[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

NZ625737B2 - Pyrazolo[1,5-a]pyrimidines as antiviral agents - Google Patents

Pyrazolo[1,5-a]pyrimidines as antiviral agents Download PDF

Info

Publication number
NZ625737B2
NZ625737B2 NZ625737A NZ62573712A NZ625737B2 NZ 625737 B2 NZ625737 B2 NZ 625737B2 NZ 625737 A NZ625737 A NZ 625737A NZ 62573712 A NZ62573712 A NZ 62573712A NZ 625737 B2 NZ625737 B2 NZ 625737B2
Authority
NZ
New Zealand
Prior art keywords
compound
alkyl
formula
aryl
compounds
Prior art date
Application number
NZ625737A
Other versions
NZ625737A (en
Inventor
Constantine G Boojamra
Hon Chung Hui
Petr Jansa
Richard L Mackman
Jay P Parrish
Michael Sangi
Dustin Siegel
David Sperandio
Hai Yang
Original Assignee
Gilead Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority claimed from PCT/US2012/071065 external-priority patent/WO2013096681A1/en
Publication of NZ625737A publication Critical patent/NZ625737A/en
Publication of NZ625737B2 publication Critical patent/NZ625737B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

Disclosed are compounds and pharmaceutically acceptable salts and esters and compositions thereof, for treating viral infections. The compounds and compositions are useful for treating Pneumovirinae virus infection including Human respiratory syncytial virus infections. The compounds have a pyrazolo[1,5-a]pyrimidines core. [1,5-a]pyrimidines core.

Description

PYRAZOLO[1,5-A]PYRIMIDTNES AS ANTIVIRAL AGENTS Cross Reference to Related Applications This patent application claims the benefit of priority ofUS. Application Serial No. 61/579625, filed December 22, 2011 and of US. application serial No. 61/618510, filed March 30, 2012. The content of each of these provisional ations is hereby incorporated herein in its entirety.
Background Pneumovirinae s are negative-sense, single—stranded, RNA viruses that are responsible for many prevalent human and animal diseases. The Pneumbvirinae sub-family of viruses is a part of the family Paramyxoviridae and includes human respiratory syncytial virus (HRSV). Almost all children will have had an HRSV infection by their second birthday. HRSV is the major cause of lower respiratory tract infections in infancy and childhood with 0.5% to 2% of those infected requiring hospitalization. The elderly and adults with c heart, lung e or those that are immunosuppressed also have a high risk for developing severe HRSV disease //www.cdc.gov/rsv/index.html). No e to prevent HRSV infection is currently available. The monoclonal antibody zumab is available for immunoprophylaxis, but its use is restricted to infants at high risk, e. g., premature infants or those with either ital heart or lung disease, and the cost for general use is often prohibitive. In addition, nucleoside analog ribavirin has been approved as the only antiviral agent to treat HRSV infections but has limited efficacy. Therefore, there is a need for anti-Pneumovirz'nae therapeutics.
Summm ed herein are methods and compounds for the treatment of infections caused by the Pneumovirinae virus family.
Accordingly, one embodiment provides a compound of formula I: WO 96681 or a salt or ester, thereof; wherein: A is —(C(R4)2)n— wherein any one C(R4)2 of said —(C(R4)2)n- may be optionally replaced with -O-, -S—, —S(O)p-, NH-or NR3; nis3,4, 5 or6; each p is l or 2; Ar is a C2-C20 heterocyclyl group or a C6-C20 aryl group, wherein the C2—C20 heterocyclyl group or the C6-C20 aryl group is optionally tuted with l, 2, 3, 4 or 5 R6; each R3, R4 and R6 is independently H, oxo, OR“, NRURIZ, NR“C(O)R11, NR“C(0)0R“, NR”C(O)NR“R12, N3, CN, N02, SR“, S(O)pRa, NR“S(O)pRa, -C(=O)R”, - C(=O)OR“, —C(=0)NR“R‘2, -C(=0)SR“, -S(O)p(OR“), -SOzNR”R12, —NR“S(0)p(0R“), pNRllR”, NR“C(=NR“)NR”R12, halogen, (C1—C3)alkyl, (C2—C3)alkenyl, (C2—C3)alkynyl, aryl(C1-C3)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—C8)carbocyclylalkyl; or two R4 on adjacent carbon atoms, when taken together, may optionally form a double bond between the two carbons to which they are attached or may form a (C3-C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by -O-, -S-, -S(O)p-, -NH- or -NRa—; or four R4 on adjacent carbon atoms, when taken er, may optionally form an optionally substituted C6 aryl ring; or two R4 on the same carbon atom, when taken er, may optionally form a (C3— C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloa1kyl ring may be optionally replaced by -O-, -S-, —S(O)p-, -NH- or —NRa—; or two R6 on nt carbon atoms, when taken together, may optionally form a (C3- C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by -O-, -S-, -S(O)p-, —NH— or ~NRa-g each R3 is independently (C1-C3)a1kyl, )haloalkyl, (C2-Cg)alkenyl, (C2-Cg)alkyny1, ary1(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—C8)carbocyclylalkyl wherein any )alkyl, (C1-C8)haloalkyl, (C2-Cg)alkenyl or (C2- Cg)alkynyl of Ra is optionally substituted with one or more OH, NH2, CO2H, C2—C20 cyclyl, and wherein any aryl(C1-C3)alkyl, C6—C20 aryl, C2—C2o heterocyclyl, (C3- C7)cycloalkyl or (C4—C3)carbocyclylalkyl of Ra is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) OH, NH2, CO2H, C2—C20 cyclyl or (C1-C3)alkyl; each R11 or R12 is independently H, (Cl—Cg)alkyl, (C2-Cg)alkenyl, )alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl, (C4—C8)carbocyclylalkyl, Ra, Ra or aryl(C1-Cg)alkyl; or R11 and R12 taken together with a nitrogen to which they are both ed form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O—, -S-, -S(O)p—, —NH-, —NRa- or -C(O)—; and wherein each (Cl-Cg)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—Cg)carbocyclylalkyl of each R6, R11 or R12 is, independently, optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) 0x0, halogen, hydroxy, NH2, CN, N3, N(Ra)2, NHRa, SH, SR3, S(O)pRa, ORa, (C1-C8)alkyl, (Cl—Cg)haloalkyl, -C(O)Ra, -C(O)H, —C(=O)ORa, -C(=O)OH, —C(=O)N(Ra 2 , -C(=O)NHRa , -C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NR“C(O)N(Ra 2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra 2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NRaS(O) pN(Ra 2, ) pNH2, NHS(O) lDNHRa, NHS(O) pN(Ra 2, NHS(O) pNH2, -OC(=O)Ra, —OP(O)(OH)2 or Ra; provided the compound is not: N N/ DM‘OH Cl Nj-l \\}\I O 6’ I Another embodiment provides a compound of formulas 1—1 11 (i.e., compounds 1-111), as described in examples 1 and 2, or a salt or ester thereof.
Another embodiment provides a compound of formula I (e.g., compounds 112-209) or a stereoisomer (e.g. enantiomer, diasteromer, atropisomer) or a salt or ester thereof.
Another embodiment provides a compound of formulas 1-111 or a stereoisomer (e.g., enantiomer, diasteromer, atropisomer) or a salt or ester thereof.
Another embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt f, and a pharmaceutically acceptable carrier.
Another embodiment provides a ceutical composition comprising a compound of formulas 1-1 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable r embodiment provides a method of treating a Pneumovirinae infection in a mammal (e.g., a human) in need thereof sing administering a therapeutically effective amount of a compound of a I or a pharmaceutically acceptable salt or ester thereof.
Another ment provides a method of treating a Pneumovirinae infection in a mammal (e.g., a human) in need f comprising administering a therapeutically effective amount of a compound of formulas 1-111, or a pharmaceutically acceptable salt or ester thereof.
Another embodiment es a method of treating a virinae infection in a mammal (e.g., a human) in need thereof comprising administering a therapeutically effective amount of a, tautomer, polymorph, pseudopolymorph, amorphous form, e or solvate of a compound of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof.
Another embodiment es a method of treating a Pneumovirinae infection in a mammal (e.g., a human) in need f comprising administering a therapeutically effective amount of a, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a compound of formulas 1—1 1 l, or a pharmaceutically acceptable salt or ester f.
Another embodiment provides a method of treating a atory syncytial Virus infection in a mammal (e.g., a human) in need thereof comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof.
Another embodiment provides a method of treating a respiratory syncytial virus infection in a mammal (e.g., a human) in need thereof comprising administering a therapeutically effective amount of a compound of formulas 1-111, or a pharmaceutically acceptable salt or ester thereof.
Another embodiment provides a method of treating a respiratory syncytial virus infection in a mammal (e.g., a human) in need f comprising administering a therapeutically effective amount of a tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or e of a nd of formula I, or a pharmaceutically acceptable salt or ester thereof.
Another embodiment provides a method of ng a atory syncytial virus infection in a mammal (e.g. a human) in need thereof comprising administering a therapeutically effective amount of a tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or e of a compound of formulas 1-111, or a pharmaceutically acceptable salt or ester f.
Another embodiment provides a method of treating a virinae infection in a mammal (e.g. a human) in need thereof comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof, and a ceutically acceptable diluent or carrier.
Another embodiment provides a method of treating a Pneumovirinae infection in a mammal (e.g. a human) in need f comprising administering a therapeutically effective amount of a compound of formulas 1-111 or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically able diluent or carrier.
Another embodiment provides a method of treating a virinae infection in a mammal (e.g. a human) in need thereof comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof, in combination with at least one additional therapeutic agent. r embodiment provides a method of treating a Pneumovirinae infection in a mammal (e.g. a human) in need thereof comprising administering a therapeutically effective amount of a nd of formulas 1-111 or a pharmaceutically acceptable salt or ester thereof, in combination with at least one additional therapeutic agent.
Another embodiment provides a method of treating a Pneumovirinae infection in a mammal (e.g. a human) in need thereof, comprising administering a therapeutically effective amount of a combination ceutical agent comprising: a) a first pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or ester thereof; and b) a second ceutical composition comprising at least one additional therapeutic agent active against infectious Pneumovirinae viruses.
Another embodiment provides a method of treating a Pneumovirinae ion in a mammal (e.g. a human) in need f, comprising administering a therapeutically effective amount of a combination pharmaceutical agent comprising: a) a first pharmaceutical composition comprising a compound of formulas 1-111 or a pharmaceutically acceptable salt or ester thereof; and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Pneumovirinae viruses.
Another ment provides a method of treating a Pneumovirz‘nae infection in a mammal (e.g. a human) in need thereof, comprising administering a therapeutically effective amount of a combination ceutical agent comprising: a) a therapeutic agent selected from a compound a of formula I and pharmaceutically acceptable salts and esters thereof; and b) a therapeutic agent active against ious virinae viruses.
Another ment provides a method of treating a Pneumovirinae infection in a mammal (e.g. a human) in need thereof, comprising administering a therapeutically effective amount of a ation pharmaceutical agent comprising: a) a therapeutic agent selected from a compound of formulas 1—1 11 and pharmaceutically acceptable salts and esters thereof; and b) a therapeutic agent active against infectious Pneumovirinae Viruses.
Another embodiment provides a method of treating a respiratory syncytial Virus infection in a mammal (e.g. a human) in need thereof, comprising administering a therapeutically ive amount of a combination pharmaceutical agent comprising: a) a first ceutical composition comprising a compound of a I or a pharmaceutically acceptable salt or ester thereof; and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious respiratory syncytial Viruses.
Another embodiment provides a method of treating a respiratory ial virus infection in a mammal (e.g. a human) in need thereof, comprising administering a therapeutically ive amount of a combination pharmaceutical agent comprising: a) a first pharmaceutical composition comprising a compound of formulas 1-111 or a pharmaceutically acceptable salt or ester thereof; and 1.0 b) a second ceutical composition comprising at least one additional therapeutic agent active against ious respiratory syncytial s. r embodiment provides a method of treating a respiratory syncytial virus infection in a mammal (e.g. a human) in need thereof, comprising administering 'a therapeutically effective amount of a combination pharmaceutical agent comprising: a) a therapeutic agent selected from a compound of formula I and pharmaceutically acceptable salts and esters thereof; and b) a therapeutic agent active against infectious Pneumovirinae s.
Another embodiment provides a method of treating a respiratory syncytial virus infection in a mammal (e.g. a human) in need thereof, comprising administering a eutically effective amount of a combination pharmaceutical agent comprising: a) a therapeutic agent selected from a compound of formulas 1-111 and pharmaceutically acceptable salts and esters thereof; and b) a therapeutic agent active against infectious Pneumovirinae viruses.
Another embodiment provides a compound of formula I or a pharmaceutically acceptable salt or ester thereof, for use in medical y.
Another embodiment provides a compound of formulas 1-111 or a pharmaceutically acceptable salt or ester thereof for use in medical y.
Another embodiment provides a compound of formula I or a pharmaceutically acceptable salt or ester thereof, for use in the prophylactic or therapeutic treat a viral infection caused by a Pneumovirinae virus or a respiratory syncytial virus.
Another ment provides a compound of formulas 1-111 or a pharmaceutically acceptable salt or ester f, for use in the prophylactic or therapeutic treat a viral infection caused by a Pneumovirinae virus or a respiratory syncytial virus.
Another embodiment provides the use of a compound of formula I or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament useful for the treatment of l 00 1 406004 a viral infection caused by a Pneumovirz‘nae virus or a respiratory syncytial virus in a mammal (e. g. a human).
Another embodiment provides the use of a compound of formulas 1-1 ll or a pharmaceutically able salt or ester thereof for the manufacture of a medicament useful for the ent of a viral infection caused by a Pneumovirinae virus or a respiratory ial virus in a mammal (e.g. a human). r embodiment provides processes and novel intermediates disclosed herein which are useful for preparing a compound of formula I or a compound of formulas 1—1 1 1.
Another embodiment provides novel methods for synthesis, analysis, separation, isolation, purification, characterization, and testing ofthe compounds as disclosed herein.
Detailed Description Definitions Unless stated ise, the following terms and phrases as used herein are intended to have the following meanings: When trade names are used herein, ants intend to independently include the tradename product and the active ceutical ingredient(s) ofthe tradename product.
As used herein, the term ”comprise” and variations ofthe term, such as "comprising", "comprises" and "comprised”, are not intended to exclude other additives, components, rs or steps.
The term “alkyl” refers to a straight or branched arbon. For example, an alkyl group can have 1 to 20 carbon atoms (i.e, C1-C20 alkyl), 1 to 8 carbon atoms (i.e., C1—C8 , or 1 to 6 carbon atoms (126., C1—C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, —CH2CH3), l-propyl (fl—Pl‘, g-propyl, —CHgCHzCl~lg), 2—propyl (i—Pr, i-propyl, —CH(CH3)2), l~butyl (n—Bu, rybutyl, -CH2CH2CH2CH3), 2—methyl~l~propyl (i—Bu, i—butyl, — CH2CH(CH3)2), 2—butyl (s—Bu, s—butyl, ~CH(CH3)CH2CH3), 2-methyl—2—propyl (t—Bu, t—butyl, — C(CH3)3), l—pentyl (n-pentyl, ~CH2CH2CH2CH2CH3), yl (—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 2—methylbutyl (—C(CH3)2CH2CH3), 3-methylbutyl (—CH(CH3)CH(CH3)2), 3~methyl-l—butyl (—CH2CH2CH(CH3)2), 2-methyl—l—butyl (—CHzCH(CH3)CH2CH3), l-hexyl (—CHzCHgCHzCHZCHZCHg), 2-hexy1 (-CH(CH3)CH2CH2CH2CH3), l (— CH(CH2CH3)(CH2CH2CH3)), 2-methyl—2—pentyl (—C(CH3)2CH2CH2CH3), 3-methyl—2-pentyl (-CH(CH3)CH(CH3)CH2CH3), ylpentyl (—CH(CH3)CH2CH(CH3)2), yl—3-pentyl (- C(CH3)(CH2CH3)2), 2-methyl—3—pentyl (—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl—2-butyl (-C(CH3)2CH(CH3)2), 3,3—dimethyl-2—butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3)_ The term “alkoxy” refers to a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon i.e., C1—C12 alkoxy), or 1 to 6 carbon atoms(i.e,, C1-C6 ). Examples of le alkoxy groups include, but are not limited to, methoxy (-O-CH3 or ~OMe), ethoxy (-OCHZCH3 or -OEt), t—butoxy (-O-C(CH3)3 or —OtBu) and the like.
