step B) hydroxy-2—methyl—2—(methylsulfonyl)butanamide The title compound (9.0 mg, 18%) was obtained as a white solid from (2R)—4-{4-[4- (difluoromethoxy)phenyl]—5—fiuorooxopyridin—1(2H)—yl}—2—methyl-2—(methylsulfonyl)—N- (tetrahydro—2H-pyranyloxy)butanamide (58.0 mg, 0.11 mmol) using a procedure analogous to that bed for the preparation of (2R)-4—{5-fluorooxo-4—[4-(2H-1,2,3— l—2-yl)phenyl]pyridin-1(2H)-yi}-N-hydroxy—2-methyl(methylsu|fony|)butanamide, Example 26, Step E. MS (LCMS) m/z 449.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.58 (s, 3 H) 2.09 — 2.26 (m, 1 H) 2.40 — 2.48 (m, 1 H) 3.12 (s, 3 H) 3.71 — 3.86 (m, 1 H) 3.98 —4.14(m, 1 H) 6.55 (d, 1 H) 7.13 — 7.57 (m, 3 H) 7.61 — 7.80 (m, 2 H) 8.05 (d, J=6.63 HZ, 1 H) 9.24 (d, J=1.76 HZ, 1 H) 11.10 (d, J=1.56 HZ, 1 H).
Example 34 0 Step A) meth I meth Isulfon I-N- tetrah dro-2H- ran lox butanamide The title compound (332.1 mg, 65.2%) was obtained as a yellow solid from (4-methoxy- 3—methylphenyl)boronic acid (280 mg, 1.69 mmol) and (2R)—4-(5-fluoroiodo-2— oxopyridin—1(2H)-yl)methyi(methylsuifonyl)~N-(tetrahyd ro-2H-pyra n—2- yloxy)butanamide, T3, (500 mg, 0.97 mmol) using a procedure analogous to that W0 2012/120397 2012/050812 described for the preparation of (2R)[5-fluoro—4-(3-fluoromethoxyphenyl) oxopyridin-1 (2H )-y|]methyl(methylsulfonyl )-N-(tetrahyd ro-2H-pyran yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 511.0 (M+1).
Step B) hydroxy—Z—methyl-2—(methylsulfonyl )butanamide The title compound (46 mg, 17%) was ed as a white solid from (2R)-4—[5—fluoro-4— (4-methoxy—3—methylphenyl)-2—oxopyridin-1(2H)-yl]methyl(methylsulfonyl)—N- (tetrahydro—2H-pyran—2-yloxy)butanamide (322 mg, 0.63 mmol) using a procedure analogous to that bed for the preparation of (2R)—4-{5-fiuoro—2—oxo-4—[4—(2H-1,2,3— triazoIyl)phenyl]pyridin—1 (2H)—yl}-N-hyd roxymethyl—2—(methylsu|fonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 427.0 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.57 (s, 3 H) 2.08 — 2.25 (m, 4 H) 2.38 —2.49 (m, 1 H) 3.11 (s, 3 H) 3.70 — 3.81 (m, 1 H) 3.84 (s, 3 H) 3.97 —4.11 (m, 1 H) 6.48 (d, 1 H) 7.05 (d, J=8.39 Hz, 1 H) 7.28 —- 7.50 (m, 2 H) 7.98 (d, J=6.63 Hz, 1 H) 9.24 (br. S., 1 H) 11.11 (s, 1 H).
Example 35 —3-f|uoro hen uoro—2-oxo h drox —2-meth I meth lsulfon lbutanamide M6028 ‘3‘ / NWNHOH F \ o F o F)\0 1 2H - lmeth l-2~ meth lsulfon l-N- tetrah dro—2H- ran yloxy)butanamide The title compound (227 mg, 42.6%) was ed as a yellow—white solid from 2—[4- (difluoromethoxy)—3-fluorophenyI]-4,4,5,5-tetramethyI-1,3,2-dioxaborolane (630 mg, 2.19 mmol) and (2R)—4-(5-fluoro—4-iodooxopyridin—1(2H)—yl)methyl(methyisulfonyl)-N- (tetrahydro-2H-pyranyloxy)butanamide, T3, (500 mg, 0.97 mmol) using a procedure analogous to that described for the preparation of (2R)[5-fluoro-4—(3—fluoro methoxyphenyl)—2—oxopyridin-1(2H)-yl]-2—methyl-2—(methylsulfonyl)—N—(tetrahydro-ZH- pyran—2—yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 549.3 (M—1).
PCT/132012/050812 Step B) ' fluoro hen lfluorooxo 1(2H )-y| {-N-hydroxy-Z-methyI-Z-imethylsulfonyl )butanamide The title compound (92 mg, 62%) was obtained as a white solid from (2R)-4—{4—[4— (difluoromethoxy)—3-fluorophenyl]f|uorooxopyridin-1(2H)—yl}—2—methyl—2— (methylsu|fonyl)—N-(tetrahydro—2H—pyran-2—yloxy)butanamide (227 mg, 0.41 mmol) using a procedure analogous to that described for the preparation of (2R)—4-{5-fluoro oxo[4-(2H-1 ,2,3—triazolyl)phenyl]pyridin-1 (2H )-yl}-N-hydroxy—2—methyl-2— (methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 467.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.57 (s, 3 H) 2.08 — 2.22 (m, 1 H) 2.40 — 2.48 (m, 1 1O H) 3.11 (s, 3 H)3.70—3.86 (m, 1 H)3.97—4.14 (m, 1 H) 6.61 (d, 1 H) 7.09 —7.38 (m, 1 H) 7.42 —— 7.57 (m, 2 H) 7.69 (d, J=11.12 Hz, 1 H) 8.07 (d, J=6.63 Hz, 1 H) 9.24 (br. 8., 1 H) 11.08 (s, 1 H).
Example 36 2R 5-Fluoro ro 2H-1 2 3—triazoI l h drox meth l meth lsulfon lbutanamide MeOZS ‘30 / N/\)\[fNH0H \ o /N\N ’N F Step A) 1E 2E -Ethanedial bis 4-bromo—2-fluoro hen | h drazone 2O (4—Bromo—3-fluorophenyl)hydrazine—hydrochloride (5.0 g, 24.3 mmol) was added to a mixture of EtOAc (60 mL) and 3 N aq NaOH (60 mL) and the mixture was stirred until all solids went into solution. The organic layer was separated and the aqueous layer was ted with EtOAc (2x60 mL). The combined organics were washed with brine (60 mL), dried (MgSO4), filtered and concentrated to afford an orange solid (3.27 g, 15.9 mmol). The solid was suspended in toluene (25 mL). dehyde (40% aq on, 912 uL, 7.92 mmol) was added dropwise to the solution and the reaction was stirred overnight at rt. The precipitate was collected via filtration and washed with e (25 mL) and hexanes (50 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (2.61 g, 78.1%). MS (LCMS) m/z 431.1 (M-1).
Step B) 2— 4-Bromo—2-fluoro hen | -2H-1 2 3-triazole W0 2012/120397 Copper (ll) trifluoromethanesulfonate (218 mg, 0.60 mmol) was added to a slurry of (1E,2E)-ethanedial bis[(4-bromo-2—f|uorophenyl)hydrazone] (2.61 g, 6.04 mmol) in toluene (25 mL). The reaction was heated to reflux and stirred at this temperature overnight. The reaction was d to cool and was filtered through , and the filter pad was washed with EtOAc (100 mL). The combined filtrates were washed with 1 N aq HCl (3x100 mL), water (100 mL), and brine (100 mL) and then dried (M9804), filtered and trated. The crude product was purified via flash chromatography using a Varian SF25—40g column and an eluent of EtOAc in hexanes (O-50%) to afford the title compound as a yellow solid (1.08 g, 73.9%). 1H NMR (400 MHz, 1O CHLOROFORM—d) 6 ppm 7.44 (ddd, 1 H) 7.47 -— 7.54 (m, 1 H) 7.76 (t, 1 H) 7.90 (s, 2 Step C) 2— 2-Fluoro—4— 4 4 5 5-tetrameth M 3 2-dioxaborolan l hen l -2H- 1,2,3-triazole The title compound (1.54 g) was obtained as a yellow solid from 2—(4—bromo—2- fluorophenyl)-2H-1,2,3-triazole (1.08 g, 4.82 mmol) using a procedure analogous to that described for the preparation of 2—[4-(4,4,5,5-tetramethyI-1,3,2-dioxaborolan yl)phenyl]-2H—1,2,3-triazole, Example 26, Step A. MS (LCMS) m/z 290.1 (M+1).
Step D) 2R ro 3-fluoro—4- 2H-1 2 3-triazol 1 2H — l—2—meth l meth n l-N— tetrah — ran—2- yloxy)butanamide The title compound (275 mg, 51 .5%) was obtained as a yellow solid from 2—[2—fluoro-4— (4,4,5,5—tetramethyl-1,3,2—dioxaborolan—2-yl)phenyli-ZH-1,2,3—triazole (420 mg, 1.45 mmol) and (2R)—4-(5—fluoroiodo—2-oxopyridin-1(2H)-yl)—2—methyl(methylsulfonyl)—N- (tetrahydro—2H-pyranyloxy)butanamide, T3, (500 mg, 0.97 mmol) using a procedure analogous to that described for the preparation of (2R)-4—{5-fluoro—4—(3-fluoro—4- methoxyphenyl)oxopyridin-1(2H)-yl]—2—methyl(methylsulfonyl)-N-(tetrahydro-2H- pyran-2—yloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 550.3 (M-1).
Step E) 1(2H )-y| {-N-hydroxy-Z-methyI-Z-g methylsulfonyl amide The title compound (133 mg, 57%) was obtained as a white solid from (2R)—4—{5-fluoro- 4-[3—fluoro—4—(2H—1 ,2,3-triazolyl)phenyl}—2-oxopyridin-1(2H)—yl}methyl—2— (methylsulfonyl)—N-(tetrahydro—2H—pyranyloxy)butanamide (275 mg, 0.50 mmol) W0 20397 through a procedure analogous to that described forthe preparation of (2R)—4-{5-fluoro— 2-oxo[4-(2H-1,2,3-triazolyl)phenyl]pyridin-1(2H)-yl}-N-hydroxymethyi (methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 468.0 (M+1). 1H NMR (400 MHz, DMSO-de) 5 ppm 1.58 (s, 3 H) 2.10 — 2.25 (m, 0 H) 2.43 — 2.56 (m, 1 H) 3.12 (s, 3 H) 3.74 — 3.89 (m, 1 H) 4.00 — 4.15 (m, 1 H) 6.70 (d, J=7.61 Hz, 1 H) 7.60 ~— 7.66 (m, 1 H) 7.75 —7.86 (m, 1 H) 8.00 (t, J=8.20 Hz, 1 H) 8.10 (d, J=6.63 Hz, 1 H) 8.23 (s, 2 H) 9.24 (br. 8., 1 H) 11.08 (s, 1 H).
Example 37 1O 5—Fluoro—4- 3-meth l—4— 2H-1 2 3—triazol—2— h drox h l-2~ meth lsulfon l butanamide Me028 / NWNHOH \ 0 [ti]? Step A) 1E 2E -Ethanedial bis 4-bromo-2—meth | hen lh drazone The title compound (1.45 g, 87.9%) was obtained as a yellow solid from (4-bromo methylphenyl)hydrazine-hydrochloride (2.00 g, 8.42 mmol) and oxalaldehyde (40% aq solution, 450 uL, 3.9 mmol) through a procedure analogous to that described for the preparation of (1 E,2E)—ethanedial bis[(4-bromo-2—fluorophenyl)hydrazone], e 36, Step A. MS (LCMS) m/z 425.0 (M+1). 1H NMR (400 MHz, DMSO-de) 5 ppm 2.20 (s, 6 H) 7.09 -— 7.33 (m, 6 H) 7.95 (s, 2 H) 9.73 (s, 2 H).
Step B) 2—(4—Bromo—2—methylphenyl)—2H-1,2,3-triazole The title compound (608 g, 59.0%) was obtained as a yellow solid from (1E,2E)- dial bis[(4-bromo—2—methylphenyl)hydrazone (1.45 g, 3.42 mmol) through a procedure analogous to that described for the preparation of 2—(4-bromo fluorophenyl)—2H-1,2,3-triazole, Example 36, Step B. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 2.38 (s, 3 H) 7.44 — 7.48 (m, 2 H) 7.50 - 7.53 (m, 1 H) 7.85 (s, 2 H).