The term “haloalkyl” refers to an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms(i.e., C1-C12 haloalkyl), or 1 to 6 carbon atoms(i.e., C1—C6 alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like.
The term “alkenyl” refers to a straight or branched hydrocarbon with at least one site of ration, z'. e. a carbon-carbon, spz double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (1'. e., C2-C20 alkenyl), 2 to 8 carbon atoms (i. e., C2-C8 alkenyl), or 2 to 6 carbon atoms (1'. e. , C2—C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl H=CH2), cyclopentenyl (-C5H7), and 5- hexenyl (-CH2CH2CH2CH2CH=CH2).
The term “alkynyl” refers to a straight or branched hydrocarbon with at least one site of unsaturation, i. e. a carbon-carbon, sp triple bond. For example, an alkynyl group can have 2 to 20 carbon atoms (i. e., C2-C20 alkynyl), 2 to 8 carbon atoms (i. e., C2-C8 alkyne,), or 2 to 6 carbon atoms (i. e., C2—C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic ), propargyl ECH), and the like.
The term en” or “halo” refers to F, Cl, Br, or I.
The term “aryl” refers to an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. l aryl groups e, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
The term “arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical kyl groups include, but are not limited to, benzyl, 2-phenylethan—1-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, thophenylethan—1-yl and the like.
The arylalkyl group can comprise 7 to 20 carbon atoms, e.g. , the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
The term “prodrug” as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
One d in the art will recognize that tuents and other moieties of the compounds of formula I should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of formula I which have such stability are plated as falling within the scope ofthe present invention.
The term “heterocycle” or “heterocyclyl” as used herein includes by way of example and 2O not limitation those heterocycles bed in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistg (WA. Benjamin, New York, 1968), particularly rs 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in ular Volumes 13, 14, 16, 19, and 28; and J Am.
Chem. Soc. (1960) 8225566. In one specific embodiment of the invention “heterocycle” includes a “carbocycle” as defined herein, wherein one or more (e.g. l, 2, 3, or 4) carbon atoms have been ed with a heteroatom (e.g. 0, N, or S). The terms “heterocycle” or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i. e. , heteroaromatic rings). Substituted cyclyls e, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl . A non-limiting example of a carbonyl substituted heterocyclyl is: Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfiir oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofiiranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, olidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H—1,2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, lH-indazoly, purinyl, 4H- quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, inyl, pteridinyl, rbazolyl, carbazolyl, fi-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, hiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, riazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, oyl, and trahydrofuranyl: By way of example and not tion, carbon bonded cycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or azole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles e 2—pyridyl, dyl, 4—pyridyl, 5-pyridyl, dyl, 3-pyridazinyl, 4-pyridazinyl, 5—pyridazinyl, 6-pyridazinyl, midinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6- pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5—pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5- thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2—pyrroline, 3—pyrroline, imidazole, imidazolidine, 2-imidazoline, azoline, pyrazole, pyrazoline, zoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH—indazole, position 2 of a ole, or isoindoline, position 4 of a line, and position 9 of a carbazole, or B-carboline. Still more typically, nitrogen bonded heterocycles include l-aziridyl, edyl, olyl, 1-imidazolyl, 1- pyrazolyl, and 1-piperidinyl.
The term “heteroaryl” refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all of those aromatic rings listed in the definition of “heterocyclyl”, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, lyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, nolyl, pyridazyl, pyrimidyl, l, etc.
The term “carbocycle” or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or ic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a o [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro- fused rings. Non-limiting examples of monocyclic carbocycles e cyclopropyl, cyclobutyl, cyclopentyl, 1 pent— 1 -enyl, 1 -cyclopent-2—enyl, 1 -cyclopent-3 -enyl, cyclohexyl, 1 - cyclohex-l-enyl, 1-cyclohexenyl, ohex-3 -enyl, and phenyl. Non-limiting examples of bicyclo carbocycles includes naphthyl, tetrahydronapthalene, and decaline.
The term “cycloalkyl” refers to a saturated or partially unsaturated ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic cycloalkyl groups have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic cycloalkyl groups have 7 to 12 ring atoms, e.g., arranged as a bicyclo (4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms arranged as a bicyclo (5,6) or (6,6) system. Cycloalkyl groups include hydrocarbon mono-, bi-, and poly-cyclic rings, whether fused, bridged, or Spiro. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, l-cyclopent—l-enyl, l-cyclopentenyl, 1-cyclopentenyl, cyclohexyl, 1—cyclohex-1—enyl, 1-cyclohexenyl, l-cyclohexenyl, bicyclo[3.1.0]hex—6-yl and the like.
The term “carbocyclylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein. Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
Selected tuents comprising the compounds of formula I may be present to a recursive degree. In this context, “recursive substituent” means that a substituent may recite another instance of itself. The multiple recitations may be direct or indirect through a sequence of other substituents. Because of the recursive nature of such substituents, theoretically, a large number of nds may be present in any given ment. One of ordinary skill in the art of medicinal chemistry tands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular , solubility or log P, ation properties such as ty against the intended target, and practical ties such as ease of synthesis. Recursive substituents may be an intended aspect of the invention. One of ry skill in the art of medicinal try understands the versatility of such substituents.
To the degree that recursive tuents are present in an embodiment of the invention, they may recite another ce of themselves, 0, 1, 2, 3, or 4 times.
“Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The al substructure of a protecting group varies widely. One function of a protecting group is to serve as an intermediate in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. 3O Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity phobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.
Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in viva, such as passage through cellular membranes and resistance to tic degradation or sequestration. In this role, protected compounds with intended eutic effects may be referred to as prodrugs. Another on of a protecting group is to convert the parental drug into a g, whereby the parental drug is released upon conversion of the prodrug in vivo. e active prodrugs may be absorbed more effectively than the al drug, prodrugs may possess greater potency in viva than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are acologically innocuous.
“Prodrug moiety” means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, tic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes which are capable of an enzymatic activation mechanism with, for example any phosphate or phosphonate prodrug compounds of the invention, include but are not limited to, amidases, esterases, microbial enzymes, olipases, cholinesterases, and phosphases. Prodrug es can serve to enhance solubility, tion and lipophilicity to optimize drug delivery, bioavailability and efficacy. A g moiety may include an active metabolite or dmg itself.
It is to be noted that all tautomers, atropisomers, polymorphs, pseudopolymorphs of compounds disclosed herein and pharmaceutically acceptable salts and esters thereof are embraced by the present invention.
A compound disclosed herein and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline nd to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal g (packing polymorphism) or differences in packing between different conformers of the same molecule rmational polymorphism). As used herein, crystalline polymorphism means the y of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in g between different conformers of the same molecule rmational pseudopolymorphism). The instant invention comprises all polymorphs and pseudopolymorphs of the compounds disclosed herein A nd disclosed herein and its pharmaceutically acceptable salts may also exist as an amorphous solid. As used herein, an amorphous solid is a solid in which there is no long- range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less. Additives, ing solvents, may be used to create the amorphous forms of the instant invention. The instant invention comprises all amorphous forms of the compounds disclosed herein and their ceutically acceptable salts.
The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).
The term “treating”, as used herein, unless otherwise ted, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more ms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.
The term “therapeutically effective amount”, as used , is the amount of compound sed herein present in a composition described herein that is needed to provide a d level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological se or desired biological effect when such a composition is stered by the chosen route of administration.
The precise amount will depend upon numerous factors, for example the particular disclosed herein, the c activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art and in reference to the information ed herein.
The term “normal saline” means a water on containing 0.9% (w/v) NaCl.
The term “hypertonic saline” means a water solution containing greater than 0.9% (w/v) NaCl. For example, 3% hypertonic saline would contain 3% (w/v) NaCl.
Physiologically acceptable salts (e.g. pharrnaceutically acceptable salt) of the compounds of the invention e salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na+, Li+, K+a Ca+2 and Mg+2), ammonium and NR4.
Physiologically acceptable salts of a en atom or an amino group include (a) acid addition salts formed with nic acids, for example, hydrochloric acid, hydrobromic acid, ic acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, c acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, onic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, enesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2—hydroxy naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for e, chlorine, bromine, and iodine. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NR4+. Each R is independently selected from H and (C1-C3)alkyl.
For therapeutic use, salts of active ingredients of the nds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the ation or purification of a physiologically acceptable compound.
All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
It is to be understood that the compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Stereochemical definitions and tions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw—Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistg of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many c nds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the s D and L or R and S are used to denote the absolute configuration of the molecule about its chiral (s). The prefixes d and l, D and L, or (+) and (-) are employed to ate the sign of rotation of plane-polarized light by the compound, with S, (—), or 1 meaning that the compound is levorotatory while a compound d with R, (+), or d is dextrorotatory.
For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic e or a racemate, which may occur where there has been no selection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture oftwo enantiomeric species, devoid of optical ty.
The compounds disclosed herein have chiral centers, e.g. chiral carbon. The compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers. Individual enantiomers or diasteromers, ed or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The stereoisomeric mixtures can ted into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of reomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. Typically, the desired l isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image r.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have ent physical properties, e.g. g points, boiling points, spectral properties, and reactivities. Mixtures of reomers may separate under high resolution analytical procedures such as electrophoresis WO 96681 and chromatography. Enantiomers" refer to two isomers of a compound which are non- superimposable mirror images of one another.
It is to be understood that for nds disclosed herein when a bond is drawn in a non-stereochemical manner (e.g. flat) the atom to which the bond is ed includes all stereochemical possibilities. It is also to tood that when a bond is drawn in a stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge) the atom to which the stereochemical bond is attached has the stereochemistry as shown unless ise noted.
Accordingly, in one embodiment, the nds disclosed herein are greater than 50% a single enantiomer. In another embodiment, the compounds disclosed herein are at least 80% a single enantiomer. In another embodiment, the compounds disclosed herein are at least 90% a single enantiomerln another embodiment, the compounds disclosed herein are at least 98% a single enantiomer. In another embodiment, the compounds disclosed herein are at least 99% a single enantiomer. In another embodiment, the compounds disclosed herein are greater than 50% a single diastereomer. In another embodiment, the compounds disclosed herein are at least 80% a single diastereomer. In another embodiment, the compounds disclosed herein are at least 90% a single diastereomer. In another embodiment, the compounds disclosed herein are at least 98% a single diastereomer. In another embodiment, the compounds disclosed herein are at least 99% a single diastereomer.
In one ment compounds are represented by formula I and la (and salts and esters, thereof) as shown below wherein one on of chirality is marked with an asterisk.
/ ‘N \ A Q N .IIOH N N F0 "‘OH Ar 0 la u ’ A“ I ON EN The stereochemistry at the carbon marked with an asterisk as shown above for formula I is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system or the (R) stereochemistry provided that A is ranked number 2 of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system (March, J Advanced Organic Chemistery, 4th on, John Wiley and Sons, pages 109-111). The stereochemistry at the carbon marked with 2012/071065 an asterisk as shown above for formula la is the (S) stereochemistry. In one embodiment, the ' compounds of formula I and la are greater than 50% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula I and la are at least 60% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula I and la are at least 70% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula I and la are at least 80% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula I and la are at least 90% a single isomer at the asterisk position. In another embodiment, the compounds of formula I and la are at least 95% a single stereoisomer at the asterisk position.
In one ment compounds are represented by formula I and la (and salts and esters, thereof) as shown below wherein three positions of ity are marked with an asterisk.
MW // N \ .1 a if .3 N N *3 N k Om” N N )=0 Odo”t Ar o *2 l Ar Ia *2 '2 I CN CN The stereochemistry at the carbon marked with an asterisk 1 (* 1) as shown above for formula I is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk 1 (*1) carbon following the Cahn-Ingold-Prelog system or the (R) stereochemistry provided that A is ranked number 2 of the three substituents of the asterisk l (* 1) carbon following the Cahn—Ingold—Prelog system. The stereochemistry at the carbon marked with an sk 1 (*1) as shown above for formula la is the (S) stereochemistry. The stereochemistry at the carbon marked with an sk 2 (*2) as shown above for formula I and formula Ia is the (S) stereochemistry. The stereochemistry at the carbon marked with an asterisk 3 (*3) as shown above for formula I and formula la is the (R) chemistry. In one ment, the nds of formula I and Ia are greater than 50% a single stereoisomer at each of the asterisk positions. In another embodiment, the nds of formula I and la are at least 60% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formula I and la are at least 70% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formula I and la are at least 80% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formula I and la are at least 90% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds formula I and la are at least 95% a single stereoisomer at each of the asterisk positions.
In one embodiment compounds are represented by formulas II or IIa or salts or esters thereof, wherein one position of chirality is marked with an asterisk.
R3 A ' N\N \ / N\ / / OH N N N u if to IIa ow CN Ar The stereochemistry at the carbon marked with an asterisk as shown above for formula II is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system or the (R) stereochemistry provided that A is ranked number 2 of the three substituents of the asterisk carbon following the Cahn-Ingold—Prelog system. The stereochemistry at the carbon marked with an sk as shown above for formula 11a is the (S) chemistry. In one ment, the compounds of a II and 11a are greater than 50% a single stereoisomer at the asterisk position. In another embodiment, the compounds of a II and 11a are at least 60% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula II and 11a are at least 70% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula II and 11a are at least 80% a single stereoisomer at the asterisk position.
In r embodiment, the compounds of formula II and 11a are at least 90% a single stereoisomer at the asterisk on. In another embodiment, the nds of formula II and 11a are at least 95% a single stereoisomer at the sk position.
One embodiment es compounds of formula II and 11a (and salts and esters, thereof) as shown below wherein three positions of chirality are marked with an asterisk. 3 N \ R3 N / *1 N/ *1 / / *3 N *3 N A N N OH OH Ar >20 0 11 *2 r Ha *2 CN CN 2012/071065 The stereochemistry at the carbon marked with an asterisk 1 (*1) as shown above for formula II is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk 1 (*1) carbon following the Cahn-Ingold-Prelog system or the (R) stereochemistry provided that A is ranked number 2 of the three substituents of the sk 1 (*1) carbon following the ngold-Prelog system. The stereochemistry at the carbon marked with an asterisk 1 (*1) as shown above for a Ila is the (S) stereochemistry.
The stereochemistry at the carbon marked with an asterisk 2 (*2) as shown above for formula II and formula 11a is the (R) stereochemistry. The stereochemistry at the carbon marked with an asterisk 3 (*3) as shown above for formula I and formula Ia is the (S) stereochemistry. In one embodiment, the compounds of formula II and Ila are r than 50% a single stereoisomer at each of the sk positions. In another embodiment, the compounds of a II and 11a are at least 60% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formula I and Ia are at least 70% a single stereoisomer at each of the sk positions. In another embodiment, the compounds of formula II and Ila are at least 80% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formula II and 11a are at least 90% a single stereoisomer at each of the asterisk positions. In another embodiment, the nds of formula II and 11a are at least 95% a single stereoisomer at each of the asterisk positions.
One embodiment provides for compounds of formulas III or IIIa or salts or esters thereof. Compounds of formula III and IIIa are shown below wherein one position of chirality is marked with an asterisk.
R3 A N \ N \ N / ‘N \ A N N N ...QH Ar): .nOH Ar 0 IIIa III ON ON The stereochemistry at the carbon marked with an asterisk as shown above for formula III is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system or the (R) stereochemistry ed that A is ranked number 2 of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system. The stereochemistry at the carbon marked with an asterisk as shown above for a IIIa is the (S) stereochemistry. In one embodiment, the compounds of formula III and Illa are greater than 50% a single stereoisomer at the sk position. In another ment, the compounds of formula III and Illa are at least 60% a single isomer at the asterisk position. In r embodiment, the compounds of formula III and IIIa are at least 70% a single stereoisomer at the asterisk position. In another ment, the compounds of formula III and Illa are at least 80% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula III and IIIa are at least 90% a single stereoisomer at the asterisk on. In another embodiment, the compounds of formula III and IIIa are at least 95% a single stereoisomer at the asterisk position.
One embodiment provides compounds of formula III and 111a (and salts and esters, thereof) as shown below wherein three positions of chirality are marked with an asterisk.
R3 A #me / WN\N/\I N\ \ / N N N *3 N k N N ”IOH MOH Ar 0 III *2 Ar Illa *2 CN ON The stereochemistry at the carbon marked with an asterisk l (*1) as shown above for formula III is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk l (*1) carbon ing the Cahn-Ingold—Prelog system or the (R) stereochemistry provided that A is ranked number two of the three substituents of the asterisk 1 (*1) carbon following the Calm—Ingold-Prelog system. The stereochemistry at the carbon marked with an asterisk 1 (*1) as shown above for formula IIIa is the (S) stereochemistry. The stereochemistry at the carbon marked with an asterisk 2 (*2) as shown above for formula III and formula IIIa is the (R) stereochemistry. The stereochemistry at the carbon marked with an asterisk 3 (*3) as shown above for formula III and formula IIIa is the (R) stereochemistry. In one embodiment, the compounds of the invention of formula III and IIIa are greater than 50% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of the invention of formula III and Illa are at least 60% a single stereoisomer at each of the asterisk positions. In another embodiment, the nds of the invention of formula III and IIIa are at least 70% a single stereoisomer at each of the asterisk positions. In r embodiment, the compounds of the invention of formula III and IIIa are at least 80% a WO 96681 single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of the invention of formula III and IIIa are at least 90% a single stereoisomer at each of the sk positions. In another embodiment, the compounds of the invention of formula III and IIIa are at least 95% a single stereoisomer at each of the asterisk positions.
One embodiment provides for compounds of formulas IV or IVa or salts or esters thereof. Compounds of formula IV and IVa are shown wherein one position of chirality is marked with an asterisk.
R3 A N\N \ N\ N N N * O &OH ):0 -IV L CN CN The stereochemistry at the carbon marked with an asterisk as shown above for formula IV is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system or the (R) stereochemistry provided that A is ranked number 2 of the three tuents of the asterisk carbon following the Cahn-Ingold-Prelog system. The stereochemistry at the carbon marked with an asterisk as shown above for formula IVa is the (S) stereochemistry. In one embodiment, the compounds of a IV and IVa are r than 50% a single isomer at the asterisk position. In another embodiment, the compounds of formula IV and IVa are at least 60% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula IV and IVa are at least 70% a single stereoisomer at the asterisk on. In another embodiment, the compounds of a IV and IVa are at least 80% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula IV and IVa are at least 90% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formula IV and IVa are at least 95% a single stereoisomer at the asterisk position.
One embodiment provides compounds of a IV and IVa (and salts and esters, thereof) as shown below wherein three positions of chirality are marked with an asterisk.
R3 A N‘” \ W R3><w/ / *1 / / N N *3 N N *3 N N k %O OH Ar 0 &OH Ar IVa *2 5 IV *2 :CN CN The stereochemistry at the carbon marked with an asterisk l (*1) as shown above for formula IV is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk 1 (*1) carbon following the Cahn—Ingold-Prelog system or the (R) chemistry provided that A is ranked number 2 of the three substituents of the asterisk l (*1) carbon following the Cahn—Ingold-Prelog System. The stereochemistry at the carbon marked with an asterisk 1 (*1) as shown above for formula IVa is the (S) stereochemistry. The stereochemistry at the carbon marked with an asterisk 2 (*2) as shown above for formula IV and formula IVa is the (S) stereochemistry. The stereochemistry at the carbon marked with an sk 3 (*3) as shown above for formula IV and formula IVa is the (S) stereochemistry. In one embodiment, the compounds of formula IV and IVa are greater than 50% a single stereoisomer at each of the asterisk ons. In another ment, the compounds of a IV and IVa are at least 60% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formula IV and IVa are at least 70% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of 2O formula IV and IVa are at least80% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formula IV and IVa are at least 90% a single stereoisomer at each of the sk positions. In another embodiment, the compounds of a IV and IVa are at least 95% a single stereoisomer at each of the asterisk positions.
Each of the compounds of formulas 1-24 described herein have a core represented by formula V wherein a position of ity is marked with an asterisk (wherein R represents an amine).
CI N The stereochemistry at the carbon marked with an asterisk as shown for formula V is the (S) stereochemistry. In one embodiment, the compounds of formulas 1-24 are greater than 50% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formulas 1-24 are at least 60% a single stereoisomer at the asterisk position. In another embodiment, the compounds of as 1-24 are at least 70% a single isomer at the asterisk on. In another ment, the compounds of as 1—24 are at least 80% a single stereoisomer at the asterisk position. In another embodiment, the compounds of formulas 1-24 are at least 90% a single stereoisomer at the sk position. In another embodiment, the compounds of formulas 1-24 are at least 95% a single stereoisomer at the asterisk position.
Each of the compounds of formula 25-111 described herein have a core represented by formula VI wherein two positions of chirality are marked with an asterisk.
MiN\* / N N/ N Ar VI *2 ’3 The stereochemistry at the carbon marked with an asterisk 1 ( 1) as shown for formula V1 is the (S) stereochemistry. The stereochemistry at the carbon marked with an asterisk 2 ( 2) as shown for formula V1 is the (S) stereochemistry. In one embodiment, the compounds of formulas 25-111 are greater than 50% a single stereoisomer at each of the asterisk positions. In r ment, the compounds of formulas 25—1 11 are at least 60% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formulas 25-111 are at least 70% a single stereoisomer at each of the sk positions. In another embodiment, the compounds of formulas 25-111 are at least 80% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formulas 25-111 are at least 90% a single stereoisomer at each of the asterisk positions. In another embodiment, the compounds of formulas 25-111 are at least 95% a single stereoisomer at each of the asterisk positions.
The compounds disclosed herein also e molecules that orate isotopes of the atoms specified in the particular molecules. Non-limiting examples of these isotopes include D, T, 14C, 13C and 15N.
Whenever a compound described herein is substituted with more than one of the same ated group, e.g., "R" or "R1", then it will be understood that the groups may be the same or different, i.e., each group is ndently selected. Wavy lines, indicate the site of covalent bond attachments to the adjoining substructures, groups, es, or atoms.
The compounds of the invention can also exist as tautomeric isomers in certain cases.
Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
Detailed ption of gy embodiments.
Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying description, structures and formulas. While the invention will be described in ction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the full scope of the present invention as described herein.
Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not e other defined values or other values within defined ranges for the radicals and substituents. Specific values listed are values for nds of formula I, II, III, IV as well as sub-formulas of these formulas (e.g. a Ia, Ila, Illa and IVa).
A specific group of compounds of formula I are compounds of formula Ia.
WN\/N N/ N F0 "'OH Ar '2 and salts and esters, thereof.
WO 96681 A specific value for R3 is H.
A specific value for n is 3.
A specific value for R4 is H.
A specific value for A is -(CH2)3-.
A specific value for Ar is phenyl, pyridyl, 4-tetrahydronaphthyl, indazolyl, 1,6- naphthyridyl, 2,3,-dihydroindanyl, yl, indolyl, 4H-benzo][d][1,3]dioxanyl, pyrazolo[1,5— a]pyridinyl, o[1,2-a]pyridinyl, 1, 2,3,4-tetrahydroquinolyl, benzo[d][1,3]dioxolyl, quinoxalyl, isoquinolyl, naphthyl, thiophenyl, lyl, 4,5,6,7-tetrahydrobenzothiophenyl or pyrazolo[3,4,b]pyridinyl, wherein any phenyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl, 1,6-naphthyridyl, ihydroindanyl, quinolyl, indolyl, 4H-benzo][d][1,3]dioxanyl, pyrazolo[1,5-a]pyridiny1, imidazo[1 ,2-a]pyridinyl, 1, 2,3,4—tetrahydroquinolyl, benzo[d][1,3]dioxolyl, quinoxalyl, isoquinolyl, naphthyl, thiophenyl, pyrazolyl, 4,5,6,7- tetrahydrobenzothiophenyl or pyrazolo[3,4,b]pyridinyl ofA is optionally substituted with 1 to 5 A specific value for Ar is phenyl, monocyclic-hetereocycle or bicyclic-heterocycle, wherein any phenyl, monocyclic—hetereocycle or bicyclic-heterocycle ofA is optionally substituted with 1 to 5 R6.
A c value for Ar is phenyl, monocyclic-hetereocycle or bicyclic-heterocycle, wherein the monocyclic-hetereocycle or bicyclic-heterocycl consists or 1-10 carbon atoms and 1-5 heteroatoms within the ring system and wherein any phenyl, monocyclic-hetereocycle or bicyclic-heterocycle ofA is optionally substituted with 1 to 5 R6.
A specific value for Ar is phenyl optionally substituted by 1, 2, 3, 4, or 5 R6 groups.
A c value for Ar is phenyl optionally substituted by 1, 2, 3, or 4 R6 groups.
A specific value for Ar is phenyl optionally substituted by 1, 2, or 3 R6 groups.
A specific value for Ar is yl optionally substituted by 1, 2, 3, 4, or 5 R6 groups.
A c value for Ar is naphthyl optionally substituted by 1, 2, 3, or 4 R6 groups.
A specific value for Ar is yl optionally substituted by 1, 2, or 3 R6 groups.
A specific value for Ar is phenyl optionally substituted by 1, 2, 3, 4, or 5 R6 groups selected from halogen, alkyl, alkoxy, -CH20H, CF3, -O-CF3, -O-CF2, -O-(C3-C6 cycloalkyl), - , -SOzNH(C1-C6 alkyl), C1-C6 a1ky1)2, -SOz-C1—C6 alkyl, —S(=O)-C1-C6 alkyl, an oxadiazole optionally substituted by CH3, and a triazole ring optionally substituted by CH3; or two R6 groups on the phenyl ring together with the atoms to which they are attached form a benzodioxole, benzodioxine, or dihydroindene ring.
A specific value for AI is phenyl substituted by 1, 2, 3, or 4 R6 groups selected from halogen, alkyl, alkoxy, -CH20H, CF3, , -O-CF2, -O-(C3-C6 cycloalkyl), -SOzNH2, - SOZNH(C1-C5 alkyl), -SOZN(C1-C5 alkyl)2, -SOz—C1-C6 alkyl, -S(=O)—C1-C6 alkyl, an oxadiazole optionally tuted by CH3, and a triazole ring optionally substituted by CH3; or two R6 groups on the phenyl ring together with the atoms to which they are attached form a benzodioxole, benzodioxine, or dihydroindene ring.
A specific value for Ar is phenyl optionally substituted by 1, 2, or 3 R6 groups selected from halogen, alkyl, alkoxy, -CH20H, CF3, -O-CF3, , —C6 cycloalkyl), -SOZNH2, - SOZNH(C1—C6 alkyl), -SOZN(C1-C6 alkyl)2, -SOz-C1-C6 alkyl, -S(=O)-C1—C6 alkyl, an zole optionally substituted by CH3, and a triazole ring optionally substituted by CH3; or two R6 groups on the phenyl ring together with the atoms to which they are attached form a benzodioxole, benzodioxine, or dihydroindene ring.
A specific value for Ar is naphthyl optionally substituted by 1, 2, 3, 4, or 5 R6 groups selected from halogen, alkyl, , -CH20H, CF3, -O-CF3, -O-CF2, -O-(C3-C6 cycloalkyl), - , -SOzNH(C1-C6 alkyl), -SOzN(C1-C6 2, -SOz-C1-C6 alkyl, —S(=O)-C1-C6 alkyl, an oxadiazole optionally substituted by CH3, and a triazole ring optionally substituted by CH3; or two R6 groups on the phenyl ring together with the atoms to which they are ed form a benzodioxole, benzodioxine, or dihydroindene ring.
A specific value for Ar is yl optionally tuted by 1, 2, 3, or 4 R6 groups selected from halogen, alkyl, , -CH20H, CF3, -O-CF3, , -O-(C3—C6 cycloalkyl), - SOzNHz, -SOZNH(C1-C6 alkyl), -SOZN(C1-C6 alkyl)2, —SOz-C1-C6 alkyl, -S(=O)-C1-C6 alkyl, an oxadiazole optionally substituted by CH3, and a triazole ring optionally substituted by CH3; or two R6 groups on the phenyl ring together with the atoms to which they are attached form a benzodioxole, benzodioxine, or dihydroindene ring.
A specific value for Ar is naphthyl optionally substituted by 1, 2, or 3 R6 groups selected from halogen, alkyl, alkoxy, -CH20H, CF3, -O-CF3, -O-CF2, -O-(C3—C6 cycloalkyl), 2, - SOZNH(C1-C5 alkyl), -SOZN(C1-C6 alkyl)2, -SOz—C1-C6 alkyl, -S(=O)—C1-C6 alkyl, an oxadiazole optionally substituted by CH3, and a triazole ring optionally substituted by CH3; or two R6 groups on the phenyl ring together with the atoms to which they are attached form a benzodioxole, benzodioxine, or dihydroindene ring.
A c value for Ar is pyridine optionally substituted by 1, 2, 3, 4, or 5 R6 .
A specific value for Ar is pyridine optionally substituted by 1, 2, 3, or 4 R6 groups.
A specific value for Ar is pyridine optionally substituted by 1, 2, or 3 R6 groups.
A specific value for Ar is pyridine optionally substituted by 1, 2, 3, 4, or 5 R6 groups independently selected from halogen, alkyl, alkoxy, -CH20H, phenyl and CF3.
A specific value for Ar is pyridine optionally substituted by 1, 2, 3, or 4 R6 groups. independently selected from halogen, alkyl, alkoxy, -CHZOH, phenyl and CF3.
A specific value for Ar is pyridine ally substituted by 1, 2, or 3 R6 groups. independently selected from halogen, alkyl, alkoxy, -CH20H, phenyl and CF3.
Individual ments provide compounds of the a I wherein Ar is, respectively, indazole, imidazopyridazine, hiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine, naphthyridine, in which, in each embodiment the Ar group is either unsubstituted or substituted by 1, 2, 3, 4, or 5 R6 groups.
Individual ments e compounds ofthe a I wherein Ar is, respectively, indazole, imidazopyridazine, benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine, naphthyridine, in which, in each embodiment the Ar group is either unsubstituted or substituted by 1, 2, 3, or 4 R6 groups. dual embodiments provide compounds of the formula I wherein Ar is, tively, indazole, imidazopyridazine, benzothiophene, benzoimidazole, indazole, ine, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine, naphthyridine, in which, in each embodiment the Ar group is either unsubstituted or substituted by 1, 2, or 3 R6 groups.