Step C) 2— 2-Meth l-4— 4 4 5 5-tetrameth H 3 2-dioxaborolan—2— l hen l -2H— 1 2 3-triazole The title compound (688 mg, 82.3%) was obtained as an orange solid from 2—(4-bromo- 2-methylphenyl)-2H-1,2,3-triazo|e (698 mg, 2.93 mmol) through a procedure analogous to that described for the preparation of 2—[4-(4,4,5,5-tetramethyI-1,3,2—dioxaborolan yl)phenyl]-2H-1,2,3—triazole, Example 26, Step A. 1H NMR (400 MHz, FORM— d) 6 ppm 1.36 — 1.41 (m, 12 H) 2.42 (s, 3 H) 7.61 (d, J=8.00 Hz, 1 H) 7.76 (d, J=7.81 Hz, 1 H) 7.80 (s, 1 H) 7.85 (s, 2 H).
Step D) 2R -4— 5-FIuoro—4- 3-meth l 2H-1 2 3-triazol 1 2H - Imeth l-2— meth lsulfon I-N- tetrah dro-2H— ran-2— 1O yloxy)butanamide The title compound (630 mg, 71.5%) was obtained as a yellow solid from 2-[2-methyl—4— (4,4,5,5—tetramethyI-1,3,2—dioxaborolan—2-yl)phenyl]-2H-1,2,3—triazole (688 mg, 2.41 mmol) and (2R)—4-(5-fluoro—4-iodooxopyridin—1(2H)-y|)-2—methyl(methylsulfonyl)-N- (tetrahydro-2H-pyranyloxy)butanamide, T3, (830 mg, 1.61 mmol) through a procedure ous to that described for the preparation of (2R)~4-[5-fluoro—4—(3- fluoromethoxyphenyl)oxopyridin-1(2H)-yl]—2-methyl(methylsulfonyl)—N- (tetrahydro-2H-pyranyloxy)butanamide, Example 19, Step A. MS (LCMS) m/z 546.2(M—1). 2O Step E) 2R 5-Fluoro 3-meth l 2H-1 2 3-triazol—2- 1(2H )—yl droxy—2-methyllmethylsulfonyl )butanamide The title compound (253 mg, 47.5%) was obtained as a white solid from (2R)-4—{5— fluoro—4—[3—methyI(2H-1,2,3—triazolyl)phenyl]—2—oxopyridin-1(2H)—y|}-2—methy|—2~ (methylsulfonyl)—N-(tetrahydro—2H—pyranyloxy)butanamide (630 mg, 1.15 mmol) through a procedure ous to that bed for the preparation of (2R)—4-{5—fluoro- 2—oxo—4—[4-(2H-1,2,3—triazolyl)phenyl]pyridin-1(2H)-yl}—N~hydroxy—2-methyl (methylsulfonyl)butanamide, e 26, Step E. MS (LCMS) m/z 464.1(M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.58 (s, 3 H) 2.11 -2.26 (m, 1 H)2.39 (s, 3 H) 3.11 (s, 3 H) 3.74 - 3.87 (m, 1 H) 3.99 - 4.16 (m, 1 H) 6.64 (d, J=7.61 Hz, 1 H) 7.60 (d, 3O J=8.00 Hz, 1 H) 7.63 - 7.77 (m, 2 H) 8.08 (d, J=6.63 Hz, 1 H) 8.16 (s, 2 H) 9.24 (br. s., 1 H) 11.09 (s, 1 H).
Example 38 -Difluoro-2—oxo hen l ridin-1 2H (methylsulfonyl )butanamide WO 20397 MeOZS / NWNHOH \ o Step A) 3,5—Difluoroiodopyridin—211 H )—one 2,3,5-Trifluoro-4—iodopyridine (6.03 g, 23.3 mmol) was suspended in 6 M aq HCI (250 mL). The mixture was heated to reflux and was stirred at this temperature overnight.
The reaction was concentrated to dryness to afford the title compound as an orange solid (4.14 g, 69.2%). MS (LCMS) m/z 257.9 (M+1).
Step B) Eth l 2R 3 5-difluoro—4—iodo~2—oxo ridin—1 2H lsulfonyl )butanoate Cesium carbonate (1.90 g, 5.84 mmol) was added to a solution of the 3,5-difluoro—4— iodopyridin-2(1H)-one (1.0 g, 3.9 mmol) and ethyl (2R)bromomethyl (methylsulfony|)butanoate, T1, (1.45 g, 5.06 mmol) in tetrahydrofuran:t-butanol (1:1, 50 mL). The ing suspension was heated to reflux and was stirred at this temperature for 72 h. The reaction was filtered through celite, and the filter pad was washed with EtOAc (3x50 mL). The combined filtrates were concentrated and the crude product was purified via flash tography on an ix SF15-24g column using an eluent of EtOAc in hexanes (0—50%) to afford the title compound as a yellow solid (575.6 mg, 32%). MS (LCMS) m/z 463.9(M+1). 1H NMR (400 MHZ. DMSO-de) 5 ppm 1.23 (s, 3 H) 1.58 (s, 3 H) 2.20 (dt, J=13.90, 7.00 Hz, 1 H) 2.52 - 2.62 (m, 1 H) 3.14 (s, 3 H) 4.00 (t, J=7.61 Hz, 2 H) 4.05 — 4.22 (m, 2 H) 7.94 (dd, J=4.20, 2.05 Hz, 1 H).
Step C) Eth l 2R —4- 3 5—difluoro—2—oxo (methylsulfonyl )butanoate The title compound (110 mg, 63%) was obtained as a white solid from phenylboronic acid (98.8 mg, 0.81 mmol) and ethyl (2R)—4-(3,5-difluoroiodooxopyridin-1(2H)-yl)— 2-methyl-2—(methylsulfonyl)butanoate (250 mg, 0.54 mmol) using a procedure analogous to that described for the preparation of ethyl (2R)—4-{5-fluoro—2-oxo[4-(2H- 1,2, 3-triazol-2—yl)phenyl]pyridin-1 (2 H )—yl}—2—m ethyl-2—(methylsu lfonyl oate, Example 26, Step B. MS (LCMS) m/z 414.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.33 — 1.46 (m, 3 H) 1.78 (s, 3 H) 2.44 — 2.65 (m, 2 H) 3.14 W0 2012/120397 PCT/IBZOIZ/050812 (s, 3 H) 3.98 — 4.16 (m, 1 H) 4.25 — 4.43 (m, 3 H) 7.23 (dd, J=5.07, 2.15 Hz, 1 H) 7.40 — 7.61 (m, 5 H).
Step D) 3 uoro-2—oxo—4— ridin-1 2H (methylsulfonyl )butanoic acid The title compound (91 mg, 79.2%) was obtained as a white solid from ethyl (2R)—4- (3,5-difluoro—2—oxo—4—phenylpyridin-1(2H)—y|)—2~methyl—2-(methylsulfonyl)butanoate (1 10 mg, 0.27 mmol) using a procedure analogous to that described for the preparation of (2 R)—4-{5—fluoro—2—oxo—4~[4-(2 H-1 riazolyl)phenyl}pyridin-1 (2H)—yl}methyl—2- 1O (methylsulfonyl)butanoic acid, Example 26, Step C. MS (LCMS) m/z 386.0 (M+1).
Step E) 2R 3 5—Difluoro-2—oxo (methylsulfonylz-N-itetrahydro-2H—pyranyloxy)butanamide The title compound (75.9 mg, 66%) was obtained as an off—white solid from (2R)-4—(3,5- difluoro—2—oxophenylpyridin-1(2H)-y|)—2-methyl-2—(methylsulfonyl)butanoic acid (91 mg, 0.36 mmol) using a procedure analogous to that described for the preparation of 2R){5-fluorooxo[4-(2H-1 riazolyl)phenyl]pyridin-1 (2H)—yl}methyl (methylsulfonyl)-N-(tetrahydro—2H-pyran—2—yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 483.2 (M+1).
Step F) 2R —4- 3 uoro—2—oxo-4— 2—(methylsulfonyl)butanamide The title compound (13.9 mg, 22%) was obtained as a white solid from (2R)—4—(3,5- o—2-oxo—4-phenylpyridin—1 (2H)—yl)-2—methyl—2—(methylsu|fonyl)—N-(tetrahydro—2H— pyranyloxy)butanamide (75 mg, 0.16 mmol) using a procedure analogous to that described for the preparation of (2R)—4-{5-fluoro—2—oxo—4—[4-(2H-1,2,3-triazo|-2~ yl)phenyl]pyridin-1(2H)—yl}—N~hydroxy—2—methyl-2—(methylsulfonyl)butanamide Example 26, Step E. MS (LCMS) m/z 401.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.59 (s, 3 H) 2.11 —2.22 (m, 1 H) 2.52 — 2.62 (m, 1 H) 3.10 (s, 3 H) 3.79 — 3.99 (m, 1 H) 4.03 3O — 4.20 (m, 1 H) 7.40 — 7.64 (m, 5 H) 7.98 (dd, J=5.85, 1.95 Hz, 1 H) 9.24 (br. 8., 1 H) 11.01 (s, 1 H).
Example 39 ridin-1 2H (methylsulfonyl )butanamide W0 2012/120397 PCT/132012/050812 M9028 ‘s‘ / NWNHOH \ O (methylsulfonyllbutanoic acid Potassium hydroxide (100 mg, 1.78 mmol) was added to a solution of ethyl -(3,5- difluorooxo—4-phenylpyridin-1(2H)~yl)methy|—2-(methylsulfonyl)butanoate (77 mg, 0.19 mmol) in tetrahydrofuran:methanolzwater (22:1 10 mL). The solution was heated to 50 °C and stirred at this temperature for 4 h. The reaction was trated and the residue was dissolved in 1 N aq NaOH (50 mL). The aqueous layer was washed with EtOAc (3x50 mL) and acidified to a pH of 3 using concentrated HCI. The solid was collected via filtration and was washed with water (30 mL) and hexanes (30 mL) to afford the title compound as a white solid (70 mg, 95%). MS (LCMS) m/z 398.0(M+1). 1H NMR (400 MHz, METHANOL-d4) 6 ppm 1.69 - 1.79 (m, 3 H) 2.30 - 2.46 (m, 1 H) 2.55 - 2.72 (m, 1 H) 3.18 (s, 3 H) 3.66 (s, 3 H) 4.08 - 4.22 (m, 1 H) 4.23 — 4.38 (m, 1 H) 7.39 - 7.51 (m, 5 H) 7.60 (d, 1 H).
Step B) 2R -4— ro—3-methox lmethylsulfonyl l-N-(tetrahyd ro—2H—pyranyloxy)butanamide The title compound (52 mg, 83%) was obtained as an off-white solid from (2R)—4-(5— fluoromethoxy—2-oxo—4—phenylpyridin—1(2H)-yl)-2—methyl-2—(methylsulfonyl)butanoic acid (50 mg, 0.13 mmol) using a ure analogous to that bed for the preparation of 2R)—4—{5—fluoro—2-oxo—4-[4-(2H—1,2,3-triazolyl)phenyl]pyridin-1 (2H)—y|}— 2—methyl-2—(methylsulfonyl)—N-(tetrahydro-2H-pyran-2—yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 497.0 (M+1). methyl-24methylsulfonyl)butanamide The title compound (20.2 mg, 48%) was obtained as an off-white solid from (2R)—4-(5- fluoro—3—methoxy—Z-oxo—4-phenylpyridin-1(2H)—y|)methyl(methylsulfonyl)—N- (tetrahydro—2H—pyran-2—yloxy)butanamide (75 mg, 0.16 mmol) using a procedure analogous to that described for the preparation of (2R)—4-{5-f|uoro—2—0xo—4—[4—(2H-1,2,3- triazol-2—yl)phenyl]pyridin-1(2H)—yl}-N-hydroxymethyl—2—(methylsu|fonyl)butanamide, WO 20397 Example 26, Step E. MS (LCMS) m/z 413.0 (M+1). 1H NMR (400 MHz, METHANOL- d4) 6 ppm 1.72 (s, 3 H) 2.30 - 2.50 (m, 1 H) 2.55 - 2.78 (m, 1 H) 3.10 (s. 3 H) 3.68 (s, 3 H) 3.95 —4.06 (m, 1 H)4.21— 4.37 (m, 1 H) 7.37 - 7.55 (m, 5 H) 7.61 (d, 1 H).