Individual ments provide compounds of the formula I wherein Ar is, respectively, indazole, imidazopyridazine, benzothiophene, midazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine, naphthyridine, in which, in each embodiment the Ar group is either unsubstituted or tuted by 1, 2, or 3 substituents selected from halogen, alkyl, alkoxy, CF3, -O-CF3, and —O-CF2.
A c value for Ar is le, imidazopyridazine, benzothiophene, benzoimidazole, indazole, ine, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine, wherein indazole, imidazopyridazine, benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine are not substituted.
A specific value for Ar is indazole, imidazopyridazine, benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine, wherein le, imidazopyridazine, benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, ydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine are each optionally substituted by l, 2, 3, 4, or 5 R6 .
A specific value for Ar is indazole, opyridazine, benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine, wherein indazole, imidazopyridazine, benzothiophene, benzoimidazole, indazole, quinoline, naline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, lopyridine or naphthyridine are each optionally substituted by l, 2, 3, or 4 R6 groups.
A specific value for Ar is le, opyridazine, benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine, wherein indazole, opyridazine, benzothiophene, benzoimidazole, le, quinoline, isoquinaline, quinoxaline, ydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine are each optionally substituted by 1, 2, or 3, or 4 R6 groups.
A specific value for Ar is indazole, imidazopyridazine, benzothiophene, benzoimidazole, indazole, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine, wherein indazole, imidazopyridazine, benzothiophene, benzoimidazole, le, quinoline, isoquinaline, quinoxaline, tetrahydroquinoline, indole, triazolopyrimidine, pyrazolopyridine or naphthyridine are each optionally substituted by 1, 2, or 3 substituents selected from halogen, alkyl, alkoxy, CF3, -O-CF3, and -O-CF2.
A specific value for R6 is OR“, CN, S(O)pRa, halogen, )alkyl, C6—C20 aryl or C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—Cg)carbocyclylalkyl, wherein any (C1-C8)alkyl, (C2-Cg)alkenyl, (C2-C3)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3- C7)cycloalkyl or (C4——Cg)carbocyclylalkyl of R6 is optionally substituted with one or more oxo, halogen, hydroxy, NH2, CN, N3, N(R3 2, NHRa, SH, SR3, S(O)pRa, ORa, (C1-C3)alkyl, (C1— Cg)haloalkyl, -C(O)Bf, -C(O)H, -C(=O)ORa, —C(=O)OH, —C(=O)N(Ra 2 , —C(=O)NHRa , -C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ra)2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra)2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NRaS(O) pN(Ra 2, NRaS(O) pNH2, NHS(O) , NHS(O) pN(Ra 2, NHS(O) pNH2, -OC(=O)Ra, (OH)2 or Ra.
Another specific value for R6 is OR”, CN, S(O)pRa, halogen, (C1—C8)alkyl, C6—C20 aryl, cz—c20 heterocyclyl, (C3-C7)cycloalkyl, )carbocyclylalkyl, NR“C(0)Rll or NR“S(O)pRa, wherein any (C1-Cg)alkyl, (C2-Cg)alkenyl, (C2-C3)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—Cg)carbocyclylalkyl of R6 is optionally tuted with one or more 0x0, halogen, hydroxy, NH2, CN, N3, N(R21 2, NHRa, SH, SR3, S(O)pRa, ORa, (C1-C8)alkyl, (C1-C8)haloalkyl, -C(O)Ra, -C(O)H, -C(=O)0Ra, -C(—‘-O)OH, -C(=O)N(Ra)2 , -C(=O)NHRa , —C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ra 2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra 2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NRaS(O) 2, NRaS(O) pNH2, NHS(O) pNHRa, NHS(O) “‘ 2, NHS(O) pNH2, —OC(=O)Ra, —OP(O)(OH)2 or Ra.
A specific value for Ar is: m“ "H” «3 CW ”‘n Cl “w ”W FQF C Q» F c F “a” “a “L a “at / F F O F F , ,F o , NH F ' F /r\\l WO 96681 O/ F N— HN \ _ > Cl / \ N\N o ’ \\ MIN 9 “LL “n ‘ “fi 0 ’ \ o Q? 1/N\ ’ 5C; N F “m “M, my C|—< ;—0 0 NH 0 f ' EG—F . :E/r‘u 0 F5 "m "m «R ”a "m "m N F N...
Cl / \ F F \ / NH HO * ’ F .
F F F WO 96681 “ % “a. M m «4% F m N N— F F . "w “R.
N_ N_% N\ /\m “an. N” "H” “W” "W V“ “a “m ’/ed QwfijF ' 'F *’ Q N0 —0 m m 1a “km —o~»..
{V @w Q Q (Q;% , O 0 a, "m “N\ _% a N‘ \,N, CI ’ SQO/ "“4“ m ”H" 11“ N— \ m m .._ N s F WO 96681 ”'11" “1a,. 4%.
/ Cl M N’ FS/\ 4%" /N F CII /N . 1 F N , \ CI M“ / \ 19, ” N | \N’N\( / or 4 Another specifc value for AI is: W0 96681 PCT/U82012/071065 / F N— HN \ _.
F o> 0 CI / \ N‘N ’ ' ' \\ ’ ”111’ ClW HN \ a M" 0 ‘LL "M N\U n 0 ’ ‘% ’ ’ ’ ' \ 0 $6 0%? I,N\ o N F £§0 “ NH 61 Cl 0 )7 ’ F5 ' §_©_F , {g/r\q b , "M. m MD ”1% ‘71 "‘M. dm d3N FN— , PM,Q.QF vHO F cg“/, FF F WO 96681 ”a m H'K‘ \ _%L “a \ /N C! ’ S\\ 0/ N_% M 1H“ a” M m \ / d O 5‘1 F , s / N\\ CI w s ©+F 1’1. m m / CI “a.
N’ a,“ /N FS/\ F CI, /N , F N \ WO 96681 “’11. “an, "11,» “H, \ /N 4< giNts Clvgfi Br~©—N\H 06“ N3 ,/S\\“ “VW “‘44, Me W1,» NH CI 0 CI 0, N 0 II F0 O In one embodiment the invention provides a compound of formula I: RBXNWNk/IR3 A N\ \ N N . "OH Ar 0 Q I ON or a salt or ester, thereof; wherein: A is —(C(R4)2)n- wherein any one C(R4)2 of said -(C(R4)2)n- may be optionally replaced with -O-, —S-, -S(O)p—, NH or NR3; ,5 or6; each p is 1 or 2; AI is a C2—C20 cyclyl group or a C6-C20 aryl group, wherein the C2—C20 heterocyclyl group or the C6-C20 aryl group is optionally substituted with 1, 2, 3, 4 or 5 R6; each R3, R4 or R6 is independently H, oxo, 0R“, NRIIR”, NR“C(0)R“, )0R“, NR”C(O)NR“R12, N3, CN, N02, SR“, 3(0),,Ra, NR“S(O)pRa, -C(=O)R“, -C(=O)OR“, —C(=O)NR”R12, -C(=O)SR“, -S(O)p(OR”), -SOZNR“R12,-NR“S(O)p(OR“), NRllsopNRllR”, NR“C(=NR“)NR”R12, halogen, (C1—C3)alkyl, (C2—C3)alkenyl, (C2~Cg)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—Cg)carbocyclylalkyl; 2012/071065 or two R4 on adjacent carbon atoms, when taken together, may optionally form a double bond between the two carbons to which they are attached or may form a (C3-C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by —O-, —S-, -S(O)p—, -NH- or -NRa—; four R4 on adjacent carbon atoms, when taken together, may optionally form an optionally substituted C6 aryl ring; two R4 on the same carbon atom, when taken together, may optionally form a (C3- C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by -O-, -S-, -S(O)p—, —NH- or —NRa—; two R6 on adjacent carbon atoms, when taken together, may optionally form a (C3— C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by —O-, -S-, -S(O)p-, -NH— or —NRa-; each Ra is ndently (C1-C8)alkyl, (C1-C3)haloalkyl, (C2-C3)alkenyl, (C2-C8)alkynyl, aryl(C1—Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—C3)carbocyclylalkyl wherein any (C1-C8)alkyl, )haloalkyl, (C2-C3)alkenyl or (C2- ynyl of Ra is ally substituted with one or more OH, NH2, COzH, C2—C20 heterocyclyl, and n any aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3- C7)cycloalkyl or (C4—C3)carbocyclylalkyl of R21 is optionally substituted with one or more OH, NH2, COzH, C2—C20 heterocyclyl or (C1—C8)alkyl; each R11 or R12 is independently H, (C1-C3)alkyl, (C2-C8)alkenyl, (C2—C3)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl, (C4—Cg)carbocyclylalkyl, Ra, -S(O)pRa, or aryl(C1-Cg)alky1; or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O—, -S—, -S(O)p-, —NH-, -NRa— or -C(O)—; and wherein each (C1-C8)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or )carbocyclylalkyl of each R6, R11 or R12 is, independently, optionally substituted with one or more oxo, halogen, y, NH2, CN, N3, N(Ra 2, NHRa, SH, SR3, S(O)pRa, ORa, (Cl-Cg)a1kyl, (Cl-Cg)haloalkyl, —C(O)Ra, —C(O)H, -C(=O)ORa, —C(=O)OH, N(Ra 2 , -C(=O)NHRa , -C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ra 2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra)2, NHC(O)NH2, =NH, =NOH, =NORa, )pNHRa, NR“S(O) pNara); NRaS(O) pNHz, NHS(O) pNHRa, NHS(O) pN(Ra 2, NHS(O) pNHz, -OC(=O)R“, -OP(O)(OH)2 or R3; provided the nd is not: / / Cl NH \\}\1 0/ l ('3 A specific group of compounds of formula I are compounds of formula Ia: / / N N N >20 “OH Ar i and salts and , thereof; provided the compound does not include: MYN \/ / N N N o o Cl NH \\}\1 O b/ I In one embodiment the compounds of formula I or Ia do not include: O—CLYN\/ / N N N .u0H o O CI NH \\>\J o‘§_ In one ment a compound of formula I is selected from: 39 " WO 96681 MN\N /N WO 96681 N\ Nx / / / / / / N N N N N N N H .nOH 0 Q 0” o F i\\ / \N ’i\\ F , “>4 WN /N/N o OOH /\I(N \\ 0’N N WO 96681 W N\ N\ / N/ / / MY// N N N N N N N N -"OH ‘OH OOH (”V/8:0 0 '— 'v 0 HN , ; , N \\ \ {5%. \\ N\ \\ \ N N N Nx _ .o I’ Hie. r0MID; /I N HN O N /N/N 0 DO“ Cl ;i\\, o N WO 96681 @4110 NCMDQ W10 Cl \\ \\ 1 i\\’ /N " Cl \ “— C: \\’\ ’ - F \\ N \ / B N r \\ _ \N / / N N \\ \\ F 'i\\ 0&1?OHS—H119 @411 \ "\:O \N \ / \ \ / \ \N F _ “L WO 96681 / / / N / N N N N OH N N/ N 0 O 0 FD-uOH o _ Om” ' s / \\\’ / N/ / / / N N N N N OH OH 0 0 \ O 0 O D-uOH N F '2, , CI \\'\\J < 1/ \i \\}\I F \\}\I and \ \ / \ O N\ | N_ and salts and , thereof.
In one embodiment a compound of formula I is selected from: WO 96681 .3 \ N3 // \\ O O 7 “Q_ “:1 CI 0 §\\ 0/’ \ N l I , , Cl \\ , N’ 2\\\ CI NH CI NO ’3 NH2 D.I\O 0 Cl NH 2, W 043“" CN 0“ CI Nj-l O ’ 028— WXQW CI NH «:33EQW8—N‘N/jf 023‘ 8 and salts and , thereof.
One embodiment provides a compound of formula II or IIa: R3><~WTN\N “/10 WT/ Q—m / N):o N CN Ar 113 Q‘OH or a salt or ester, thereof, provided the compound is not One embodiment provides a compound of formula III or IIIa: s><2mm Ar 0 Q‘HOH mg .IloH 111a III CN CN or a salt or ester, thereof, provided the compound is not: N N .HOH CI N\H \kl One ment provides a compound of formula IV or IVa: N OH 0 0‘ CI N\H I)“ O o/ | In one embodiment the compounds of formula IV or IVa do not include: / / N N N OH 0 if Cl NH \\>\‘ O 5’ I One embodiment provides for a mixture of a compound of formula III with a corresponding compound of a IV. The mixture of the compound of a III with the corresponding compound of formula IV is thus a mixture of trans diastereomers wherein the trans substituents are the substituents connected to the carbon marked with an asterisk 2 (*2) and the carbon marked with an asterisk 2 (*3). The invention also provides a mixture of a compound of a IIIa with a corresponding compound of formula IVa. The mixture of the compound of formula IIIa with the corresponding compound of formula IVa is thus a e of trans diastereomers wherein the trans substituents are the substituents connected to the carbon marked with an asterisk 2 (*2) and the carbon marked with an asterisk 2 (*3).
One embodiment does not include: N N OH Cl N‘H \kl 0’II In one embodiment a compound is selected from: and salts and , thereof, or a mixture of a compound of formula 111a and a corresponding compound of formula IVa or a salt or ester, thereof; wherein Ar is selected from: ”R “m Cl "R “R @ CW 4} c~ QC.
F C I F g F /// E “L” "but, +64 “L {$4 “a “a .F F . ,F43O , NH >K‘F ' F F Au WO 96681 111, ”‘m‘, ”’01, ”M, “‘4, “L11 F N— HN __ F 0/ \ > Cl / \ , ~{q o , \ “'11 CIH HN \ "m «M 9 “A“ W” o "k ‘ _§ O ’ ' R? \ Q? 1/ O HN N F % “m, m 0&0 Q {30 “a )— 94}8 F . /r\\l b F5 m "m ”‘1 "Wu “b < g /“ F ”— Cl F F ‘— \ / F . /NH F F F WO 96681 “a M» F “m Cl /_\ Cl F‘Q‘ OiBrN.— , Q , F@‘ @F F F W» "M" m m \ / \ / — — 1 , \ / “W M” "m m ;— "m / \ —</ / F \N _N Pb 67% , _ , F // —O m m ”a —o m “a," 430, {ya (3 Q04 m (330/ , O F 0 “a "m HN \ _% 1% \ /N Cl 1 S\\ 0/ 4% M “a“ 11" “w W N_ 6—6FF \N \ / O O 3/5 NJ Cl , w s F '91.. 4%. 4%.
/ CI "’“M F N, F%’/\ 11"” /N F Cl! /N . ’ 5‘1 , F \ C: "M“ 14 ‘ \ ,N\< N N N and K In one embodiment a compound is selected from: / / N N/ N N N N "‘OH OH )___O IIIa AI’ IIa CN MYN\/ / N N N >=o @0H Ar IVa 3, and salts and esters, thereof, or a mixture of a nd of formula 111a and a corresponding compound of formula lVa or a salt or ester, thereof; wherein Ar is selected from: “m "“w "m Cl “m “w 0do/ FQF C/~_ Gel F Cl F f f>—F // ' WO 96681 Cl };<N HN ML NW “at “m N\ 9 ; o N\ \ —S HNQ 0%r 5 ' ’ I / \ o g N F "m “m ”m My Q @o a ' 9@F N 0 “53 m “m ”Li “L n“ g M F “- Q CI F \ / NH HO _ F <3' / F F F WO 96681 “M, “4m. M‘" Mm- 11"“ F “k.
N N_ Cl /_\ F \ / Br, F F F F ”an M 44,.“ N' “-44% /“\ 4% / \ N—% \ / F ' \ / — —” , Qi; \ / “v “F Wu” "m «h "bu.
/ \N 46 67 g g / F \N /0 OH , _ _ , F // —O m m 1a —o m 43m. {ya .Q m $304 M (3&4 , O F 0 a _m "m ”"3 \ a \ /N CI , S\\ 0/ 4“” ”w m ‘11.
N_ \ “m. “E ..— [‘1 F s F WO 96681 1111 “’1’. “’14 / Cl 11% y N’ 1’14” /N F Cl, /,\3 F , N . , , F \ CIZTfN\<w, 92, ' :EI‘IY “'91, "'44, my» up“, 8 ‘ 0”“ N3 fix” 0 d 0 WW "we “Wu “1% 04?)— ):0 One embodiment provides a ceutical composition comprising a compound of formula II, Ila, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
One ment provides a ceutical composition comprising a mixture of a compound of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof, and a pharmaceutically acceptable carrier.
One embodiment provides a pharmaceutical composition comprising a mixture of a compound of formula 111a and a corresponding compound of a IVa or pharmaceutically acceptable salts or esters thereof, and a pharmaceutically acceptable carrier.
One embodiment provides a method of ng a Pneumovirinae infection in a mammal (e. g. a human) in need thereof by administering a therapeutically effective amount of a compound of formula 11, Ha, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or ester thereof.
One embodiment provides a method of treating a Pneumovirinae ion in a mammal (e. g. a human) in need thereof by administering a eutically effective Mount of a mixture of a nd of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof.
One embodiment provides a method of treating a Pneumovirinae ion in a mammal (e. g. a human) in need thereof by administering a therapeutically ive amount of a mixture of a compound of formula 111a and a corresponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need thereof by administering a therapeutically effective amount of a, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or e of a compound of formula II, IIa, III, Illa, IV or IVa or a pharmaceutically acceptable salt or ester thereof.
One embodiment provides a method of ng a Pneumovirinae infection in a mammal (e. g. a human) in need f by stering a therapeutically effective amount of a, tautomer, polymorph, polymorph, amorphous form, hydrate or solvate of a compound a mixture of a compound of formula III and a corresponding compound of formula IV or ceutically acceptable salts or esters thereof.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e.g. a human) in need f by administering a therapeutically effective amount of a, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a mixture of a compound of formula Illa and a corresponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof.
One embodiment provides a method of treating a respiratory syncytial virus infection in a mammal (e.g. a human) in need thereof by administering a therapeutically effective amount of a nd of formula 11, Ha, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or ester thereof.
One embodiment provides a method of treating a atory syncytial virus infection in a mammal (e.g. a human) in need thereof by administering a therapeutically effective amount of a mixture of a compound of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof.
One embodiment provides a method of ng a respiratory ial virus infection in a mammal (e.g. a human) in need thereof by administering a therapeutically effective amount of a mixture of a compound of formula Illa and a ponding nd of formula IVa or pharmaceutically able salts or esters thereof.
One embodiment provides a method of treating a respiratory syncytial Virus infection in a mammal (e.g. a human) in need thereof by administering a therapeutically effective amount of a tautomer, polymorph, pseudopolymorph, amorphous form, e or solvate of a compound of formula 11, Ha, III, Illa, IV or IVa or a pharmaceutically acceptable salt or ester thereof.
One embodiment provides a method of treating a respiratory syncytial virus infection in a mammal (e.g. a human) in need thereof by administering a eutically effective amount of a tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a mixture of a compound of formula III and a corresponding compound of formula IV or pharmaceutically able salts or esters thereof.
One embodiment provides a method of treating a respiratory ial virus infection in a mammal (e.g. a human) in need thereof by administering a therapeutically effective amount of a tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a mixture of a compound of formula Illa and a ponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof.
One ment provides a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need thereof by administering a therapeutically effective amount of a compound of formula II, Ila, III, Illa, IV or IVa or a ceutically acceptable salt or ester thereof, and a pharmaceutically acceptable diluent or carrier.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need thereof by administering a therapeutically ive amount of a mixture of a compound of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof, and a pharmaceutically acceptable diluent or carrier.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need thereof by administering a eutically effective amount of a mixture of a compound of formula Illa and a corresponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof, and a pharmaceutically able diluent or carrier.
One embodiment es a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need thereof by administering a therapeutically effective amount of a compound of formula II, Ila, III, Illa, IV or IVa or a pharmaceutically acceptable salt or ester thereof, in combination with at least one additional therapeutic agent.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need thereof by administering a therapeutically effective amount of a mixture of a compound of a III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof, in ation with at least one additional therapeutic agent.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e.g. a human) in need thereof by administering a therapeutically effective amount of a mixture of a compound of formula Illa and a corresponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof, in ation with at least one additional therapeutic agent.
One embodiment provides a method of ng a virinae infection in a mammal (e. g. a human) in need thereof, by administering a therapeutically effective amount of a ation pharmaceutical agent comprising: a) a first pharmaceutical composition comprising a compound of formula II, IIa, III, Illa, IV or IVa or a pharmaceutically acceptable salt or ester thereof,; and b) a second ceutical composition comprising at least one additional therapeutic agent active t infectious Pneumovirinae viruses.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need f, by administering a therapeutically effective amount of a combination pharmaceutical agent sing: a) a first pharmaceutical composition comprising a mixture of a compound of formula III and a corresponding compound of formula IV, or pharmaceutically able salts or esters thereof; and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Pneumovirinae viruses.
One embodiment provides a method of treating a Pneumovirz‘nae infection in a mammal (e.g. a human) in need thereof, by administering a eutically effective amount of a combination pharmaceutical agent comprising: a) a first pharmaceutical ition comprising a mixture of a compound of formula 111a and a corresponding compound of formula IVa or ceutically acceptable salts or esters f; and b) a second pharmaceutical composition comprising at least one onal therapeutic agent active t infectious Pneumavirinae viruses.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need thereof, by administering a therapeutically effective amount of a combination pharmaceutical agent sing: a) a compound of formula II, Ila, III, IIIa, IV or IVa or a pharmaceutically able salt or ester thereof; and b) a therapeutic agent active against infectious Pneumovirinae viruses.
One embodiment provides a method of treating a Pneumovirinae infection in a mammal 2O (e. g. a human) in need thereof, by administering a therapeutically effective amount of a combination pharmaceutical agent comprising: a) a mixture of a compound of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof; and b) a eutic agent active against infectious Pneumovirinae viruses.
One embodiment es a method of treating a Pneumovirinae infection in a mammal (e. g. a human) in need f, by administering a therapeutically effective amount of a combination pharmaceutical agent comprising: a) a mixture of a compound of formula 111a and a corresponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof; and b) a therapeutic agent active t infectious Pneumovirinae viruses.
One embodiment provides a method of ng a respiratory syncytial Virus infection in a mammal (e.g. a human) in need thereof, by administering a therapeutically effective amount of a combination pharmaceutical agent comprising: a) a first pharmaceutical composition comprising a compound of formula II, Ila, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or ester thereof; and b) a second pharmaceutical ition comprising at least one additional eutic agent active against infectious respiratory syncytial viruses.
One embodiment provides a method of treating a atory syncytial virus infection in effective amount of a mammal (e.g. a human) in need f, by administering a therapeutically a combination pharmaceutical agent sing: a) a mixture of a compound of formula III and a corresponding compound of a IV or pharmaceutically acceptable salts or esters thereof; and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active t infectious respiratory syncytial Viruses.
One embodiment provides a method of treating a respiratory syncytial virus infection in effective amount of a mammal (e.g. a human) in need thereof, by administering a therapeutically a combination pharmaceutical agent comprising: a) a mixture of a compound of formula 111a and a corresponding nd of formula IVa or a pharmaceutically acceptable salt thereof a pharmaceutically able salt or ester thereof; and b) a second ceutical composition comprising at least one additional therapeutic agent active against infectious respiratory syncytial viruses.
One embodiment provides a method of treating a respiratory syncytial virus infection in amount of a mammal (e.g. a human) in need thereof, by administering a therapeutically effective a combination pharmaceutical agent sing: a) a compound of formula II, Ila, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or ester thereof; and b) a therapeutic agent active against infectious respiratory syncytial viruses.
One embodiment es a method of treating a respiratory syncytial virus infection in effective amount of a mammal (e.g. a human) in need f, by administering a therapeutically a combination pharmaceutical agent comprising: a) a mixture of a compound of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof; and b) a therapeutic agent active against infectious respiratory syncytial viruses. 2012/071065 One ment provides a method of treating a respiratory syncytial virus infection in a mammal (e.g. a human) in need thereof, by administering a eutically effective amount of a combination pharmaceutical agent comprising: a) a mixture of a compound of formula 111a and a corresponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof; and b) a therapeutic agent active t infectious respiratory syncytial viruses.
One embodiment provides a compound of a II, Ila, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or ester thereof for use in medical therapy.
One embodiment provides a mixture of a compound of formula III and a corresponding nd of formula IV a ceutically acceptable salts or esters thereof, for use in medical therapy.
One embodiment provides a mixture of a compound of formula 111a and a corresponding nd of formula IVa or pharmaceutically acceptable salts or esters thereof, for use in medical therapy.
One embodiment es a compound of formula II, IIa, III, IIIa, IV or IVa or a pharmaceutically acceptable salt or ester thereof, for use in the prophylactic or therapeutic treatment of a viral infection caused by a Pneumovirinae virus or a respiratory syncytial virus.
One embodiment provides a mixture of a compound of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof, for use in the prophylactic or eutic treat a Viral infection caused by a Pneumovirinae virus or a respiratory syncytial virus.
One embodiment provides a mixture of a compound of formula 111a and a ponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof, for use in the prophylactic or therapeutic treatment of a viral infection caused by a Pneumovirinae Virus or a respiratory syncytial virus.
One embodiment provides the use of a compound of formula II, Ila, III, IIIa, IV or IVa or a ceutically acceptable salt or ester thereof, for the manufacture of a medicament useful for the treatment of a viral infection in a mammal (e.g. a human) caused by a Pneumovirinae virus or a respiratory syncytial Virus.
One embodiment provides the use of a e of a compound of formula III and a corresponding compound of formula IV or pharmaceutically acceptable salts or esters thereof, for the manufacture of a medicament useful for the treatment of a Viral infection in a mammal (e. g. a human) caused by a Pneumovirinae Virus or a respiratory syncytial Virus.
One embodiment provides the use of a mixture of a compound of a Illa and a ponding compound of formula IVa or pharmaceutically acceptable salts or esters thereof, for the cture of a medicament useful for the treatment of a Viral infection in a mammal (e. g. a human) caused by a Pneumovirinae Virus or a respiratory syncytial virus.
In one embodiment a compound is selected from: CI CI WO 96681 PCT/U82012/071065 0‘s?O HN Cl WO 96681 04350\ / >340 HN Cl 0/H\N CI \ //o \ o o’/ \ 43¢ HN Cl 0 HM WO 96681 PCT/U82012/071065 04st HN c: WO 96681 \ Nx / / / / / / N N N N NQ‘NHZ N N N WNH NH2 2 o O @wa Wig W? O>VF NH F F WO 96681 “I“Fé‘ ~/ “Cr / Mi/ Mi/ N N/ D, N NH2 n’ N O NHZ o Cl HN O O \ ’ ’ n ' —§ H2N s O O F F WO 96681 ’ 0 Cl 0 NH )7 \ / N ol WO 96681 WO 96681 WN\ MYN\ / N /N/N WAN/fN\ / N/ N N N N/ NH2 NH2 N NH2 o o o / \ 1 CH1“!N\/ / W /N/N MiN\/ N N Nm» N N N/ N NH2 NH2 o 0 o Cl N WO 96681 /=§7 NHZ ’N Na, N\ N\ w 4 {HM/ MY/ N N/ N N N/ N \ , 0e °\ / 3 0—5:?N ”it my NH2 NH2 QANHZ / \ Cl lN/rgio Cl .
CI LN N/N NHZ /N/N N_° QTNHZ \/c: WN\/ / and N N F O DANHZ and salts and esters f.
One embodiment provides a compound selected from: /N\N \ / / N N W Cl N wherein W is: WO 96681 'flH H H j/N 'fl YN H NH H NH HN ‘K‘H 31 L I HN , N W I ' N , H , "‘le fit NH *3 "m / o "‘14, H N/ H Q ~\J‘HJH _\\f\\lH §_N:j é—NQ 0H HoH , ©/\O/\/\N}kw , , / 0 O if”/E (QN/2 /,, }LL H Ne [\‘IH H , N (j mHNJ HN é—g H , H .- ’ HO’i\O ' or a salt, or stereoisomer thereof.
In another embodiment the compound is selected from: WO 96681 WO 96681 F<r \ “\NH NvN / NO stmH o // N /\\ O/i\ o N o / 0 HN\//0 /,S\ Q , O /NH H \Séo ”\r‘qH O/H‘N Cl N’Ni/ NCI GA N /,\ HNQ 0 \ /o 435 \ /o HN Cl 048" HN CI OéfiN \ Cl Q‘s/O HN Cl w Olsfo NH HN CI >540 //S/ /’ 0 HM O Cl “N C' o o and salts and esters thereof.
One embodiment es a compound of formula: MYN \/ N N/ N >20 NH2 wherein Y is selected from: “a "m, M “m my,“ N— go/ HzN—figoo / \ / F F ) I F 1 O F F Cl "l1,” CI F F > < j 0/ F F , WO 96681 Cl “m >§<N HN \ O WO 96681 N_ “La W» Cl F N “N \ F F F, / —- , , F, F F F W \—/ and @O/ or a salt, or stereoisomer thereof.
In another ment the compound is selected from: N\ N\ / / / / N N NQANHZ N / N N / NH2 N N N o o NH2 \ / ’ 0 F F N\ N\ N\ / / / / / / N N N 9 / ' F F HzN—§ 0 CI F Cl F 2012/071065 \ N4 / / / / N N N NQANHQ N N N N N NH2 NH2 O O 0 Q4;X& 2CN+4;X& Q4;X +653 ””64 64 WO 96681 a ' /N NCr N\ "j N/ N \ N\ / N \ / / / / N / N N N NH2 N N NH N o 0 2 OW Cl , , , \ (R o —§ HZN S O O F F WO 96681 _ 91H / / N N/ / / N N N N/ N NH2 NH2 o o 0 f N o ’ 0 I /N\ N F Cl 0 NH WO 96681 WO 96681 MiN\ N\ N\ / MY N/ / MT/ N N N N/ N N N/ NH2 NH2 N NH2 O o o /\N ' / / MYN\ / / N N Nm» N N/ Mi N N N/ N NH2 NH2 o 0 o Cl N WO 96681 /:§' NHZ / N / NH2 NH2 O O OO O\ / 8 N N , ’ CI / \ . l CI CI /N ANN’N)I / MYNe/ / and N and salts and esters thereof.
Esters of compounds of the invention.
The compounds disclosed herein also include “esters” of the compounds of the invention. Accordingly, one example of esters of the compounds of the invention include esters wherein a hydroxyl group of the compound of the invention is an ester. These esters of the invention are typically labile and thus the ester may be converted to the corresponding hydroxyl group in vivo (6.g. after stration). Esters include those esters based on carbon and phosphorus.