Example 40 methyl-Z-(methylsulfonyl )butanamide Boron tribromide (760 uL, 0.76 mmol, 1.0 M in dichloromethane) was added to a solution of (2R)-4~(5-fluoro—3-methoxy—2-oxo—4-phenylpyridin-1(2H)-yl)-N-hydroxy methyl(methylsulfonyl)butanamide (156 mg, 0.378 mmol) in DCM (16.0 mL) at 0 °C.
The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated to afford a brown solid. The crude product was ed via prepratory HPLC to afford the title compound as a yellow solid (25.4 mg, 16.9%). MS (LCMS) m/z 399.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 5 ppm 1.59 (s, 3 H) 2.11 — 2.25 (m, 1 H) 3.07 (s, 1 H) 3.13 (s, 2 H)3.70 - 3.88 (m, 1 H) 4.02 - 4.26 (m, 1 H) 7.11 (d, J=7.81 Hz, 1 H) 7.37 - 7.65 (m, 5 H).
Example 41 Step A) 3— 4- 4 4 5 5—Tetrameth 1-1 3 aborolan—2— l hen l isoxazole The title compound (730 mg, 67.0%) was obtained as a white solid from 3-(4- henyl)isoxazo|e (900 mg, 4.02 mmol) using a procedure analogous to that described for the preparation of 2-[4—(4,4,5,5—tetramethyl-1,3,2—dioxaborolan—2— yl)phenyl]—2H-1,2,3—triazole, Example 26, Step A. MS (APCl) m/z 272.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.36 — 1.41 (m, 12 H) 2.42 (s, 3 H) 7.61 (d, J=8.00 Hz, 1 H) 7.76 (d, J=7.81 Hz, 1 H) 7.80 (s, 1 H) 7.85 (s, 2 H). 1H NMR (400 MHz.
CHLOROFORM-d) 6 ppm 1.35 (s, 12 H) 6.66 - 6.70 (m, 1 H) 7.83 (s, 2 H) 7.88 (s, 2 H) 8.42 — 8.48 (m, 1 H). 1O Step B) 2R ~4- 5-Fluoro—4— 4—isoxazol~3~ l hen l ridin—1 2H 2- meth lsulfon l-N-tetrah dro-2H— ran lox butanamide The title compound (655 mg, 63.4%) was obtained as a colorless oil from 3-(4-(4,4,5,5- ethyl-1,3,2-dioxaborolanyl)phenyl)isoxazole (525 mg, 1.94 mmol) and (2R)—4- (5-fluoro-4—iod o-2—oxopyridin-1 (2H )-yl)methyl-2—(methylsulfonyl)-N-(tetrahydro—2 H- pyranyloxy)butanamide, T3, (1.00 g, 1.94 mmol) using a procedure analogous to that described for the ation of (2R)-4—[5-fluoro—4-(3-fluoro—4—methoxyphenyl) idin-1(2H)-yl]-2—methyl(methylsulfonyl)-N-(tetrahydro-2H-pyran yloxy)butanamide, Example 19, Step A. MS (APCl) m/z 532.3 (M—1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.53 — 1.97 (m, 9 H) 2.31 — 2.47 (m, 1 H) 2.47 — 2.60 (m, 1 H) 3.19 (d, J=2.54 Hz, 3 H) 3.53 - 3.74 (m, 1 H) 4.00 (br. s., 1 H)4.12 (s, 1 H) 4.27 - 4.40 (m, 1 H) 5.15 (d, J=14.24 Hz, 1 H) 6.63 — 6.75 (m, 2 H) 7.42 (d, J=5.46 Hz, 1 H) 7.62 (d, J=8.00 Hz, 2 H) 7.92 (d, J=8.59 Hz, 2 H) 8.49 (d, J=1.56 Hz, 1 H) 11.85 (d, J=17.76 Hz, 1 H). y—2—methvl-2—( methylsulfonyl )butanamide A solution of 1.0 M aq HCI (15 mL) was added slowly to a solution of (2R)—4-[5-fluoro (4—isoxazol-3—ylphenyl)oxopyridin-1(2H)—yl]~2-methyl(methylsulfonyl)-N—(tetrahydro- 2H-pyran—2-yloxy)butanamide (655 mg, 1.23 mmol) in 1,4—dioxane (30 mL) at rt. The reaction was allowed to stir at rt overnight. The reaction was concentrated to a crude material. Water (30 mL) was added to the crude material and the mixture was boiled for minutes. The mixture was allowed to cool to it and the solid that formed was collected via tion and dried under high vacuum to afford the title compound as a light yellow solid (314 mg, 56.9%). MS (APCl) m/z 450.1 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.55 (s, 3 H) 2.10 - 2.21 (m, 1 H) 2.42 — 2.49 (m, 1 H) 3.09 (s, 3 H) 3.66 - 3.85 (m, WO 20397 PCT/IBZOIZ/050812 1 H) 3.98-4.09 (m, 1 H)8.59 (d, J=7.61 Hz, 1 H) 7.21 (d, J=1.56 Hz, 1 H)7.71 (dd, J=8.39, 1.76 Hz, 2 H) 8.00 (d, J=8.39 Hz, 2 H) 8.04 (d, J=6.44 Hz, 1 H) 9.03 (d, J=1.56 Hz, 1 H) 9.16— 9.28 (m, 1 H) 11.08 (s, 1 H).
Example 42 -4— 5-Fluoro-4— 4— 1 3-oxazol l Step A) 2- 4— 4 4 5 5-Tetrameth H 3 2-dioxaborolan l hen l -1 3-oxazole The title nd (240 mg, 34.3%) was obtained as a white solid from 2—(4— iodophenyl)-1,3-oxazole (700 mg, 2.58 mmol) using a procedure analogous to that described for the preparation of 2—[4-(4,4,5,5-tetramethyI-1,3,2—dioxaborolan-2— yl)phenyl]-2H—1,2,3—triazole, Example 26, Step A. MS (APCI) m/z 272.2 (M+1). 1H NMR (400 MHz, CHLOROFORM—d) 6 ppm 1.35 (s, 12 H) 7.23 - 7.24 (m, 1 H) 7.69 - 7.73 (m, 1 H) 7.86 — 7.91 (m, 2 H) 7.98 — 8.05 (m, 2 H).
Step B) 2R 5—Fluoro 4- 1 3—oxazol—2- | ridin—1 2H methyl( methylsulfonyl )-N~§tetrahyd ro—2H-pyranyloxy )butanam ide The title compound (145 mg, 30.7%) was obtained as a colorless oil from 4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenyl]—1,3-oxazole (240 mg, 0.89 mmol) and (2R)- 4—(5-fluoro—4-iodooxopyrld in-1 (2H )-yl)—2—methyl~2~(methylsulfonyl )-N-(tetrahyd ro-2H- pyranyloxy)butanamide, T3, (435 mg, 0.84 mmol) using a procedure analogous to that described for the preparation of (2R)—4-[5-fluoro-4—(3-fluoro-4—methoxyphenyl)-2— oxopyridin-1(2H)-yl]—2-methyl-2—(methylsulfonyl)—N-(tetrahyd ro-2H-pyran-2— yloxy)butanamide, Example 19, Step A. MS (APCI) m/z 532.5 (M-1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.52 - 1.98 (m, 9 H) 2.35 — 2.47 (m, 1 H) 2.48 - 2.60 (m, 1 H) 3.20 (d, J=2.93 Hz, 3 H) 3.56 - 3.71 (m, 1 H) 3.96 — 4.07 (m, 1 H) 4.12 -4.22 (m, 1 H) 4.32 — 4.48 (m, 1 H) 5.12 — 5.23 (m, 1 H) 6.69 - 8.75 (m, 1 H) 7.27 (s, 1 H) 7.37 - 7.45 (m, 1 H) 7.83 (dd, J=8.39, 1.58 Hz, 2 H) 7.75 (s, 1 H) 8.14 (d, J=8.39 Hz, 2 H) 11.79 — 11.95 (m, 1 H).
W0 2012/120397 PCT/lBZOlZ/050812 hydroxy—Z—methyl—Zgmethylsulfonyl)butanamide The title compound (31 mg, 25%) was obtained as a solid from (2R)—4-{5-fluoro[4- (1 ,3-oxazolyl)phenyl]—2-oxopyridin-1(2H)-yl}—2-methyl(methylsulfonyl)-N— (tetrahydro—2H-pyranyloxy)butanamide (145 mg, 0.27 mmol) using a procedure analogous to that described for the preparation of (2R)—4—[5~fluoro(4-isoxazol-3— ylphenyl)—2—oxopyridin—1(2H)—yl]—N—hydroxy—2-methyl-2—(methylsulfonyl)butanamide, Example 41, Step C. MS (APCI) m/z 450.2 (M+1). 1H NMR (400 MHz, DMSO-ds) 6 1O ppm 1.55 (s, 3 H) 2.11 - 2.23 (m, 1 H) 2.39 - 2.47 (m, 1 H) 3.09 (s, 3 H) 3.61 - 3.84 (m, 1 H) 3.91 -4.12 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.41 (s, 1 H) 7.72 (d, J=7.02 Hz, 2 H) 7.91 - 8.12 (m, 3 H) 8.25 (s, 1 H) 9.12 - 9.29 (m, 1 H) 10.87 — 11.17 (m, 1 H).
Example 43 5-Fluoro 4-trideuterometh | hen loxo -Z-(methylsulfonyl )butanamide M6028 ‘\‘ F -~ / NWNHOH 2O Step A) meth l-2— meth lsulfon l-N- tetrah - ran lox butanamide The title nd (216 mg, 76.9%) was obtained as a light orange oil from (4- trideuteromethylphenyl)boronic acid (85 mg, 0.61 mmol) and (2R)(5-fluoro—4-iodo—2- oxopyridin—1(2H)—yl)—2-methyl(methylsulfonyl)-N—(tetrahyd ro—2H-pyra n-2— yloxy)butanamide,T3, (300 mg, 0.58 mmol) using a procedure analogous to that described for the preparation of (2R)—4-[5-fluoro—4-(3-fluoromethoxyphenyl) oxopyridin—1(2H)—y|]methyl-2—(methylsulfonyl)-N-(tetrahyd pyran yloxy)butanamide, Example 19, Step A. MS (APCI) m/z 482.4 (M-1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.50 - 1.97 (m, 9 H) 2.32 - 2.44 (m, 1 H) 2.44 - 2.59 (m, 1 H) 3.17 (d, J=2.34 Hz, 3 H) 3.53 - 3.69 (m, 1 H) 4.00 (br. s., 1 H) 4.10 - 4.20 (m, 1 H) 4.31 (br. s., 1 H) 5.14 (d, J=14.44 Hz, 1 H) 6.65 (dd, J=7.22, 1.56 Hz, 1 H) 7.21 - 7.28 (m, 2 H) 7.36 (d, J=5.27 Hz, 1 H) 7.38 — 7.44 (m, 2 H) 11.89 - 12.06 (m, 1 H).
Step B) 4-trideuterometh i hen I ridin-1 2H hydroxy-Z-methyi-Z-g methylsulfonyl )butanamide The title compound (62 mg, 35%) was obtained as a solid from (2R)—4—[5-fluoro—4—(4— trideuteromethylph enyl opyridin-1 (2H)-yl}-2—methyl—2-(methylsulfonyl)-N- (tetrahydro—2H—pyran—2-yloxy)butanamide (145 mg, 0.27 mmol) using a procedure analogous to that described for the preparation of (2R)[5—fiuoro(4-isoxazoI—3- ylphenyl)-2—oxopyridin-1(2H)~yl]-N-hydroxy—2-methyl-2~(methyisuIfonyi)butanamide, Example 41, Step C. MS (APCI) m/z 400.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 6 ppm 1.54 (s, 3 H) 2.14 (br. s., 1 H)2.47 (br. s., 1 H) 3.08 (s, 3 H) 3.75 (br. s., 1 H)4.02 1O (br. s., 1 H) 6.47 (d, J=7.61 Hz, 1 H) 7.28 (d, J=8.00 Hz, 2 H) 7.44 (d, J=7.02 Hz, 2 H) 7.98 (d, J=6.63 Hz, 1 H) 9.21 (s, 1 H) 11.07 (s, 1 H).