Typical esters include: (RaO)2P(=O)O-, (HO)2P(=O)O—, (C1-C3)alkyl(C=O)O-, C6— C2oaryl(C=O)O-. heterocyclyl(C=O)O- or (C4—Cg)carbocyclylalkyl(C=O)O- wherein each (C1-Cg)alkyl(C=O)O-, C6—C2oaryl(C=O)O-. C2—C2oheterocyclyl(C=O)O- or (C4—Cg)carbocyclylalkyl(C=O)O—, is independently, ally substituted with one or more oxo, halogen, hydroxy, NH2, CN, N3, N(Ra 2, NHRa, SH, SRa, S(O)pRa, ORa, (C1-C3)alkyl, (C1- C8)haloalkyl, a, -C(O)H, -C(=O)0Ra, OH, —C(=O)N(Ra)2 , -C(=O)NHRa , -C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, NHC(O)ORa, )ORa, NRaC(O)NHRa, NRaC(O)N(Ra)2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra 2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NR"S(O) pN(Ra 2, NRaS(O) pNH2, NHS(O) pNHRa, NHS(O) l,,N(Ra 2, NHS(O) pNH2, )Ra, —OP(O)(OH)2 or Ra; each Ra is independently (Cl-Cg)alkyl, (C1-C3)haloalkyl, (C2-C8)alkenyl, (C2-C3)alkynyl, 1—Cg)alkyl, C6~C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4-Cg)carbocyclylalkyl wherein any (C1-C8)alkyl, )haloalkyl, (C2—C3)alkenyl or (C2- C3)alkynyl of R21 is optionally substituted with one or more OH, NHz, COzH, C2—C20 heterocyclyl, and wherein any aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3- loalkyl or (C4-—Cg)carbocyclylalkyl of Ra is optionally substituted with one or more OH, NH2, COZH, C2—C20 heterocyclyl or (C1-C8)alkyl; and each p is 1 or 2.
It is to be tood that the point of connection of the esters (RaO)2P(=O)O-, (HO)2P(=O)O-, (C1-C3)a1kyl(C=O)O-, C6—C20aryl(C=O)O-, C2-C20heterocyclyl(C=O)O- and (C4—Cg)carbocyclylalkyl(C=O)O- to the compound ofthe ion is through the oxygen of the ester.
In one embodiment the compounds of formula I include compounds of formula Ib R3 A \H N*N \ R3><NHA» / N/ N Ar 0 Q'IIORX 1b CN or a salt or ester, f; wherein: A is —(C(R4)2)n- wherein any one C(R4)2 of said —(C(R4)2)n- may be optionally replaced with —o—, —s—, —S(0),,—, NH or NRa; nis3,4,5 or6; each p is l or 2; Ar is a C2—C20 heterocyclyl group or a C6-C20 aryl group, wherein the C2—C20 heterocyclyl group or the C6-C20 aryl group is optionally substituted with 1, 2, 3, 4 or 5 R6; each R3, R4 or R6 is independently H, 0x0, 0R“, NRUR”, NR“C(0)R“, NR“C(0)OR“ NR“C(O)NR“R12, N3, CN, N02, SR“, S(O)pRa, NR”S(O)pRa, -C(=O)R”, -C(=O)OR“, — C(=O)NR”R12,-C(=O)SR“, —S(O)p(OR“), —s02NR“R‘2, -NR“S(O)p(OR“), —NR”sopNR“R12, NR”C(=NR“)NR“R12, halogen, (C1—C3)alkyl, (C2—C8)alkenyl, )alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 cyclyl, (C3-C7)cycloalkyl or (C4—Cg)carbocyclylalkyl; two R4 on nt carbon atoms, when taken together, may optionally form a double bond n the two carbons to which they are attached or may form a (C3—C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by -O-, -S—, -S(O)p-, —NH— or -NRa—; four R4 on nt carbon atoms, when taken together, may optionally form an optionally tuted C6 aryl ring; two R4 on the same carbon atom, when taken together, may optionally form a (C3- C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by -O-, —S-, -S(O)p-, -NH— or —NRa-; two R6 on adjacent carbon atoms, when taken together, may optionally form a (C3- C7)cycloalkyl ring wherein one carbon atom of said (C3—C7)cycloalkyl ring may be optionally replaced by -O-, -S-, -S(O)p-, -NH- or —NRa-; each Ra is independently (C1—C3)alkyl, (C1-C3)haloalkyl, (C2-C8)alkenyl, (C2-C3)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—C3)carbocyclylalkyl wherein any (C1-C3)alkyl, (Cl-Cg)haloalkyl, (C2-C8)alkenyl or (C2- Cg)alkynyl of Ra is optionally substituted with one or more OH, NH;, COZH, C2—C20 heterocyclyl, and wherein any aryl(C1-C8)alkyl, C6~C20 aryl, C2—C20 heterocyclyl, (C3- C7)cycloalkyl or (C4—C3)carbocyclylalkyl of R21 is optionally substituted with one or more OH, NH2, COZH, C2—C20 heterocyclyl or (C1—C3)alkyl; each R“ or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C3)alkynyl, 1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl, (C4—C3)carbocyclylalkyl, -C(=O)Ra, -S(O)pRa, or aryl(C1—Cg)alkyl; or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, ~S-, -S(O)p-, -NH—, -NRa— or -C(0)-; n each (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C8)alkynyl, 1-C3)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—Cg)carbocyclylalkyl of each R6, R11 or R12 is, independently, optionally tuted with one or more oxo, halogen, hydroxy, NH2, CN, N3, N(Ra 2, NHRa, SH, SRa, S(O)pRa, ORa, (C1-C8)alkyl, (C1-C8)haloalkyl, a, -C(O)H, —C(=O)ORa, -C(=O)OH, -C(=O)N(Ra)2 , -C(=O)NHRa , -C(=O)NH2 , pRa, NRaS(O)pRa, Ra, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ral 2, NRaC(O)NH2, NHRa, NHC(O)N(Ra 2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NRaS(O) pN(Ra 2, NRaS(O) l[,NH2, NHS(O) pNHRa, NHS(O) pN(Ra 2, NHS(O) pNH2, -OC(=O)Ra, (OH)2 or Ra; and RK is H, (RaO)2P(=O)—, (=O)O-, )alkyl(C=O)-, C6-C20aryl(C=O)—, C2-C20heterocyclyl(C=O)- or (C4—Cg)carbocyclylalkyl(C=O)-, wherein each(C1-Cg)alkyl(C=O)-, C6-C2oaryl(C=O)-, C2-C20heterocyclyl(C=O)- or (C4—C3)carbocyclylalkyl(C=O)- is ndently, optionally substituted with one or more oxo, halogen, hydroxy, NH2, CN, N3, N(R'rl 2, NHRa, SH, SR3, S(O)pRa, ORa, (C1-C3)alkyl, (C1-C3)haloalkyl, -C(O)Ra, —C(O)H, -C(=O)ORa, -C(=O)OH, N(Ra)2 , -C(=O)NHRa , —C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)R3, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ra 2, NRaC(O)NH2, NHC(O)NHR“, NHC(O)N(Ra)2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NR"S(O) pN(Ra 2, NRaS(O) pNH2, NHS(O) pNHR“, NHS(O) pN(Ra 2, NHS(O) pNH2, -OC(=O)Ra, -OP(O)(OH)2 or R3; provided the compound is not: MYN,/ / N N N .uOH o O CI NH \\}\1 0’bI A specific value for Rx is H, (HO)2P(=O)-, )alkyl(C=O)— or C2—C20heterocyclyl(C=O)-, wherein each (C1-Cg)alkyl(C=O)- or C2—C2oheterocycyl(C=O)- is independently, optionally substituted with one or more hxo, halogen, hydroxy, NH2, CN, N3, N(Ra 2, NHRa, SH, SR3, S(O)pRa, ORa, (C1-C8)alkyl, (C1-C3)haloalkyl, -C(O)Ra, —C(O)H, —C(=O)0Ra, -C(=O)OH, -C(=O)N(Ra 2 , -C(=O)NHRa , ~C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ra)2, NRaC(O)NH2, NHC(O)NHR“, NHC(O)N(Ra 2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NRaS(O) pN(Ra 2, NRaS(O) 1{,NH2, NHS(O) pNHR", NHS(O) pN(Ra 2, 2012/071065 NHS(O) pNHz, —OC(=O)Ra, —OP(O)(OH)2 or Ra.
Another specific value for RX is H, (HO)2P(=O)-, (C1-C8)alkyl(C=O)- or C2-C20heterocyclyl(C=O)-, wherein each )alkyl(C=O)— or C2-C20heterocyclyl(C=O)- is independently, optionally substituted with one or more NHZ, —C(=O)OH or NRaC(O)Ra.
Another c value for Rx is: O NH2 H C? 0 H , pkg: , , 34f NH] O Hf Wm0 3W/N or MM 1)} 0 NH2 . S C”).
Pre aration of com ounds of the invention.
The compounds of formulas I and la were be prepared by the procedures described in examples 3, 4 and 6-31. The compounds of formulas 1-24 (i.e. compounds of formula V) were prepared by the procedures described in example 1 and example 4. The compounds of formulas -111 (i.e. compounds of formula VI) were prepared by the procedures described in examples 2, 4 and 5.
The compounds of formula II and Ila can be ed ing the procedures described in examples 3, 4, 5 and 6 by using intermediate 9b instead of intermediate 9a.
The compounds of formulas III, Illa, IV and IVa can be prepared following the procedures described in examples 3, 4, 5 and 6 by using the enantiomers of trans-3—cyano hydroxypyrrolidine instead of the cis enantiomers. The enantiomers of 3-cyano hydroxypyrrolidine can be prepared following literature procedures (Schauss, S.E., et al., Organic Letters, 2(7), 2000, pages 1001-1004).
Pharmaceutical Formulations The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. s formulations are prepared in sterile form, and when intended for delivery by other than oral administration lly will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, yalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
While it is possible for the active ingredients to be stered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for nary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ients, particularly those additional therapeutic ingredients as discussed herein. The r(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing administration . The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are ed by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely d solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral stration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a in-oil liquid emulsion. The active ingredient may also be stered as a bolus, electuary or paste.
A tablet is made by compression or g, optionally with one or more accessory ingredients. Compressed tablets may be prepared by ssing in a suitable machine the active ingredient in a owing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
For infections of the eye or other external tissues e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for e, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), ably 0.2 to % w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water—miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in—water cream base.
If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more yl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol ding PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl xide and related analogs.
The oily phase of the emulsions of this invention may be tuted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an nt), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. ably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or t stabilizer(s) make up the so-called fying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily sed phase of the cream formulations. nts and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl l, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic ties. The cream should preferably be a non~greasy, non—staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or ed chain, mono- or c alkyl esters such as di-isoadipate, isocetyl te, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2—ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in ation depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
Pharmaceutical formulations according to the present invention comprise a combination according to the invention together with one or more ceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or es, emulsions, hard or soft capsules, syrups or elixirs may be prepared. itions intended for oral use may be prepared according to any method known to the art for the manufacture of ceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, ng agents and preserving agents, in order to e a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic ceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
Tablets may be ed or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a ned action over a longer period. For e, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard n capsules where the active ingredient is mixed with an inert solid diluent, for e calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the ion n the active materials in admixture with excipients suitable for the manufacture of aqueous sions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and sing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a sation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a sation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ne oxide with a partial ester derived from a fatty acid and a hexitol ide (e.g., polyoxyethylene sorbitan monooleate).
The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxy-benzoate, one or more ng agents, one or more flavoring agents and one or more ning agents, such as sucrose or saccharin.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral sions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. sible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more vatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally—occurring gums, such as gum acacia and gum tragacanth, naturally-occurring 2012/071065 phosphatides, such as soybean in, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan eate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile inj e preparation, such as a sterile able aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile able ation may also be a sterile inj ectable solution or sion in a non-toxic erally acceptable diluent or solvent, such as a solution in 1,3—butane-diol or ed as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In on, e fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed ing synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active al compounded with an appropriate and ient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ug of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about mL/hr can occur.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w/w.
Formulations le for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, l, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. le formulations include aqueous or oily solutions of the active ingredient.
Formulations le for aerosol or dry powder administration may be ed according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of Pneumovirinae infections as described below.
In another aspect, the invention is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable ition comprising a compound of formula I or a compound of formulas 1-111, or a pharmaceutically acceptable salt thereof, le for treating Pneumovirinae infections and potentially associated bronchiolitis. Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts as they may cause less pulmonary irritation. Preferably, the inhalable formulation is delivered to the endobronchial space in an aerosol sing particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 pm. ably, the compound of formula I or as 1-1 11 is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI). miting es of zers include atomizing, jet, ultrasonic, rized, Vibrating porous plate, or equivalent nebulizers including those nebulizers utilizing adaptive l delivery technology (Denyer, J Aerosol ne Pulmonary Drug Delivery 2010, 23 Supp 1, 81-810). A jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small l droplets. A pressurized nebulization system forces solution under pressure through small pores to te aerosol droplets. A Vibrating porous plate device utilizes rapid Vibration to shear a stream of liquid into riate droplet sizes.
In a preferred embodiment, the formulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 um and about 5 um using a zer able to aerosolize the formulation of the compound of formula I or as 1-111 into particles of the required MMAD. To be optimally therapeutically effective and to avoid upper atory and systemic side effects, the majority of aerosolized les should not have a MMAD greater than about 5 urn. If an aerosol contains a large number of particles with a MMAD larger than 5 pm, the particles are deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 um then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.
When formulated and delivered according to the method of the invention, the aerosol formulation for zation delivers a therapeutically efficacious dose of the compound of formula I or formulas 1-111 to the site of Pneumovirinae infection sufficient to treat the Pneumovirinae ion. The amount of drug stered must be adjusted to reflect the efficiency of the ry of a therapeutically efficacious dose of the compound of formula I or formulas 1-111. In a preferred embodiment, a ation of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of the compound of formula I or as 1-111 into the airways. In a preferred embodiment, at least about 30 to about 50% of the active compound is delivered.
More preferably, about 70 to about 90% of the active nd is delivered.
In another embodiment of the instant invention, a compound of formula I or formulas 1- 111 or a pharrnaceutically acceptable salt thereof, is delivered as a dry inhalable powder. The compounds of the invention are administered endobronchially as a dry powder formulation to efficacious deliver fine particles of nd into the endobronchial space using dry powder or metered dose inhalers. For delivery by DPI, the compound of formula I or formulas 1-111 is processed into particles with, predominantly, MMAD between about 1 um and about 5 um by milling spray drying, al fluid processing, or precipitation from solution. Media milling, jet milling and spray—drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 pm and about 5 pm are well known in the art. In one embodiment, excipients are added to the compound of formula I or as 1-1 11 before processing into particles of the required sizes. In another embodiment, excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for e by using e as an excipient. le size determinations are made using devices well known in the art. For example a multi-stage Anderson cascade or or other suitable method such as those specifically cited within the US Pharmacopoeia r 601 as terizing devices for aerosols within metered-dose and dry powder inhalers.
In r preferred embodiment, a compound of formula I or as 1-1 11 is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices. Non-limiting examples of dry powder inhalers and devices include those disclosed in USS,458,135; USS,740,794; USS775320; USS,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; USS,522,385; US4,668,218; US4,667,668; US4,805,8ll and USS,3 88,572. There are two major designs of dry powder inhalers. One design is a metering device in which a reservoir for the drug is place within the device and the patient adds a dose of the drug into the inhalation chamber. The second design is a factory- metered device in which each individual dose has been manufactured in a separate container.
Both systems depend on the ation of the drug into small particles of MMAD from 1 pm and about 5 pm, and often involve co-formulation with larger excipient particles such as, but not limited to, lactose. Drug powder is placed in the tion chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs. In preferred embodiments, a compound of formula I or formulas 1-1 1 l, or a ceutically acceptable salt thereof, is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, ive of any excipients, is predominantly in the range of 1 mm to about 5 pm.