Example 44 4-trideuteromethox hen | meth I—2- meth n l-N-tetrah dro—2H— ran-2— lox butanamide The title nd (216 mg, 76.9%) was obtained as a colorless oil from (4— trideuteromethoxyphenyl)boronic acid (120 mg, 0.78 mmol) and (2R)—4-(5-f|uoro—4—iodo- 2—oxopyridin—1(2H)-y|)methy|—2-(methylsuIfonyl)-N—(tetrahydro—2H-pyran yloxy)butanamide, T3, (400 mg, 0.78 mmol) using a procedure analogous to that described for the preparation of (2R)—4-[5-fluoro—4-(3—fluoro-4—methoxyphenyl) oxopyridin-1(2H)-yl]methyI(methylsulfonyl)—N—(tetrahydro—2H-pyran yloxy)butanamide, e 19, Step A. (122 mg, 31.5%). MS (APCI) m/z 498.3 (M-1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.49 - 1.98 (m, 9 H) 2.38 (dd, , 3.80 Hz, 1 H) 2.44 - 2.61 (m, 1 H) 3.18 (d, J=2.54 Hz, 3 H) 3.65 (d, J=11.51 Hz, 1 H) 3.89 - 4.04 (m, 1 H)4.11 — 4.22 (m, 1 H)4.24 - 4.38 (m, 1 H) 5.15 (d, J=14.63 Hz, 1 H) 6.64 (dd, J=7.41, 1.37 Hz, 1 H) 6.96 (d, J=8.78 Hz, 2 H) 7.35 (d, J=5.66 Hz, 1 H) 7.43 - 7.51 (m, 2 H) 12.02 (d, J=15.02 Hz, 1 H). 2012/050812 Step B) 2R 5-fluoro 4-trideuteromethox hen l hydroxy-Z-methyI(methylsulfonyl)butanamide The title compound (55 mg, 55%) was obtained as a solid from (2R)[5-fluoro—4—(4— trideuteromethoxyphenyl)oxopyridin-1(2H)-y|]-2—methyl-2—(methylsulfonyl)~N- (tetrahydro—2H-pyranyloxy)butanamide (120 mg, 0.24 mmoi) using a ure analogous to that described for the preparation of (2R)—4-[5-fluoro-4—(4-isoxazoI ylpheny|)-2—oxopyridin-1(2H)—yl]—N—hydroxy—2-methyI-2~(methylsulfonyl)butanamide, Example 41, Step C. MS (APCl) m/z 416.1 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.54 (s, 3 H)2.14 (br. 3., 1 H) 2.47 (br. s., 1 H) 3.08 (s, 3 H) 3.74 (br. s., 1 H)4.02 1O (br. s., 1 H) 6.46 (d, J=7.81 Hz, 1 H) 7.02 (d, J=8.39 Hz, 2 H) 7.51 (d, J=7.41 Hz, 2 H) 7.96 (d, J=6.63 Hz, 1 H) 9.20 (s, 1 H) 11.07 (s, 1 H).
Example 45 4—Pentadeuteroethox hen lfluoro—2—oxo meth I meth lsulfon lbutanamide M6028 o‘ / NWNHOH \ o D 0 DD\1)<OD Step A) 2R -4— 4- 4-Pentadeuteroethox hen l —5-f|uoro—2-oxo meth | meth lsuifon i—N- tetrah dro—2H- ran on butanamide The title compound (184 mg 46.0%) was obtained as a colorless oil from (4- pentadeuteroethoxyphenyl)boronic acid (132 mg, 0.78 mmol) and -(5—fluoro—4- iodo—2—oxopyridin-1(2H)—yl)—2-methyl-2~(methylsuifonyl)-N-(tetrahydro—2H-pyran-2— yloxy)butanamide, T3, (400 mg, 0.78 mmol) using a procedure ous to that described for the preparation of (2R)-4—{5—fluoro—4—(3-fluoro—4-methoxyphenyI) oxopyridin-1(2H)-yl]methyl—2-(methylsulfonyl)—N-(tetrahydro-2H-pyran yloxy)butanamide, e 19, Step A. MS (APCI) m/z 514.4 (M—1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.53 — 1.97 (m, 9 H) 2.39 (dt, J=7.27, 3.68 Hz, 1 H) 2.45 — 2.60 (m, 1 H) 3.19 (d, J=2.73 Hz, 3 H) 3.65 (d, J=11.51 Hz, 1 H) 3.90 - 4.04 (m, 1 H) 4.16 (dd, J=11.22, 2.44 Hz, 1 H) 4.24 — 4.38 (m, 1 H) 5.16 (d, J=14.83 Hz, 1 H) 6.64 (dd, J=7.42, 1.17 Hz, 1 H) 6.95 (d, J=8.59 Hz, 2 H) 7.34 (d, J=5.66 Hz, 1 H) 7.40 - 7.52 (m, 2 H) 12.03 (br. 8., 1 H).
W0 2012/120397 Step B) 2R 4- 4—Pentadeuteroethox hen l fluorooxo hydroxy-Z—methyl( methylsulfonyl )butanamide The title nd (152 mg, 98.7%) was obtained as an off-white solid from (2R)[4- (4—pentadeuteroethoxyphenyl)—5-fluoro—2-oxopyridin-1(2H)—yl]—2-methyI—2- (methylsulfonyl)-N—(tetrahydro—2H—pyran~2~yloxy)butanamide (120 mg, 0.24 mmol) using a procedure analogous to that described for the preparation of (2R)~4-[5—fluoro(4- isoxazol—3—ylphenyl)oxopyridin-1 (2H)—yl}~N-hyd roxy—2-methyl-2— (methylsulfonyl)butanamide, Example 41, Step C. MS (APCI) m/z 432.1 (M+1). 1H 1O NMR (400 MHz, DMSO-de) 6 ppm 1.54 (s, 3 H) 1.89 - 2.22 (m, 1 H) 2.32 — 2.47 (m, 1 H) 2.92 - 3.15 (m, 3 H) 3.57 - 3.80 (m, 1 H) 4.01 (br. s., 1 H) 6.45 (d, J=7.81 Hz, 1 H)7.01 (d, J=8.78 Hz, 2 H) 7.50 (d, J=7.22 Hz, 2 H) 7.96 (d, J=6.83 Hz, 1 H) 9.21 (br. s., 1 H) 11.08 (s, 1 H).
Examgle 46 fluorooxo ridin-12H -21 methylsulfonyl )butanamide MeOZS / NWNHOH \ o Step A) 2- 4— C clo ro lox hen l-4 4 5 ameth M 3 2-dioxaborolane Pd(dppf)Cl2 (770 mg, 0.94 mmol) was added to a degassed sion of 1-bromo—4- (cyclopropyloxy)benzene (2.0 g, 9.39 mmol), potassium acetate (2.76 g, 28.12 mmol), and 4,4,4‘,4',5,5,5’,5'-octamethyl-2,2'—bi—1,3,2—dioxaborolane (2.62 g, 10.32 mmol) in anhydrous DMSO (20 mL). The reaction was heated to 80 °C and stirred at this temperature for 5 h. The reaction was allowed to cool to rt and diluted with water and diethyl ether. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The organics were combined, dried (MgSO4), filtered, and concentrated in vacuo. Hexanes were added to the residue and the resulting yellow solution was decanted from the brown residue. The yellow solution was concentrated, and the residue was ed via column chromatography using an eluent of 2% ethyl e in hexanes to afford title compound as a colorless oil (878 mg, 36%). MS (LCMS) m/z 261.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 0.74 - 0.83 (m, 4 H) 1.34 (s, 12 H) 3.73 - 3.82 (m, 1 H) 7.05 (d, 2 H) 7.75 (d, 2 H).
Step B) hen lfluorooxo methyl-H methylsulfonyl )—N—(tetrahyd ro-2H-pyran-2—yloxy)butanamide The title compound (560 mg 55.3%) was obtained as a colorless oil from 2—[ - (cyclopropyloxy)phenyl]—4,4,5,5—tetramethyl—1,3,2-dioxaborolane (554 mg, 2.13 mmol) and (2R)(5-fluoro—4-iodo—2—oxopyridin—1(2H)-yl)—2-methyl(methylsulfonyl)—N- (tetrahydro—2H-pyranyloxy)butanamide,T3, (1.0 g, 1.94 mmol) using a procedure analogous to that described for the ation of (2R)—4-[5-fluoro—4-(3-fluoro—4- yphenyl)-2—oxopyridin-1(2H)-yl]—2-methyl-2—(methylsulfonyl)-N-(tetrahydro-2H- pyran—2-yloxy)butanamide, Example 19, Step A. MS (APCI) m/z 521.4 (M-1). 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.57 - 0.82 (m, 4 H) 1.42 - 1.91 (m, 9 H) 2.27 - 2.41 (m, 1 H) 2.41 -2.58 (m, 1 H) 3.13 (s, 4 H) 3.45 - 3.64 (m, 1 H)3.72 (dd, J=5.46, 2.93 Hz, 1 H) 3.80 - 3.98 (m, 1 H) 4.12 (d, J=10.93 Hz, 1 H) 4.17 - 4.31 (m, 1 H) 5.11 (d, J=13.85 Hz, 1 H) 6.59 (d, J=7.41 Hz, 1 H) 6.97 - 7.13 (m, 2 H) 7.36 (d, J=5.46 Hz, 1 H) 7.43 (d, J=8.59 Hz, 2 H) 11.82 — 12.08 (m, 1 H).
Step B) R 4- 4-C clo ro ox hen l—5—fluoro—2-oxo hydroxy—Z—methyl-Z—gmethylsulfonyl)butanamide The title compound (280 mg, 59.6%) was obtained as an off-white solid from (2R)—4—(4- (4—cyclopropoxyphenyl)f|uoro—2-oxopyridin—1(2H)—yl)methyl—2~(methylsulfonyl)-N- hydro-2H-pyran—2-yloxy)butanamide (560 mg, 1.07 mmol) using a procedure analogous to that described for the preparation of (R)—4-(5—fluoro-4—(4—(isoxazol yl)phenyl)~2~oxopyridin-1(2H)-y|)-N-hydroxy—2—methyl-2—(methylsulfonyl)butanamide, Example 41, Step C. MS (APCI) m/z 439.0 (M+1). 1H NMR (400 MHz, DMSO-ds) TM ppm 0.55 — 0.69 (m, 2 H) 0.74 — 0.85 (m, 2 H) 1.54 (s, 3 H) 2.03 - 2.26 (m, 1 H) 2.33 — 2.46 (m, 1 H) 3.08 (s, 3 H) 3.64 - 3.80 (m, 1 H) 3.88 (dt, J=6.05, 3.02 Hz, 1 H) 3.94 - 4.10 (m, 1 H) 6.46 (d, J=7.81 Hz, 1 H) 7.02 — 7.23 (m, 2 H) 7.52 (dd, J=8.78, 1.95 Hz, 2 H) 7.97 (d, J=6.63 Hz, 1 H) 9.21 (s, 1 H) 11.08 (s, 1 H).
Example 47 2 2-Difluoro-1 odioon l —5—fluorooxo 2—methyl—2~(methylsulfonyl )butanamide PCT/IBZOlZ/050812 Step A) ' ' fluorooxo l -2—meth l—2- meth lsulfon l -N— tetrah dro-2H— ran yloxy)butanamide The title compound (560 mg 55.3%) was obtained as a colorless oil from (2,2-difluoro— 1,3-benzodioxolyl)boronic acid (129 mg, 0.639 mmol) and (2R)(5-f|uoro—4-iodo oxopyridin-1(2H)-y|)-2—methyl(methylsulfonyl)—N-(tetrahydro—2H-pyran yloxy)butanamide, T3, (300 g, 0.581 mmol) using a procedure analogous to that described for the preparation of (2R)—4-[5-f|uoro—4—(3-fluoro—4-methoxyphenyI) oxopyridin-1(2H)-yl]methyI(methylsuIfonyl)-N-(tetrahydro—2H-pyran butanamide, Example 19, Step A. MS (LCMS) m/z 545.3 (M1).
Step B) 2R 4- 2 2—Difluoro-1 3-benzodioon—5- ~5-fluorooxo yl l-N-hyd -methyI-2—( methylsulfonyl )butanamide Aqueous HCI (1.42 mL, 1.42 mmol) was added to a solution of (2R)—4-[4-(2,2-leluoro- 1,3-benzodioxol-5—yl)f|uoro—2-oxopyridin—1(2H)—y|]methy|—2-(methylsulfonyl)—N— (tetrahydro—2H-pyranyloxy)butanamide (259 mg, 0.474 mmol) in ethanol (5 mL) and water (2 mL) and the reaction was stirred overnight at rt. The solid was ted via filtration, washed with water (5x3 mL) and dried under reduced re to afford the title nd (143 mg, 65.3%). 1H NMR (400 MHz, DMSO-de) d ppm 1.58 (s, 3 H) 2.07 — 2.24 (m, 1 H) 2.36 - 2.49 (m, 1 H) 3.11 (s, 3 H) 3.68 — 3.86 (m, 1 H) 3.98 — 4.13 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.36 — 7.49 (m, 1 H) 7.55 (d, J=8.39 Hz, 1 H) 7.68 (s, 1 H) 8.06 (d, J=6.63 Hz, 1 H) 9.24 (br. s., 1 H) 11.08 (s, 1 H).
Example 48 -Fluorooxo hen leth n | (methylsulfonyl )butanamide Step A) (methylsulfonyl oate A solution of ethyl (2R)(5—fluoro—4~iodooxopyridin-1(2H)—yl)—2-methyl-2— (methylsulfonyl)butanoate (500 mg, 1.12 mmol) and diisopropylethylamine (6.0 mL, 30 mmol) in tetrahydrofuran (15 mL) was degassed with nitrogen. 3)4 (65.4 mg, 0.056) and copper iodide (21.8 mg, 0.112 mmol) were added to the solution, followed by phenylacetylene (150 uL, 1.4 mmol). The reaction was allowed to stir until complete via TLC. The reaction was diluted with EtOAc (100 mL) and washed with saturated aq NH4C| (100 mL) and brine (100 mL), dried ), filtered, and concentrated. The crude residue was purified via flash chromatography using a Varian SF15-24g column and an eluent of EtOAc in hexanes (30-80%) to afford the title compound as a yellow solid (389 mg, 82.6 %). MS (LCMS) m/z 420.0 (M+1). 1H NMR (400 MHz, CHLOROFORM—d) 5 ppm 1.35 (t, 3 H) 1.75 (s, 3 H)2.42 - 2.61 (m, 2 H) 3.11 (s, 3 H) 3.91 — 4.00 (m, 1 H) 4.19 - 4.27 (m, 1 H) 4.30 (q, J=7.02 Hz, 2 H) 6.72 (d, J=6.63 Hz, 1 H) 7.27 (t, J=2.34 Hz, 2 H) 7.35 - 7.44 (m, 2 H) 7.55 — 7.60 (m, 2 H).
Step B) 2R 5—Fluoro—2~oxo-4— (methylsulfonyl2butanoic acid The title compound (195.1 mg, 72.1%) was obtained as a white solid from ethyl (2R)—4- [5—fluoro-2—ox0—4—(phenylethynyl)pyridin—t (2H)-yl}—2-methyl(methylsulfonyl)butanoate (290 mg, 0.52 mmol) using a procedure ous to that described for the preparation of ethyl (2R)—4-{5—fluoro-2—oxo—4-[4-(2H-1,2,3—triazol~2—yl)phenyl]pyridin~1(2H)—yl} methyl(methylsulfonyl)butanoate, Example 26, Step C. MS (LCMS) m/z 392.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 5 ppm 1.55 (s, 3 H) 2.10 - 2.24 (m, 0 H) 2.40 - 2.56 (m, 1 H) 3.16 (s, 3 H) 3.87 - 4.06 (m, 2 H) 6.65 (d, J=6.83 Hz, 1 H) 7.43 - 7.55 (m, 3 H) 7.57 - 7.65 (m, 2 H) 8.07 (d, J=5.46 Hz, 1 H).
Step C) 2R 5-Fluoro—2-oxo-4— (methylsulfonyl etrahydro—2H—pyran-2—yloxy)butanamide The title compound (232 mg, 95.0%) was obtained as a white solid from (2R)[5- fluoro-2—oxo—4-(phenylethynyl)89yridine-1(2H)—yl]—2-methyl—2-(methylsulfonyl)butanoic PCT/IBZOIZ/050812 acid (195.1 mg, 0.50 mmol) using a procedure analogous to that bed for the preparation of (2R)—4-{5-f|uoro-2—oxo[4-(2H-1,2,3-triazol-2—yl)phenyl]pyridin-1(2H)—yl}- 2—methyl—2-(methylsuIfonyl)—N-(tetrahydro-2H-pyranyloxy)butanamide Example 26, Step D.
Step D) 2R -4— 5-Fluoro-2—oxo hen leth n I90 ridine-1 2H methyl( methylsulfonyl )butanamide The title compound (124.4 mg, 64.7%) was obtained as a white solid from (2R)—4-[5- fluoro—2-oxo(phenylethynyl)90yridine—1(2H)-yl]—2—methyl-2—(methylsulfonyl)-N- (tetrahydro—2H-pyran—2-yloxy)butanamide (232 mg, 0.47 mmol) using a procedure analogous to that described for the preparation of —{5—Fluoro—2-oxo[4-(2H- 1 ,2,3—triazoIyl)phenyl]pyridin—1(2H)-yl}-N-hydroxy—2—methyl (methylsulfony|)butanamide, Example 26, Step E. MS (LCMS) m/z 407.0 (M+1). 1H NMR (400 MHz, DMSO-ds) 5 ppm 1.56 (s, 3 H) 2.04 — 2.21 (m, 1 H) 2.37 — 2.49 (m, 1 H) 3.10 (s, 3 H) 3.69 — 3.85 (m, 1 H) 3.92 — 4.12 (m, 1 H) 6.69 (d, 1 H) 7.39 — 7.57 (m, 3 H) 7.57 — 7.68 (m, 2 H) 8.05 (d, J=5.46 Hz, 1 H) 9.22 (s, 1 H) 11.04 (s, 1 H).
Example 49 methy|~2-( methylsulfonyl )butanamide M9028 ‘3‘ / NWNHOH <5? \ o Step A) 2—(3-lodophenoxy)-1,3-thiazole Cesium carbonate (4.52 g, 13.87 mmol) was added to 2-bromo-1,3-thiazole (1.90 g, 11.6 mmol) and 3-iodophenol (2.54 g, 11.5 mmol) in anhydrous DMF (30 mL). The reaction was heated to 135 °C and stirred at this temperature overnight. The reaction was allowed to cool, then was poured into water (100 mL), and extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried ), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian 4g column and an eluent of EtOAc in hexanes (0—10%) to afford the title nd as a yellow oil (2.52 g, 71.8%). MS (LCMS) m/z 304.1 (M+1).
Step B) 2- 3- 4 4 5.5-Tetrameth [-1 3 2-dioxaborolan | henox —1 3-thiazole The title compound (1.33 g) was prepared as a crude brown solid from 2-(3- iodophenoxy)-1,3-thiazole (500 mg, 1.65 mmol) using a procedure analogous to that described for 2-[4-(4,4,5,5—tetramethyl-1,3,2-dioxaborolanyl)phenyl]—2H-tetrazole, Example 1, Step A. MS (LCMS) m/z 304.0 (M+1).
Step C) Eth I 2R 5—fluorooxo—4- 3— 1 3-thiazol—2- yltmethyl(methylsulfonyl)butanoate The title compound (534 mg) was prepared as a crude brown oil from 2-[3-(4,4,5,5— tetramethyl-1,3,2-dioxaborolan—2-yl)phenoxy}-1,3-thiazole (1.33 g, 4.39 mmol) and T2 (400 mg, 0.90 mmol) using a procedure analogous to that described for ethyl (2R)[5- fluorooxo—4—(4-{[trans—4—(tetrahydro-2H-pyran-2— yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)—yl]-2—methyl (methylsulfonyl)butanoate, Example 18, Step D. MS (LCMS) m/z 495.2 (M+1).
Step D) methyl-24 methylsulfonyl )butanoic acid The title compound (144 mg, 28.4%) was prepared as an off-white solid from ethyl (2R)- 4-{5-flu0ro—2—oxo-4—[3—(1,3—thiazolyloxy)phenyl]pyridin-1 (2H )-yl}—2-methyI (methylsulfonyl)butanoate (538 mg, 1.09 mmol) using a procedure analogous to that bed for —{5-fluoro—2—oxo-4—[4-(2H—1,2,3—triazolyl)phenyl]pyridin-1 (2H)—yl}- 2—methyl(methylsulfonyl)butanoic acid, Example 26, Step C. MS (LCMS) m/z 467.1 (M+1). 1H NMR (400 MHz, DMSO~d5) 6 ppm 1.57 (s, 3 H) 2.12 - 2.27 (m, 1 H) 3.17 (s, 3 H) 3.85 — 4.11 (m, 2 H) 6.55 (d, J=7.61 Hz, 1 H) 7.24 — 7.35 (m, 2 H) 7.44 - 7.66 (m, 4 H) 8.07 (d, J=6.44 Hz, 1 H).
Step E) 2R —4- 5-Fluorooxo 3- 1 zol—2— methyl-2—( sulfonyl )-N-(tetrahyd ro-2H—pyranyloxy )butanam ide The title compound (115 mg, 65.8%) was prepared as an off-white solid from (2R)—4—{5— fluoro-Z—oxo—4-[3-(1 ,3-thiazolyloxy)phenyl]pyridin-1(2H)—yl}methyl (methylsulfonyl)butanoic acid (144 mg, 0.31 mmol) using a ure ous to that described for (2R){5-fluorooxo[4-(2H-1,2,3—triazol—2—yl)phenyl]pyridin-1(2H)-yl}- 2~methyl-2—(methylsulfonyl)-N-(tetrahydro-2H—pyranyloxy)butanamide, Example 26, Step D. MS (LCMS) m/Z 566.2 (M-1).
W0 2012/120397 hydroxy-Z-methyl(methylsulfonyl )butanamide The title compound (66.8 mg, 68.4%) was prepared as a white solid from (2R)—4-{5- fluoro—2—oxo—4—[3—(1 ,3—thiazolyloxy)phenyl]pyridin~1(2H)-yl}-2—methyl—2- (methylsulfonyl)—N-(tetrahydro—2H-pyran-2—yloxy)butanamide (115 mg, 0.20 mmol) using a procedure analogous to that described for (2R)~4-{5-fluoro—2-oxo—4-[4—(2H—1,2,3- triazoly|)phenyl}pyridin-1 (2H)-yl}-N-hyd roxy—2—methyl(methylsulfony|)butanamide, Example 26, Step E. MS (LCMS) m/z 482.2 (M+1). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.57 (s, 3 H) 2.09 - 2.23 (m, 1 H) 3.11 (s, 3 H) 3.70 - 3.87 (m, 1 H) 3.97 - 4.14 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.25 - 7.35 (m, 2 H) 7.45 - 7.67 (m, 4 H) 8.06 (d, J=6.44 Hz, 1 H)9.23 (s, 1 H) 11.08 (s, 1 H).
BIOLOGICAL EXAMPLES In order to assess the compounds biological activity, selected in vitro assays were conducted on selected compounds. One of the assays measured the compounds ability to t the synthesis of lysaccharide, LPS, which is a component of the outer membrane of Gram-negative bacteria. Disruption of this synthesis is lethal to the bacteria. The assay determined the compounds ability to inhibit prC, which is the first enzyme in the biosynthetic pathway for LPS (measured as ICso). Additionally, Mle (minimal inhibitory concentrations) were determined for several bacteria. The specific protocols are described below: A) lC50 assay, LQXC enzyme from P. aeruginosa (labeled as PA prC enzyme Ice-m: |C50 determination in the prC enzyme assay was carried out in a r manner to that described by ay et al in the 2006 Poster, Screening LpXC (UDPO-(R hydroxymyristoyl)~GlcNAc deacetylase) using BioTrove RapidFire HTS Mass ometry (aNew Lead ery and blnflammation and Infectious Disease, cStructural try, Schering-Plough Research ute, Kenilworth, NJ 07033, (BioTrove, Inc. 12 Gill St., Suite 4000, Woburn, MA 01801). Briefly, Pseudomonas aeruginosa prC enzyme (0.1 nM) ed from E. coli-overexpressing ia was incubated at 25 °C in a final volume of 50 ul containing 0.5 uM UDPO—(R—3- hydroxydecanoyl)—N-acety|glucosamine, 1mg/mL BSA, and 50 mM sodium phosphate buffer, pH 8.0 in the presence and absence of inhibitor compound. At the end of 1 hour, ul of 1 N HCI was added to stop the enzyme reaction, the plates were centrifuged, and then processed with the BioTrove Rapidfire HTMS Mass Spectrometry System. A no- PCT/IBZOIZ/OSOSIZ enzyme control was used in calculating the leo values from the percent conversion values.