In another preferred embodiment, a compound of formula I or formulas 1-111 is delivered as a dry powder using a metered dose inhaler. Non—limiting examples of metered dose rs and s include those disclosed in USS,261,538; USS,544,647; US5,622,163; US4,955,371; US3,565,070; US3,361306 and US6,116,234. In preferred embodiments, a compound of a I or formulas 1—1 11, or a pharmaceutically able salt thereof, is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 um.
Formulations suitable for vaginal administration may be presented as ies, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations le for parenteral administration include aqueous and non—aqueous sterile injection solutions which may contain anti-oxidants, buffers, iostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non—aqueous e suspensions which may include ding agents and thickening agents.
The formulations are presented in unit—dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the on of the sterile liquid carrier, for example water for injection, immediately prior to use. oraneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously bed. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly ned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. 3O The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier or.
Veterinary carriers are materials useful for the purpose of stering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These nary compositions may be administered orally, parenterally or by any other desired route.
Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient are lled and regulated to allow less frequency dosing or to improve the pharmacokinetic or ty profile of a given active ingredient.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; lly, from about 0.01 to about 10 mg/kg body weight per day; more lly, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
Routes of Administration One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
Combination y itions ofthe ion are also used in combination with other active ingredients.
For the treatment ofPneumovirinae virus infections, preferably, the other active therapeutic agent is active against Pneumovirinae virus infections, particularly respiratory syncytial virus infections. Non-limiting es of these other active therapeutic agents are ribavirin, palivizumab, motavizumab, IV (RespiGam®), MEDI-557, A-60444 (also known as ), MDT-637, EMS-433771, ALN—RSVO, ALX-0171 and es thereof.
Many ofthe infections of the Pneumovirinae s are respiratory infections.
Therefore, additional active therapeutics used to treat respiratory ms and ae of infection may be used in combination with the nds of formula I or formulas 1-111. The additional agents are preferably stered orally or by direct inhalation. For example, other preferred additional therapeutic agents in combination with the nds of a I or formulas 1—1 11 for the treatment of Viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.
Glucocorticoids, which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282—287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents an and Gilman, 10th n, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled osteroids (ICS) have been developed to mitigate the severe adverse s of oral steroids. miting examples of corticosteroids that may be used in combinations with the compounds of formula I or compounds of as 1- 111 are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone e, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludroco'rtisones, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropn'onate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin—21-butylate, flumethasone, flumetasone pivalate, budesonide, halobetasol nate, mometasone e, fluticasone propionate, ciclesonide; or a pharmaceutically acceptable salts thereof.
Other anti-inflamatory agents working through anti-inflamatory cascade mechanisms are also useful as additional eutic agents in combination with the compounds of formula I or the compounds of formulas 1-111 for the treatment of Viral respiratory infections. Applying “anti-inflammatory signal transduction modulators” (referred to in this text as AISTM), like phosphodiesterase inhibitors (e.g. PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g. blocking NFKB through IKK inhibition), or kinase inhibitors (6.g. blocking P38 MAP, INK, PI3K, EGFR or Syk) is a logical approach to switching off inflammation as these WO 96681 small molecules target a limited number of common intracellular pathways - those signal uction pathways that are critical points for the anti-inflammatory therapeutic intervention (see review by R]. Barnes, 2006). These non-limiting additional therapeutic agents include: 5— (2,4—Diflu0ro-phenoxy)— l —isobutyl- 1 H—indazolecarboxy1ic acid (2-dimethylamino-ethyl)— amide (P38 Map kinase inhibitor ARRY-797); 3-Cyclopropylmeth0xy-N—(3,5-dichlor0-pyridin— 4-yl)-4—difluorormethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy—4- yphenyl)phenyl-ethyl]—pyridine (PDE-4 inhibitor CDP-840); N—(3,5-dichloro pyridinyl)(difluoromethoxy)—8—[(methylsulfonyl)amino] dibenzofurancarboxamide (PDE-4 tor Oglemilast); N—(3 ,5-Dichloro-pyridin—4—yl)—2—[ l -(4-fluorobenzyl)—5-hydroxy- 1 H—indol— 3-yl]—2—oxo-acetamide (PDE—4 inhibitor AWD 12-281); 8-Methoxytrifluoromethyl~quinoline- 5-carboxylic acid (3,5—dichlorooxy—pyridin—4-yl)—amide (PDE-4 inhibitor Sch 351591); 4-[5- (4-Fluorophenyl)—2-(4—methanesulfinyl—phenyl)-lH-imidazolyl]—pyridine (P38 inhibitor SB- 203 850); 4-[4-(4-Fluor0-phenyl)—1-(3-phenyl-propyl)-5 -pyridinyl- l H-imidazol-Z-yl]—but-3 — yn—l —01 (P3 8 inhibitor RWJ-67657); 4-Cyano(3—cyclopentyloxymethoxy-phenyl)- cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE—4 inhibitor); or0fluorophenyl)—[7-meth0xy—6-(3 ~morpholin—4-yl- propoxy)-quinazolin—4-yl]-amine (Gefitinib, EGFR inhibitor); and 4—(4-Methyl-piperazin ylmethyl)—N-[4-methyl(4-pyridin—3-yl-pyrimidin—2-ylamino)—phenyl]-benzamide (Imatinib, EGFR inhibitor).
Combinations comprising inhaled‘fi2-adrenoreceptor t bronchodilators such as forrnoterol, albuterol or salmeterol with the compounds of formula I or formulas 1—1 11 are also le, but non-limiting, combinations useful for the treatment of respiratory viral infections. ations of d BZ—adrenoreceptor agonist bronchodilators such as forrnoterol or erol with ICS’s are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively). The combinations comprising these ICS and BZ-adrenoreceptor agonist combinations along with the compounds of formula I or formulas 1—1 11 are also suitable, but non-limiting, combinations useful for the treatment of respiratory Viral infections.
For the treatment or prophylaxis of pulmonary broncho-constriction, anticholinergics are of potential use and, therefore, useful as an additional therapeutic agents in ation with the compounds of formula I or formulas l—1 11 for the treatment of viral respiratory infections.
These olinergics include, but are not limited to, antagonists of the muscarinic receptor (particularly of the M3 subtype) which have shown therapeutic y in man for the control of cholinergic tone in COPD (Witek, 1999); ydroxy[3,3,3—tris-(4-fluoro-phenyl)— propionyl]-pyrrolidine—2-carbony1}-pyrrolidine—2—carboxylic acid (1—methy1-piperidin ylmethyl)-amide; 3—[3-(2-Diethylamino-acetoxy)phenyl-propionyloxy]isopropylmethyl- 8-azonia-bicyclo[3.2.1]octane (Ipratropium-N,N-diethylglycinate); 1-Cyclohexy1—3,4-dihydro- 1H—isoquinolinecarboxylic acid 1-aza-bicyclo[2.2.2]oct—3 -y1 ester (Solifenacin); 2- Hydroxymethylmethanesu1f1nylphenyl-butyric acid 1—aza-bicyclo[2.2.2]oct—3 -y1 ester (Revatropate); 2—{ 1-[2-(2,3 -Dihydro-benzofuranyl)-ethyl] -pyrrolidin-3 -yl } —2,2-diphenyl- acetamide (Darifenacin); 4-Azepan-l—y1-2,2-diphenyl-butyramide (Buzepide); 7—[3 -(2- Diethylamino-acetoxy)phenyl-propionyloxy]ethylmethyloxa—9-azonia— tricyclo [3 .3. 1 .02,4]nonane (Oxitropium-N,N-diethylglycinate); 7-[2-(2—Diethylamino-acetoxy)- 2,2—di-thiophen—2-yl-acetoxy]-9,9—dimethyl-3 -oxa—9-azonia—tricyclo [3 .3 . 1 .02,4]n0nane (Tiotropium—N,N—diethylglycinate); Dimethylamino-acetic acid 2—(3-diisopropy1amino-1— phenyl-propyl)—4-methy1-phenyl ester rodine-N,N-dimethy1glycinate); -Bis-(4- fluoro-phenyl)oxo-imidazolidin-1 -y1]-1 l— 1 -(2-oxopyridin—2-yl-ethyl)-pyrrolidinium; 3-Fluoro-benzyl)—piperidinyl]-4,4-bis-(4-fluoro-phenyl)-imidazolidinone; 1— Cycloocty1(3—methoxy—1-aza-bicyclo[2.2.2]oct-3 -yl)—1 1-prop—2-yn-l -ol; 3—[2—(2— Diethylamino—acetoxy)—2,2-di-thiophen—2-yl-acetoxy] — l -(3-phenoxy—propy1)— 1 —azonia- bicyclo[2.2.2]octane (Aclidinium-N,N-diethylglycinate); or (2-Diethylamino-acetoxy)-di— thiophen—Z-yl-acetic acid l—methyl-l—(2-phenoxy-ethyl)—piperidinyl ester.
The compounds of a I or formulas 1-111 may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections. A miting example of a mucolytic agent is ambroxol. Similarly, the compounds of formula I or formulas 1-111 may be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an orant is guaifenesin.
Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung diseases (Kuzik, .1 Pediatrics 2007, 266). The compounds of formula I or formulas 1-111 may also be combined with nebulized hypertonic saline particularly when the Pneumovirz'nae Virus infection is complicated with bronchiolitis. The combination of the compounds of formula I or formulas 1-111 with hypertonic saline may also comprise any of the additional agents discussed above. In a preferred aspect, nebulized about 3% hypertonic saline is used.
It is also le to combine any compound ofthe invention with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
Co-administration of a compound of the ion with one or more other active therapeutic agents lly refers to simultaneous or sequential administration of a compound of the ion and one or more other active therapeutic agents, such that therapeutically effective s of the compound of the invention and one or more other active therapeutic agents are both t in the body of the t.
Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit s of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the invention can be stered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1—12 hours), by stration of a unit dose of one or more other active therapeutic . In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by stration of a unit dose of a compound of the invention.
The combination therapy may provide “synergy” and gistic”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) WO 96681 by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the nds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A istic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
Another embodiment provides for methods of treating virinae Virus infection in a patient, comprising: stering to the patient a therapeutically effective amount of a compound of formula I or formulas 1-1 1 l, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.
Another embodiment provides for s of ng Pneumovirinae virus infection in a patient, sing: administering to the patient a eutically effective amount of a compound of formula I or formulas 1-1 1 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent.
Another ment provides for methods of treating Human respiratory syncytial virus infection in a patient, comprising: administering to the t a eutically effective amount of a compound of formula I or formulas 1-111, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent.
Metabolites of the Compounds of the Invention Also falling within the scope of this invention are the in viva metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes novel and unobvious compounds ed by a process comprising contacting a compound of this ion with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. 14C or 3H) compound of the invention, stering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes ing in the metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or NMR is. In general, analysis of metabolites is done in the same way as conventional drug lism studies well—known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HSV antiviral activity of their own.
Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are ected in surrogate inal or gastric juice upon incubation for 1 hour at 37°C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The prodrugs of the invention typically will be stable in the digestive system but may be substantially hydrolyzed to the al drug in the digestive lumen, liver, lung or other metabolic organ, or within cells in general.
Tissue Distribution It has also been discovered that certain compounds of the invention show high lung to plasma ratios which may be beneficial for therapy. One particular group of compounds of the invention that demonstrate this property are compounds that e an amine functional group.
Examples.
Certain iations and acronyms are used in describing the mental details.
Although most of these would be understood by one skilled in the art,‘Table 1 contains a list of many of these abbreviations and acronyms.
Table 1. List of iations and acronyms. acetic anhydride WO 96681 benzylbromide bis(trimethylsilyl)acetamide benzoyl chloride carbonyl diimidazole 1,4-diazabicyclo[2.2.2]octane 1,5-diazabicyclo [5 .4.0]undecene dichloroacetamide dimethylformamide ethyl acetate electrospray tion 2-(1H—7-azabenzotriazol-l -yl)-—1 , 1 ,3 ,3 -tetramethyl uronium hexafluorophosphate Methanaminium thyldisilazane High pressure liquid chromatography isopropyl alcohol lithium diisopropylamide low resolution mass spectrum meta-chloroperbenzoic acid acetonitrile TMSOTf (trimethylsilyl)trifluoromethylsulfonate TEA triethylamine TBA tributylamine ' TBAP ylammonium pyrophosphate TBSCl t-butyldimethylsilyl chloride TEAB triethylammonium bicarbonate TFA trifluoroacetic acid TLC or tlc thin layer chromatography triphenylmethyl 4-methylbenzoyl 1:1 mixture of isopropylmagnesium chloride and lithium chloride parts per million down field from tetramethylsilane The invention will now be illustrated by the preparation of the following miting compounds of the invention. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a nd may be combined and then carried forth in the next synthetic step.
Example 1. Procedure for the preparation of compounds of formulas 1—24.
MYN\ \ / / / N N Cl 85°C,16h / / 0 N N R - (Boc) DMA 0 Cl NH K2CO3 (2M) or DIPEA >S//O Cl NH 3 equiv. amine (e.g. R-(Boc)) \ //O o/ \ o//S\ A1 R—(Boc) represents a diamine wherein one A2 of the amine groups is protected with a Boc group MYN\/ RT, 1h N N/ R DCM CI NH R re resents a diamine \S// P O/ \/ nds 1—24 In 50 mL, d necked, round bottomed flask was placed (s)-N-(4-chloro—2-(2-(5- chloromethylpyrazolo[l ,5-a]pyrimidineyl)piperidine- l — carbonyl)phenyl)methanesulfonamide (A1), (1200 mg, 2.49 mmol) in DMA (10.8 mL). The amines (R—(Boc)) (0.12 mmol) were placed in separate 2—ml' Vials. Then, into each vial was dispensed a solution of A1 (0.2 mL, 0.041 mmol) followed by 0.1 mL of K2CO3 (2M) or DIPEA. The resulting reaction mixtures were placed on a hot plate at 85 °C for 16 h. Then, to each on mixture was added EtOAc (4 mL), washed with saturated NaHCO3 (2 mL x 2), and concentrated in Genevac to give A2 as a solid. The crude t A2 was redissolved in dichloromethane (0.5 mL) followed by the addition of TFA (0.2 mL). After the reaction mixture was stirred at room temperature for 1 h, it was loaded onto the CUBCX column. The mixture was washed with MeOHzEtOAc (1:4, 4 mL) and MeOH:dichloromethane (1 :4, 4 mL), eluted with 7 N NH40Me:EtOAc (3:7, 4 mL), and concentrated to afford the final compound (i.e. compounds 1-24). nd calculated -H 520056 520 5 532.067 532.5 582.127 582.6 2012/071065 582.127 2012/071065 590.103 546.094 546.094 590.103 HN CI 13 0 8 652.7 14 576.076 576.5 560.121 560.6 16 ' 558.105 558.6 HN CI 17 0 622.192 622.7 HN CI 8 544.078 544.6 9 576.076 576.6 YW 560.121 560.6 2% \ \ i2 2 °\\,w/ Iz Cl 2—-\ 0 558.105 558.5 HN Cl 22 /‘Q/ N’N\ N 574.148 574.6 589.119 589.6 560.5 Example 2. General procedure for the preparation of compounds of formulas 25-111.