B) MIC determinations: The in vitro antibacterial activity of compounds described in the Examples was evaluated by m inhibitory concentration (MIC) testing according to Clinical and Laboratory Standards ute (CLSI). See: Clinical and Laboratory rds ute. Methods for on Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Eighth Edition. CLSI document M7-A8 [ISBN 1689-1]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2006; also Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement. CLSI document ZO [ISBNi—56238—716-2].Clinical and Laboratory Standards Institute.
The MIC determination is a standard laboratory method for evaluating the antibacterial activity of a nd. The MIC represents the lowest drug concentration that inhibits visible growth of ia following overnight incubation. In order to determine the MIC value, a range of drug trations (e.g. 0.06 pg/mL to 64 ug/mL) are incubated with a defined strain of bacteria. Typically, the drug tration range is broken down into 2-fold increments (e.g. 0.06 pg/mL , 0.12 pg/mL. 0.25 gg/mL, 0.50 pg/mL, 1.0 pg/mL, etc.) and the various drug concentrations are all individually incubated overnight with approximately the same number of bacteria. The MIC is then determined by visually inspecting the drug effect at each concentration, and identifying the lowest drug concentration that has inhibited bacterial growth as compared to the drug free control. Typically, bacteria continue to grow at drug concentrations lower than the MIC and don’t grow at concentrations at and above the MIC.
The MIC values described In Table 2 and 3 below were derived from assays wherein each test nd was evaluated in duplicate. In cases where the duplicate values varied by 0 - 2—fold, the lower of the two values was reported below. Generally speaking, if the duplicate values varied by more than 2-fold, the assay was considered lid and was repeated until the variation between duplicate runs was g 2—fold. In line with the CLSI guidelines referred to above, both control organisms and reference compounds were utilized in each MIC assay to e proper quality control. MIC values generated with these control organisms and reference compounds were required to fall within a defined range for the assay to be considered valid and be included herein. Those d in the art will recognize that MIC values can and do vary from W0 2012/120397 PCT/IBZOlZ/OSOSIZ experiment to experiment. Generally speaking, it should be recognized that MIC values often vary +/- 2-fold from experiment to experiment. While a single MIC is reported for each compound and each microorganism, the reader should not conclude that each compound was only tested once. Several of the compounds were subjected to multiple tests. The data reported in Tables 2 and 3 is reflective of the compounds relative activity and ent Mle may have been generated on these occasions in line with the ines bed above.
The following bacterial strains were used in these MIC determinations: 1) Pseudomonas aeruginosa Ul-18: Wild-type, labeled as PA—7 in Tables 2 and ’IO 3; 2) Acinetobacter baumannii/haemolyticus: Multidrug-resistant clinical isolate labeled as AB-3167 in Tables 2 and 3; 3) Escherichia coli EC-I: VOGEL, mouse virulent labeled as EC-1 in Tables 2 and 3; ‘15 4) Klebsiella pneumoniae: Ciprofloxacin-resistant isolate, expresses extended- spectrum actamases (ESBL), clinical isolate, labeled as KP-3700 in Tables 2 and Table 2, below, shows the results that were obtained with the final products described in Examples 1—47. If a particular table entry is left blank, then the data is not available at the current time.
Column 1 corresponds to the Example number, column 2 provides the lUPAC name, column 3 provides the results from the prC enzyme assay described above, and columns 4—7 provide the MIC data as described above. _'|_'__________able2 PA'IC50 AME ' :16? (-EC1 PA-7 3700 (PM) .lmL “‘3'“!ml“) .ImL (“g/m” (2R)—4-{5-fluoro--oxo[4—(2H— tetrazoI-2—]yl)phenyl]pyridin—1(2H) 9 >64.0 >64.0 >64.0 32 yl}-N- y—Z-methyl- meth lsulfon Ibutanamide —[5-fluoro-4—(2-fluoro—3— methylphenyl)oxopyridin-1(2H)- 0.000595 >64.O yl]-N-hydroxy—2-methyl meth Isulfon Ibutanamide (2R)—4—[4-(4-chlorophenyl)—5—fluoro— 2-oxopyrid in—‘l |]-N—hydroxy—2- 0.000325 methyl-2— (methylsulfonyjbutanamide (2R)—4-[5—fluoro-4——(2fluorophenyl)- 17 >640 2——oxo ridin-1(2H W0 20121120397 PCT/[82012/050812 meth Isulfon Ibutanamide I (-2R)-4[4-((2,3dihydro benzofuran-yl)---5fluoro—2- oxopyridin—1(2H)-y|]-N-hydroxy—2— 0.000822 A methyl-2— meth Isulfon I)butanamide (2R)—4-[4-(3,4—difluorophenyl)—5— fluoro—Z—oxopyridin—1(2H)-y|]-N— 0.000833 A .0 U1 hydroxy—2~methyl (methylsulfonyl )butanamide (2R){5—fluoro—2—oxo[4—(2,2,2- trifluoroethoxy)phenyl]pyridin-1(2H)— 76 0.25 yl}—N—hydroxy—2—methyl meth Isulfon amide (2R)—4—[4-(3,4—dihydro-ZH-chromen- 6-yl)fluoro—2—oxopyridin-1(2H)-yl]— 0.000377 >64.0 05 N-hydroxy—2—methyl-2— meth Isulfon Ibutanamide (2R){5—fluoro~4~[4- 19 (methylthio)phenyl]-2—oxopyridin- 0.00051 0.25 .0 01 1 (2H)—yl}-N—hydroxy—2-methyl-2— meth Isulfon lbutanamide (2R)[4—(4-ethoxyphenyl)-5—fluoro— 2-oxopyridin-1(2H)-y|]—N-hydroxy—2— 0.000823 >64.0 0.25 meth Isulfon I)butanamide (2R)[5-fluoro-2—oxo-4—(4— 11 propylphenyl)pyridin-1(2H)-yl]-N- 0.000482 0125 O 01 .0 01 hydroxy-Z-methyI-Z- meth Isulfon amide (2R)—4-{5—fluoro—2—oxo-4—[ - fluoro—GA— 12 su|fanyl)phenyl]pyridin—1(2H)—yI}-N- 0.00114 hydroxy-Z—methyI-Z- meth Isulfon Ibutanamide (2R)—4-[5-fluoro—4-(3—methylphenyl)— 13 2-oxopyridin-1(2H)-yI]—N-hydroxy~2— methyl meth Isulfon amide (2R)-4—[5-fluoro(4—fluoro 14 methylphenyl)—2—oxopyridin-1(2H)- 0.000758 o m .0 01 y|]-N—hydroxy~2~methy|—2— meth Isulfon Ibutanamide (2R){5-fluoro—4—[4—(oxetan-3~ yloxy)phenyl]—2—oxopyridin-1 (2H)- ._\ O) WM _\ C) y1}-N-hydroxy—2—methyt-2— (meth Isulfon Ibutanamide (2R)[4—(4-chIoro—2-fluorophenyl)— 16 5-fluorooxopyridin-1(2H)—yl]-N- 0.000336 0.25 .0 01 hydroxy—Z—methyI-Z- meth Isulfon Ibutanamide —[5-fluoro(2-fluoro—3— 17 methoxyphenyl)oxopyridin-1(2H)— 0.0005 >64.0 05 yI]-N-hydroxy—2-methyl (meth Isulfon Ibutanamide (2R)[5—fluoro-4—{4—[(trans—4— hydroxycyclohexyl)methoxy]pheny|}- 18 2-oxopyridin-1(2H)-y|]—N-hydroxy-2— 0.000463 >64.0 0.125 methyl meth lsulfon Ibutanamide 19 (2R)—4—[5-fluoro—4—(3—fluoro—4— 0.5000879 >64.0 WO 20121120397 PCT/IBZOIZ/OSOSIZ methoxyphenyl)oxopyridin-1 (2H)- yIJ-N-hydroxy—2-methyl-2— meth lsulfon lbutanamide -[5-fluoro-2—oxo—4-(4- pyrimidin-Z—ylphenyl)pyridin—1(2H)— 0.000945 0.125 0 0‘1 hydroxy—Z—methyl-Z— meth lsulfon lbutanamide -{5—fluoro—4—[4-(5— methoxypyrimidin-2—yl)phenyl]~2~ 21 idin-1(2H)—yI}—N-hydroxy—2- 0.000436 0.125 0 methyl meth lsulfon Ibutanamide (2R)-4—{5-fluoro[4—(4-methoxy— 2H-1,2,3-triazol-2—yl)phenyI] 22 oxopyridin-1(2H)—yI}-N—hydroxy~2— 0.000181 50.0600 0.125 O methyl meth lsulfon I)butanamide (2R)-4—{5—fluoro[4-(4—methyl~2H- 1,2,3—triazoI-2—yl)phenyI]—2— 23 oxopyridin-1(2H)-yl}-N-hydroxy—2- 0.000287 0.125 O 01 methyl (meth lsulfon Ibutanamide (2R)—4-(5—fluorooxo—4-quinoxalin- 6-ylpyridin-1 (2H)—yl)—N-hydroxy—2- 24 0.00123 methyl meth lsulfon lbutanamide (2R)—4-[5-fluoro(3- methoxyphenyl)oxopyridin-1(2H)- 0.000412 yl]-N~hydroxymethyl-2— (meth lsulfon lbutanamide (2R){5—fluorooxo—4-[4—(2H- 26 1,2,3—triazoly|)phenyl]pyridin- 0.0000743 50.0600 0 0.25 1(2H)—y|}-N-hydroxy-Z—methyl~2— (meth lsulfon lbutanamide (2R)—4-[5-fluoro—4—(2-fluoro-4~ 27 ypheny|)-2—oxopyridin~1(2H)- 0.0000498 0.25 O 0‘! 0 5 yl]-N—hydroxy—Z—methyI—Z- (meth lsulfon l)butanamide (2R)—4-[5-fluoro-4—(4- methoxyphenyl)—2-oxopyridin-1(2H)— 28 0.000564 1 0.5 y|]-N~hydroxymethyI-2— meth n Ibutanamide (2R)-4~[5-fluoro(4-methylphenyl)— 29 2—oxopyridin-1(2H)—yl]—N-hydroxy-2— 0.000514 0.5 0.5 methyl—2~ meth lsquon ibutanamide (2R){5-fluoro—2-oxo—4—[4— (trifluoromethoxy)phenyl]pyridin— 0.000106 0.25 0 5 1 (2H)-yl}-N-hyd roxymethyl meth lsulfon Ibutanamide -[5—f|uoro(4-fluorophenyl)— 31 2-oxopyridin-1(2H)—yl]—N—hydroxy—2~ 0.000213 O 01 methyl (meth lsulfon |)butanamide (2R)—4-{5-fluoro—4-[4-(6- methoxypyridinyl)phenyI] oxopyridin-1(2H)-y|}—N-hydroxy—2— 1 (meth lsuifon I)butanamide (2R){4—[4- (difluoromethoxy)phenyI]f|uoro—Z— 0.0000606 0.5 O oxo- ridin-1 2H - | N-h drox WO 20397 PCT/IBZOIZ/OSOSIZ methyl meth lsulfon Ibutanamide (2R)~4-[5-fluoro(4-methoxy methylphenyI)oxopyridin-1(2H)- 0.000834 .0 mm N 0.5 hydroxy-Z-methyl—Z— meth lsulfon lbutanamide (2R)~4-{4-[4-(difluoromethoxy) henyl]fluoro—2—oxopyridin— 0.000589 1 I}—N-hydroxymethyI meth lsulfon lbutanamide (2R)—4—{5~fluoro—4—[3—fiuoro—4-(2H- 1,2,3—triazo|—2-yl)phenyl]—2- 36 oxopyridin—1(2H)-yI}-N-hydroxy—2— 98 O 01 _\ _x meth lsulfon Ibutanamide (2R)—4-{5-fluoro-4—[3-methyI(2H- 1,2,3—triazolyl)phenyI] 37 oxopyridin~1(2H)-yl}-N-hydroxy—2— O 01 methyl meth lsulfon lbutanamide (2R)—4—(3,5—difluoro—2-oxo—4- 38 phenylpyridin—1(2H)-yI)-N-hydroxy- 0.00055 2—methyI (meth Isulfon Ibutanamide (2R)—4—(5-fluoro-S-methoxy—Z-oxo—4- phenylpyridin-1 (2 H)—yl)—N-hyd roxy- 39 0.00807 (D 2-methyI meth Isulfon Ibutanamide (2R)(5-fluoro~3-hydroxyoxo phenyl pyridin-1 (2 H)-yI)-N-hyd roxy- 40 >0.100 64 _\ CD (A)N _\ O) 2-methyI meth lsulfon |)butanamide (2R)—4—[5-fluoro-4—(4—isoxazoI-3— 41 ylphenyl)oxopyridin-1(2H)-y|]—N- 0.000237 16 0 5 0.25 hydroxy—Z-methyl—Z— meth Isulfon Ibutanamide (2R){5-fluoro-4— [4-(1 ,3-oxazol-2— 42 yl)pheny!]—2—oxopyridin-1 (2 H)—yI}—N- 0.000328 0.25 0.25 hydroxy—Z—methyl-2~ meth Isulfon lbutanamide (2R)—4-[5-fiuoro-4—(4—methylphenyl)— 43 2—oxopyridin-1(2H)-yI]-N-hyd roxy—Z- 53 0.25 methyl—2- meth lsulfon | butanamide—d 3 (2R)[5-fluoro—4—(4~ methoxyphenyl)-2—oxopyridin-1(2H)- 44 0.000664 >64.0 0.25 1 0.25 yl]—N-hydroxy—2—methyl-2— lsulfonyl)butanamid§:g_3 (2R)—4-[4—(4-ethoxyphenyl)—5-fluoro~ 2-oxopyridin—1(2H)-yl]—N—hydroxy—2— 45 0.000547 >64.0 0.125 0.5 O 5 methyl meth Isulfon | butanamide—d 5 (2R)4-{4-[ - propyloxy)phenyl]—5-fluoro 46 oxopyridin-1(2H)-y|}—N-hydroxy 0.000229 >64.0 0.125 P 9 (’1 methyl meth lsulfon Ibutanamide (2R)[4-(2,2—difluoro—1,3- benzodioxol—S—yl)—5—fluoro 47 oxopyridin—1(2H)—y|]-N—hydroxy—2— >64.0 0.25 .A methyl Ibutanamide .- .O U1 meth lsulfon PCT/lBZOlZ/050812 (2R)[5-fluoro—2-oxo-4~ (phenylethynyl)pyridin-1(2H)-yI]-N- 0.000555 >640 0.25 0.5 hydroxy—2-methyl meth lsulfon lbutanamide (2R)—4-{5-Fluorooxo[3—(1 ,3- thiazolyloxy)phenyl]pyridin—1(2H)- 0.000758 >64 0.25 1 2 yl}-N—hydroxy—2—methyI-2— (meth lsulfon l)butanamide es 50 to 125 The compounds named below can be made following the l procedures outlined in Examples 1-49 above. Products are typically derived from a Suzuki—Miyaura cross coupling, as described above ing the appropriate starting materials, with optional deprotection of a terminal hydroxamic acid protecting group. Methods used to describe the synthesis of the precursors or coupling partners such as boronic acids or esters are known to those d in the art.
In Table 3 below, column 1 corresponds to the Example number, column 2 provides the IUPAC name, columns 3—6 provide in vitro biological data generated in the same manner as in Table 2, columns 7 and 8 provide the retention times and mass spectra generated via LCMS, using the method described below. All data is not currently ble for all compounds, as ted by a blank cell in Table 3.
The LCMS retention times reported in column 7 were ted in the following manner: 0.05% TFA 95:5 to 5:95 WaterzACN Flow rate: 1.3 mL/min Column dimensions: Acquity UPLC BEH C18 1.7 pm 2.1x30 mm.
Run time: 1.1 minutes Table3 Example PA:lC50 EC-1 PA1UC12120 Retention lUPACNAME 3167 Mass Number (PM) (Hg/mL) (ugme) Tlme. 4-[5-fluoro-2—oxo-4—(3-oxo-2,3- dihydro-1H-isoindol-S—yl)pyridin— 50 0.0682 >64.0 >640 0.42 438.1 1(2H)—y|]-N-hydroxy—2-methyI-2— (meth lsulfon lbutanamide 4-[5-fluoro(1H-indazol-G-yl)- yridin-1(2H)—yI]-N- 51 0.0039 >640 >64.0 0.49 423.1 hydroxy—Z—methyl-Z- (meth lsulfon l)butanamide 2-fluoro{5-fluoro[4- (hydroxyamino)—3-methyl-3— 0.0022 64 32 0.45 458.1 (methylsulfonyl)-4—oxobutyl]-2— oxo-1,2—dih drOo ridin IN- 2012/050812 meth Ibenzamide _____ 4-[5-fluoro(4-hydroxypheny|)- 2-oxopyridin-1(2H)—yI]-N- 53 0.0042 >640 64 0.46 399 hydroxymethyl meth lsulfon Ibutanamide 4-[4-(2,5-dimethoxyphenyl)—5- fluoro-2—oxopyridin-1(2H)—yI]—N~ >0.100 >640 >64.0 443.1 hydroxy-Z-methyI-Z— meth lsulfon Ibutanamide 4—(5,5'—difluoro-2'—oxo-3,4'- bipyridin—1'(2'H)-yI)-N~hydroxy- 55 0.0668 >64.0 64 yl (meth lsulfon |)butanamide 4-[4-(3—chlorofluoropheny!)~5— 56 fluoro-2—oxopyridin~1 (2 H)~yl]—N- >64.0 hydroxymethyl-2— meth lsulfon Ibutanamide 4-[5-fluoro(2-methyl-3—oxo— 2,3-dihydro-1H—isoindol~5-yl)—2- 57 oxopyridin-1 (2H)-yl]—N-hydroxy— >64.0 0.46 452.1 2-methyI (meth lsulfon I)butanamide 4-[4-(4-cyanofluoropheny|)—5— fluoro-2—oxopyridin-1(2H)-yl]—N- 58 >64.0 hydroxy-Z—methyl-Z— (meth lsulfon namide 4-[5—fluoro(4~ methoxyphenyI)oxopyridin- 59 0.0010 >64.0 1 1 (2 H)-y|]-N-hydroxy—2-methyl (meth lsulfon lbutanamide 4-{4-[4-(1-cyano-1— ethyl)phenyl]—5-fluoro-2— 60 oxopyridin—1(2H)—yI}-N-hydroxy— 0.0039 >64.0 32 0.61 450.1 2-methyl-2— (meth lsulfon Ibutanamide 3-acetamidophenyl)~5~ fluoro—2—oxopyridin-1(2H)—yl]~N~ 61 >64.0 0.47 440.1 y—Z-methyl-Z- (meth lsulfon l)butanamide 4—[4-(3,5-difluoro—4- methoxyphenyI)-5—fluoro—2— 62 oxopyridin—1 (2H)-yl]-N~hydroxy— 4 0.62 449 2—methyl—2- meth lsulfon Ibutanamide 4-[4-(3,5—difluorophenyl)—5— fluorooxopyridin-1(2H)-yl]-N- 62 0.61 419 hydroxy—2—methyl—2- meth lsulfon |)butanamide 4-[5-fluoro(2—methyIoxo~ 2,3—dihydro—1H-isoindol-S-yl)—2- 64 oxopyridin-1 (2H)-yl]—N—hydroxy— >64.0 64 0.44 452.1 2-methyl-2— meth lsulfon Ibutanamide 4-(5'-fluoro-2'-oxo-3,4'—bipyridin- 65 1'(2'H)-yl)— N-hydroxy—2-methyl- 0.0823 >64.0 32 0.31 384.1 meth lsulfon amide 4-[4-(4—chlorofluorophenyl) fluoro-2—oxopyridin-1(2H)-yI]—N— 0.0008 0'5 0'5 - y—Z-methyI-Z- (meth lsulfon Ibutanamide 4-[5-fluoro—4—(4-fluoro-3— methox phen |oxo ridin— W0 2012(120397 1 (2H)-yl]~N-hydroxy—Z-methyl—Z- meth Isulfon amide 4-{5—fluoro-1—[4—(hydroxyamino)— 3—methyl(methylsulfonyl)—4- oxobutyl]oxo-1,2— >64.0 >640 >640 0.46 454.1 dihydropyridin-4—yl}—N,N— dimeth Ibenzamide 4-(5'—fluoro—2—methoxy—2'-oxo— 3,4'-bipyridin-1'(2'H)-yI)—N- 0.0166 hydroxy-Z—methyI-Z- meth isulfon |)butanamide 4-(6-cyano—5'-fluoro-2‘-oxo-3,4‘- bipyridin—1'(2'H)—yl)-N-hydroxy— 70 0.0333 0.47 409 2—methyl meth Isulfon Ibutanamide uoro—4~(3—methyl~3H- imidazo[4,5-b]pyridin~6~yl) oxopyridin-1 (2H)-yl]~N-hyd roxy~ >0.100 >64.0 >640 >64.0 2—methy!~2— meth Isulfon lbutanamide 4-(5—fluorofuro[3,2-b]pyridin~ 6-yl-2—oxopyridin—1(2H)-yl)-N— 0.0348 >64.0 64 32 hydroxy—Z—methyl—Z- (meth n I)butanamide 4-(3',5-difluoro—2-oxo—4,4'- bipyridin-‘I (2H)-yl)—N—hydroxy—2- 0.0083 >640 >64.0 methyl meth Isulfon Ibutanamide I 4-[4-(4-cyano methoxyphenyl)fluoro-Z- oxopyridin-1(2H)—yl]-N—hydroxy- >64.0 64 16 2-methyI meth Isulfon {butanamide 4-(5'-fluoro‘5,6—dimethoxy—2'- oxo-3,4'-bipyridin—1'(2'H)—yl)-N- >640 >64.0 >64.0 hydroxy—Z—methyI—Z— (meth Isulfon l)butanamide 4-[4-(4—ethoxyphenyl)—5-fluoro— 2-oxopyridin-1(2H)—yl]—N- >64.0 0.25 0.5 hydroxy—2—methyl meth Isulfon |butanamide 4—{4-[4—(2—cyanoethyl)phenyl]—5~ fluoro—2-oxopyridin~1(2H)—yl}-N~ >640 32 hydroxy—2—methyl (meth n Ibutanamide 4-(5—fluoro—2-oxo phenylpyridin-1(2H)—y|)-N— 0.0028 >640 hydroxy-Z—methyl-Z— (methylsu|fonyl)butanamide 4-[4-{4— [(dimethylamino)methyl]phenyl}— ooxopyridin-1(2H)-yl]- 0.0359 >64.0 >640 16 N-hydroxy-2~methyl (meth Isulfon l butanamide 4-(5'-fluorohydroxy-2'-oxo- 3,4'—bipyridin-1'(2'H)-yl)-N— >64.0 >640 >640 y—Z-methyl—Z— meth Isulfon lbutanamide 4-[4-(4-acetamidophenyl)—5- fluorooxopyridin—1(2H)—yI]—N- >64.0 64 hydroxy—Z—methyl—Z- meth n [butanamide W0 20397 4-[4-(3-cyanophenyl)~5-fluoro oxopyridin-1 (2H)-yl]-N-hydroxy— yl meth lsulfon lbutanamide 4-(5,5'-difluoro-6—methyl—2‘—oxo— 3,4'—bipyridin-1'(2‘H)—y|)-N- hydroxy—Z—methyl-Z— (meth lsulfon lbutanamide 4-{5—fluoro—1-[4-(hydroxyamino)- 3-methyl(methylsulfonyl)~4~ 84 oxobutyl]—2-oxo—1 ,2- 0.0145 >64.0 dihydropyridin—4-yI}-N- methylbenzamide 4—[5'—fluoro-G-(hydroxymethyl)- ‘—oxo-3,4'—bipyridin-1'(2'H)~yl]~ 85 >0.100 >64.0 N-hydroxy—2—methyI-2— (meth lsulfon Ibutanamide 4—[5-fluoro(4-fluorophenyt)~2— oxopyridin-1 (2H)-yl]-N—hydroxy— 86 0.0017 >640 4 1 2—methyl meth lsulfon Ibutanamide 4-(5-fluorooxoquinolin—3- ylpyridin-1(2H)-y|)—N-hydroxy—2— 87 0.0061 >64.0 16 8 0.46 434.1 methyl meth lsulfon lbutanamide luoro—4— [4-(1 - methoxyethyl)phenyI]—2— 88 oxopyridin-1 (2H)-yl}—N-hydroxy- 0.0076 16 4 0.59 441.1 2-methyl (meth lsulfon |)butanamide 4-(5'—fluoromethoxy—2'~oxo— 3,4'—bipyridin-1'(2'H)—yl)—N— hydroxy—Z-methyI meth lsulfon amide 4—(5-ch|oro-5‘-f|uoro-2'—oxo-2,4'~ bipyridin—1'(2’H)-yl)—N-hydroxy~ 2-methyl-2— (meth lsulfon l)butanamide 4—{4—[4—(cyanomethyl)phenyI] fluoro—2~oxopyridin—1(2H)—yI}-N- 91 0.0023 hydroxy—Z-methyl-Z- methylsulfonyi)butanamide 4-(2'—ethoxyfluorooxo~4,4'— bipyridin—1(2H)—yl)-N-hydroxy—2~ 92 0.0057 methyl-2— meth n Ibutanamide 4-{5—fluoro[3- (methoxymethyI)phenyl]-2~ 93 oxopyridin—1(2H)-yI}—N-hydroxy— 0.0142 >64.0 32 8 2-methyl meth lsulfon l)butanamide 4-[4-(2—cyanophenyl)—5-fluoro-2— oxopyridin-‘l l]-N-hydroxy— 94 0.0323 32 8 32 0.52 408 2-methyl-2— (meth n I butanamide 4-[4-(4-ethoxy—3-fluorophenyl)- ooxopyridin—1(2H)-y|]- N-hydroxy—Z—methyl—Z- (meth lsulfon l)butanamide 4-[5—fluoro(2—methquuinolin— 7—yl)—2-oxopyridin-1 (2H)—yl]—N- 0.0108 16 32 0.39 448.1 h drox -2—meth [ W0 20121020397 2012/050812 (meth Isulfon I)butanamide ——— 4-[4-(2,4-difluorophenyI) fluorooxopyridin-1(2H)-yl]—N- 97 0.0012 4 1 0.59 419 hydroxy—Z—methyl—Z— (meth lsulfon l)butanamide 3,4-dimethoxyphenyI) fluoro—2—oxopyridin—1 (2 H)-yl]-N- 98 0.0285 64 32 0.53 443.1 hydroxy—Z-methyl-Z- (meth lsulfon l)butanamide 4-(6-ethoxy—5'—fluoro—2‘-oxo- 3,4'—bipyridin—1'(2'H)-yI)—N- hydroxy-Z—methyl—Z- (meth lsulfon l)butanamide 4—[5—fluoro—4-(3— methoxyphenyl)—2—oxopyridin~ 1 (2H)—yl]-N-hydroxy—2-methyI—2~ (methylsuIfonyl)butanamide 4—[4-(4—cyano-2— methoxyphenyl)—5-fluoro 101 oxopyridin-1(2H)—y|]—N-hydroxy- 2—methyl-2— (methylsulfonyl)butanamide 4—[4-(4-ch Iorocya nophenyl)— -fluoro—2-oxopyridin-1(2H)—yl]- N-hydroxy-Z-methyl-Z- meth Isulfon |)butanamide 4-[5-fluoro(2-fluoropheny|) oxopyridin-1(2H)-yI]-N-hydroxy- 103 0.0014 >64.0 4 0.5 0.57 2-methyl~2- (methxlsulfo tanamide 4-(5'-f|uoro—2—isopropoxy—2'—oxo- 3,4'-bipyridin—1'(2‘H)—yl)-N— 104 >0.100 32 8 32 hydroxy-Z—methyI-Z— meth lsulfon l)butanamide 4—{5—fluoro-4—[4-fluoro—3— (hydroxymethyl)phenyl]—2- 105 oxopyridin—1 (2H)—yl}—N-hyd roxy- 0.49 2—methyl—2— (meth n Ibutanamide 4—[5—fluorooxo(2—pyrrolidin- 1-y|pyrimidin—5-yl)pyridin—1(2H)- 106 >64.0 0.5 454.1 yI]—N—hydroxy—2—methy1—2— (methyIsulfo_nxl)butanamide 4-[4—(4—chIorophenyI)—5-fluoro idin-1(2H)-yl]-N—hydroxy— 107 >64.0 0.64 417 2—methyl-2— (methylsulfonxl)butanamide 4-[5—fluorooxo—4—(1-oxo-2,3- dihydro-1H-isoindol—S-yl)pyridin- 108 0.0072 >64.0 0.4 438.1 1(2H)-yl]-N-hydroxy—2-methyI meth lsulfon lbutanamide 4—chloro-3— yphenyl)fluoro 109 oxopyridin-1(2H)-yl]-N-hydroxy- 0.0073 32 32 0.56 433 2-methyl meth lsulfonyl)butanamide 4-{5-fluoro[2— (methoxymethyI)pheny|]—2- 110 oxopyridin-1 (2H)-yl}-N-hydroxy— >0.100 >640 >64 0 >64 0 0.56 2-methyl-2— meth Isulfon l butanamide 111 0500000200000- 0.0030 0.01 445.1 PCT/182012/050812 y-S-methylphenyi) oxopyridin-‘l (2H)-y|]-N-hydroxy— yI meth lsulfon amide 4-[4-(3-ethoxyphenyl)—5-fluoro- yridin-1(2H)-yl]—N— 112 0.0031 >64 0 2 4 hydroxy-Z—methyl-Z— (meth lsulfon |)butanamide 4—[5'—fluoro—2'-oxo-6— (trifluoromethyI)-3,4‘-bipyridin- 113 32 0.58 452 1'(2'H)—yl]—N- hyd roxy—2—methyl- meth lsulfon lbutanamide 4-[4—(4—cyano—3-methylphenyl)- —fluoro—2—oxopyridin-1(2H)~yi]- 4 2 0.57 422 1 N—hydroxy—Z—methyl-Z- meth lsulfon l butanamide (dimethylamino)pyrimidin—S-yl]~ -fluorooxopyridin~1(2H)—yl}- 0.0741 3 N-hydroxy-2—methyl meth lsulfon lbutanamide 4-[5-fluoro—4-(3—fluorophenyl) oxopyridin-1(2H)—yl]—N—hydroxy— 2-methyl-2— meth lsulfon lbutanamide 4-[4-(2,3—difluorophenyI)—5- Z-oxopyridin-1(2H)—yl]—N— hydroxy—Z-methyI (meth lsulfon Dbutanamide 4-[5-fluoro—4-(2-fluoro methoxyphenyl)oxopyridin- . 1 1 0.57 1(2H)-y|]-N-hydroxy—2—methyl meth lsulfon I butanamide 3—cyano—5— methoxyphenyl)—5—fluoro—2— oxopyridin-1 (2H)—yI]-N-hydroxy- . 64 0.57 2-methyl-2— (meth lsulfon l butanamide 4-[4-(2,3-dihydro—1—benzofuran- —fluoro-2—oxopyridin- 2 1 0.57 1(2H)—y|]-N-hydroxy—2—methyI-2— meth lsulfon I butanamide 4—[5—fluoro0xo—4—(1 H—pyrazol- 3—yl)pyridin-1(2H)—yI]-N~ hydroxy-Z-methyI-Z- meth lsulfon lbutanamide I-- 4-{5-fluoro—4—[2-fluoro—3- xymethyl)phenyI] oxopyridin-1 (2H)-yl}-N-hyd roxy— 0.0024 I 2-methyl-2— (meth lsulfon l)butanamide 4-{4-[3—(2—amino oxoethyl)phenyI]fluoro-Z- 123 oxopyridin~1 (2H)-yl}-N-hydroxy- >640 >640 2-methyI meth lsulfon I)butanamide 4-[4-(4—cyanophenyl)—5-fluoro-2— oxopyridin-1(2H)-yI]—N-hydroxy- 124 0.0034 >640 8 0.53 408 2-methyl-2— (meth lsulfon |)butanamide 4-[5-fiuoro-4—(2- 8 0.57 413.1 PCT/132012/050812 1 (2H)-yl]-N-hydroxy-Z-methyl-Z- meth n Ibutanamide Claims

Claims (10)

What is claimed 1. is:
1. A compound of the formula: — 02-R1 H . N\ or a pharmaceutically acceptable salt thereof, in which: 10 R1 is represented by 01-03 alkyl; R2 is represented by hydrogen or 01-03 alkyl; R3 is ented by hydrogen, halogen, hydroxy, cyano, C1—Csalkyl, Cj-CBalkoxy, trifluoromethyl or trifluoromethoxy; T is represented by ethynyl, optionally substituted (CB-C10)aryl or optionally tuted 15 heteroaryl; D is absent, or is ented by —(CH2)r-, -(CH2)n-O-(CH2)p-, 0r a bond; r is represented by the integer 1, 2, or 3; n and p are each independently represented by the integer 0, 1, or 2; E is absent, or is represented by a substituent selected from the group consisting of: 20 i) (C3_C1o)cyc|oalkyl, optionally substituted; ii) (Ce—C10)aryl optionally substituted; iii) heteroaryl, optionally substituted; and iv) heterocyclic, optionally substituted; with the o that: 25 1) if E is absent, then D is also absent; 2) T is not ented by unsubstituted phenyl; when E and D both are absent, R3 is hydrogen and R1 and R2 are each methyl.
2. A compound according to claim 1 in which R1 and R2 are each methyl.
3. A compound according to claim 1 or 2 in which R3 is hydrogen. 5
4. A compound according to claim 2 or 3 in which said compound is the R- enantiomer, substantially pure.
5. A compound according to any one of claims 1, 2, 3 or 4 in which T is represented by phenyl which may be optionally substituted.
6. A compound according to any one of claims 1, 2, 3, 4 or 5 in which D and E are both absent.
7. A compound according to any one of claims 1—5 in which D is a bond.
8. A compound according to claim 7 in which E is represented by cyclohexyl, pyrimidinyl, triazolyl, pyridinyl, isoxazolyl, or cyclopropyl, any of which may be optionally substituted. 20
9. A compound of the a R3 \\ or a pharmaceutically acceptable salt thereof, in which; 25 R3 is represented by hydrogen, halogen, hydroxy, cyano, lkyl, C1- CBalkoxy, trifluoromethyl or trifluoromethoxy; Ra is represented by one or more tuents selected from the group consisting of C1—Cgalkyl, 01-03 alkoxy, fluorine, chlorine, y, trifluoromethyl and trifluoromethoxy.
10. (2R){5-Fluorooxo—4-[4-(2H-1 ,2,3-triazol-2—yl)phenyl]pyridin—1(2H)—yl}-N- hyd roxymethyl-2—(methylsulfonyl)butanamide, or a pharmaceutically acceptable salt thereof. 1 1 . (2 R)[5—Fluo ro(2-fluoro—4-methoxyphenyl)-2—oxopyridin-1 (2H)-yl]-N-hydroxy— yl-2—(methylsulfonyl)butanamide, or a pharmaceutically acceptable salt thereof. 10 12. A pharmaceutical composition comprising a compound according to any one of claims 1—11 in admixture with at least one ceutically acceptable excipient. 13.Use of a compound according to any one of claims 1—11 in the manufacture of a medicament for treating bacterial infections. 14.A compound according to any one of claims 1 or 9—1 1, substantially as herein described with reference to any one of the Examples thereof. 15.A compound according to any one of claims 1-11, substantially as herein 20 descflbed. 16.A pharmaceutical composition according to claim 12, ntially as herein 25 17.Use according to claim 13, substantially as herein described.
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