/ N/ D R OH N NH N D B1 H’N\< HN\< OA< B3 HATU, TEA, DMF OA< 16h,rt R '3 1 h, rt NH2 Compounds 25—1 11 In 50 mL, singled necked, round bottomed flask was placed tert-butyl (S)—1—(6-methyl ((S)—piperidin—2-yl)pyrazolo[l,5-a]pyrimidin—5-yl)pyrrolidin—3-ylcarbamate (B1) (2640 mg, 6.59 mmol) and TEA (1.83 mL, 13.2 mmol) in DMF (8.8 mL). The ylic acids B2 (between 0.10 mmol and 0.50 mmol) were placed in 132 separate 2—ml Vials. Then, into each Vial was dispensed a solution of B1 (0.050 mmol) followed by the on of HATU (38 mg, 0.10 mmol). The resulting reaction mixtures were placed on an orbital shaker at room ature for 16 h. Then, to each on mixture was added EtOAc (4 mL), washed with sat. NaHC03 (2 mL x 2), and concentrated in Genevac to give B3 as a solid. The crude product B3 was redissolved in dichloromethane (0.5 mL) followed by the addition of TFA (0.2 mL). After the reaction mixture was stirred at room temperature for 1 h, it was loaded onto the CUBCX column. The mixture was washed with MeOH:EtOAc (1 :4, 4 mL) and MeOszichloromethane (1 :4, 4 mL), eluted with 7 N NH40MezEtOAc (3:7, 4 mL), and concentrated to afford the final compound (i.e. compounds 25-1 1 1). compound ated Structure observed MW formula MW 436.535 437.6 423.496 434.544 435.6 492.933 493.5 WO 96681 2012/071065 490.652 486.542 486.542 506.504 444.543 N N/ D‘NHZ F O 39 5 454.525 455.5 N N/ N o m» F 8 479.6 456.554 457.6 481.604 482.6 N N 43 V360 ‘3‘ 444.543 445.5 WO 96681 490.505 483.595 455.566 480.544 456.554 473. 556 485.636 2012/071065 54 444.543 445.6 / / N N N58:o D‘NHZ 55 hiN 474.573 475.6 56 478.988 N\ N 479.6 N N o "(34w2 57 509.561 510.6 CH11N N/ D‘NHz 58 -3 496.634 497.2 2 498.6 459.598 460.6 448.527 449.5 502.598 503.6 497.043 497.6 WO 96681 458.57 459.6 475.553 476.5 66 488.636 489.6 N N/ D‘NHZ 67 § F 514.624 515.6 N N/ N o QANHZ _ 455.566 456.6 \ N/ WO 96681 438.963 435.532 423.496 454.525 440.498 474.396 454.525 484.407 436.535 79 440.498 441.5 80 N- 481.604 482.6 81 “0 423.496 424.2 82 3 457.5 83 {Hi/j: 439.951 440.5 2012/071065 448.571 462. 598 463.6 473.503 474.6 432.572 433.6 432.572 . 452.99 453.5 6 497.5 436.535 437.6 0 Q 448.571 449.5 0/ ”MHz N N 93 0 Q‘ 2 439.951 440.5 484.604 504. 038 484.604 539.505 474.396 445.531 466.608 104 8 508.5 105 507.948 508.5 N N o O‘NHZ 106 506.96 507.5 Cl F N N 107 o Q‘NHZ 453.522 454.6 N N/ D‘NHZ 108 444.543 445.2 2012/071065 433.56 434.5 452.534 453.5' Example 3. General procedure for the preparation of compounds 112-191.
/ / NH N/ DMOH R OH N>:o N [DMOH 02 .7 R ’CN C1 CN HATU, TEA, DMF Compounds 112—191 16 h, rt In 50 mL, singled necked, round bottomed flask was placed tert—butyl (3 S,4R)—4- hydroxy- l -(6-methyl-2—((S)-piperidin—2-yl)pyrazolo [1 ,5 -a]pyrimidinyl)pyrrolidine-3 — carbonitrile (C1) (1932 mg, 5.90 mmol) and TEA (1.64 mL, 11.8 mmol) in DMF (13 mL). The carboxylic acids C2 0.040 mmol) were placed in separate 2-ml Vials. Then, into each Vial was dispensed a solution of C1 (0.037 mmol) followed by the addition ofHATU (15.2 mg, 0.04 mmol). The resulting reaction mixtures were placed on an orbital shaker at room temperature for 16 h. Then, to each reaction mixture was added EtOAc (4 mL), washed with sat. NaHC03 (2 mL x 2), and concentrated in Genevac. Then, it was loaded onto the CUSIL column, washed with EtOAczHexane (1:1, 4 mL), eluted with MeOH2EtOAc (5:95, 3 mL), and trated in c to give the final compound (i.e. compounds 112—191).
Compound calculated 112 523.4 460.538 461.5 518.927 519.4 WO 96681 115 465.945 466.4 116 482.947 483.4 117 0 0 473.512 474.5 F i\\ N N/ DMOH 118 480.519 481.5 o D-HOH 119 / '3 516.646 517.6 0 \\\N 512.536 532.498 470.537 480.519 2012/071065 125 / \ ’§\\ 507.598 508.5 126 F \\ 478.528 479.5 127 " 482.548 483.5 128 507.598 508.5 6< \II/ . 129 N 2 512 574. 5135.
O,N N 478.984 500.603 135 ’ 470.537 471.5 N N/ N 136 (3|wa 0‘0” 2 505.4 N\ N \\}q N N/ N O O\OH 137 HN \ (\L 535.555 536.5 / / N N o DMOH 0 a 138 _§ (\ 522.628 523.5 N N o DMOH 139 3/ 485.592 486.5 HN \\\N 2012/071065 140 474.521 475.5 141 528.592 528.5 142 523.037 523.5 N N/ N .“OH 143 Q 484.564 485.5 '3” \\N 144 Cg: ’(\\ 514.63 515.5 540.618 541.5 464.957 465.4 6 462.4 499.497 500.5 480.519 481.5 2012/071065 466.492 467.5 469.549 470.5 500.39 500.5 480.519 481.5 510.401 510.4 WO 96681 462.529 462.529 466.492 507.598 445.527 2012/071065 557.396 484.604 N N 0 O\OH 165 2 474.565 475.2 0 D-HOH 166 / ", 8 462.2 0 \\\N N N 167 ‘3,.HOH 488.592 489.5 168 F 499.497 500.5 \ 5/ F N \\\ F — N N N/ N -I\OH 159 O Q 458.566 459.5 ’(\\ 2012/071065 N N .HOH 170 0 Q 478.984 479.5 CI 1\ N N .
O Q. m 171 a, 523.44 523.4 Br \\}\I 172 462.529 463.5 173 474.565 475.5 174 510.598 511.5 470.537 445.527 466.564 445.527 2012/071065 180 506.61 181 “0.11011 436.538 3 / V)“ 182 \ 482.976 N N NQ _. 10H 183 / \ <\\N 490.63 184 0F D-HOH 498.509 F <\\ 185 483.576 484.5 186 482.947 483.4 187 484.564 485.5 N N/ D'HOH 188 C' 0 3 495.5 ’\\\ N N/ DMOH F%/\N O 189 F N. \ ”<1 502.501 503.5 \ N 497.003 497.5 513.606 Example 4: Procedure for the preparation of intermediate A1.
Intermediate 1: %OH %0Me Boc 0 Bee 0 N—Boc-(S)—piperidinecarboxylic acid (5.0 g, 22 mmol) in DMF (100 mL) was d with C82CO3 (3.5 g, 10.9 mmol) and Mel (1.5 mL, 24 mmol). The mixture was stirred for 4 hours and diluted with MTBE (250 mL). The mixture was washed with water (2 x 100 mL) and saturated sodium chloride solution (1 x 100 mL). The on was dried over anhydrous sodium sulfate and concentrated to afford the ester intermediate 1 which was used Without fiirther purification. 1H NMR (CDC13, 300MHz): 8 4.80 (m, 1H), 3.97 (m, 1H), 3.73 (s, 3H), 2.93 (m, 1H), 2.18 (app d, J: 13.2 Hz, 1H), 1.67 (m, 2H), 1.45 (br s, 10H), 1.20 (app t, J: 13.5 Hz, 1H).
Rf: 0.90 (30% EtOAc~hexanes).
Intermediate 2: (pygmy?|OH N\ o/£%)O o/£> O Boc-piperidine-2—carboxy1ic acid (25 g, 109 mmol, Sigma—Aldrich) in DMF (500 mL) was treated sequentially with MeNHOMe-HCI (11.2 g, 115 mmol), N—methylmorpholine (36 mL, 327 mmol), HOBt (16.2 g, 120 mmol), and EDCI (23 g, 120 mmol) and stirred for 18 h.
The solution was d with EtOAc (1000 mL) and washed with H20 (2 x 500 mL) and saturated NaCl solution (500 mL). The solution was dried over MgSO4, filtered and concentrated. The residue was subjected to a 330 g Si02 ash High Performance Gold column (0—100% EtOAc—hexanes gradient) to afford the Weinreb amide intermediate 2: 1H NMR (CDC13, 300MHz): 6 5.06 (br m, 1H), 3.93 (br m, 1H), 3.77 (br s, 3H), 3.18 (s, 3H), 2.01 (app d, J: 13.5 Hz, 1H), 1.71 (m, 4H), 1.45 (s, 9H).
LCMS (ESI) m/z 273 [M + H]+, IR = 2.31 min.
HPLC (RP: 6—98% MeCN—HZO gradient, 0.05% TFA modifier) I}; = 4.423 min.
Rf= 0.60 (50% EtOAc—hexanes).
Intermediate 3 : N‘NH N -———)> N CN ————)» ./ N . NH2 0 ()0 O/K: hoe 2< K0 To a solution of acetonitrile (5 m1, 93.8 mmol) in dry THF (50 m1) at —78 0C was added dropwise NaN(TMS)2 (34 ml, 68 mmol, 2M in hexanes). The solution was warmed up to -40 0C and stirred for 20 min. The solution was then cooled down to -78 OC and a solution of the ester (Intermediate 1) (7.6 g, 31.1 mmol) in THF (20 ml) was added dropwise. The solution was warmed up to -40 OC and stirred for 2 h. The solution was then cooled down to -78 °C and a solution of acetic acid (4.8 ml, 80 mmol) in THF (20 m1) added dropwise. The solution was then warmed to RT and les were d under reduced pressure at 40 °C. The resulting WO 96681 residue was dissolved in EtOAc (300 mL) and the organic phase was washed with brine twice.
Volatiles were removed under reduced pressure at 40 0C. 1H NMR (DMSO, 300 MHz) 5 4.63 (br s, 1H), 4.18-4.13 (m, 1H), 3.82-3.78 (m, 1H), 3.65 (s, 2H), 2.85-2.63 (m, 1H), 1.65—1.52 (m, 9H), 1.38 (s, 9H).
LCMS m/z .' 153 [M-Boc group+H], tR= 2.50 min.
The residue was dissolved in EtOH (150 ml) and hydrazine acetate (4.5 g, 47 mmol) was added. The solution was d for 16 h at RT. Volatiles were removed under reduced pressure at 40 0C, EtOAc added (200 ml) and the organic phase washed with aqueous dilute NaHCO3, then H20 ed by brine. Volatiles were removed under reduced pressure at 40 °C, the resulting e was purified by silica gel column (DCM/ MeOH, gradient from 0% to 20%) to afford the product intermediate.
LCMS m/Z [M+H]Jr C13H22N402 requires: 266.34. Found 266.84.
HPLC (min, purity) Q; = 2.13, 100%. 1H NMR (DMSO, 300 MHz) 11.20 (br s, 1 H), 5.09 (m, 1H), 5.07 (s, 1H), 4.67 (br s, 2H), 3.81 (app d, J: 12.0 Hz, 1H), 2.72 (app br t, J= 12.0 Hz, 1H), 2.08 (app d, J: 12.9 Hz, 1H), 1.57 (m, 4H), 1.39 (s, 9H); MS (ESI) m/z 267 [M + H]+, tR= 1.97 min. (3.5min method); HPLC (Chiral: Chiralpak AD—H, isocratic ane—isopropanol 70:30). he (desired) = 22.42 min, tR (enantiomer of desired isomer) = 25.67 min; %ee = 93.
Intermediate 3 via Weinreb amide: N \0 —> N CN ——> / O/KO O | N 0&0 O NH2 \Boc /< )< MeCN (3.20 mL, 60.7 mmol) in THF (50 mL) was cooled to —78 °C under Ar. NaHMDS solution (1.0 M in THF, 36.8 mL, 36.8 mmol) was added dropwise over 5 min, during which time an off-white suspension had formed. The suspension was warmed to —20°C and stirred for min. The suspension was cooled to —78 °C and erred Via carmula to the Weinreb amide WO 96681 intermediate 2 (5.02 g, 18.4 mmol) in THF (50 mL) at ‘78 °C over 5 min. The sion is warmed to —45 °C and stirred for 3 h, during which time the suspension became a yellow solution. The solution was cooled to —78 °C and AcOH (4.2 mL in 10 mL THF, 73.6 mmol) was added dropwise. The solution was warmed to room temperature and diluted with EtOAc (100 mL). The solution was washed with H20 (50 mL) and saturated NaCl solution (50 mL). The solution was dried over MgSO4 and concentrated to afford the cyano ketone which was used without further purification.
The crude OL-cyano ketone was used in the next reaction with hydrazine acetate to synthesize desired amino pyrazole intermediate 3 as described above.
MS (ESI) m/z 267 [M + Hr", tR = 1.81 min.
HPLC (RP: 6—98% MeCN—HZO gradient, 0.05% TFA modifier) 17; = 3.212 min (>95% purity @ 254 nM).
HPLC l: Chiralpak AD—H 250 4.6 mm, 5 micron; isocratic n-heptane—isopropanol 70:30) tR (a isomer, desired) = 22.35 min, 0; (b isomer) = 25.78 min; 0!, = 1.15; %ee = >90%.
Intermediate 4: N\ N\ / / N NH N N O )20 2 Cszcog, DMF >10)20 (E)-ethylEthoxymethylacrylate (Intermediate 32) (11.8 g, 67.6 mmol) and CSzCO3 (22.0 g, 67.6 mmol) were added to a solution of intermediate 3 (12.0 g, 45.1 mol) at room temperature and the reaction mixture was heated to 130 °C. After 17 h, the reaction mixture was allowed to cool to room temperature and was concentrated under d pressure. The crude residue was diluted with ethyl acetate (250 mL) and was filtered. The resulting filtrate was concentrated under reduced pressure and the residue was d Via SiOz column chromatography (330 g SiOz ash HP Gold Column, 0—100% ethyl acetate/hexanes) to afford intermediate 4. 1H NMR (CDC13, 400MHz): 8 12.01 (br s, 1H), 7.99 (s, 1H), 5.73 (s, 1H), 5.42 (br s, 1H), 4.01 (br (1, J: 12.2 Hz, 1H), 2.81 (br t, J: 11.2 Hz, 1H), 2.29 (d, J: 13.5 , 2.07 (d, J=1.1 Hz, 3H), 1.87 — 1.69 (m, 1H), 1.68 — 1.41 (m, 4H), 1.48 (s, 9H). 13C NMR (CDC13, 100MHz): 5 162.87, 156.34, 155.43, 140.16, 135.00, 113.29, 86.50, 79.75, 28.41, 27.79, 25.27, 21.00, 19.88, 13.38.
LCMS (ESI) m/z 333.0 [M + H]+, tR = 2.24 min.
HPLC IR (min), purity %: 3.969, 99%.
Rf: 0.50 (EtOAc).
Chiral HPLC, 98%ee (Chiralpak IC 5 mM, 4.6 150 mm, 10 —95% MeCN/ H20, 0.05% roacetic acid modifier) (S)—isomer tR = 22.234 min, (R)-isomer tR = 20.875 min.
Intermediate 5: Mi ”0'3 MY / N H O / >10):0 NH N/ CI POCl3 (5.60 mL, 59.8 mmol) was added to intermediate 4 (993.4 mg, 2.99 mol) at room temperature and the on mixture was heated to 100 °C. After 2 h, the reaction mixture was allowed to cool to room temperature and was concentrated under reduced re to afford intermediate 5 which was used directly in the following step. 1H NMR (DMSO-d6, 400MHz): 5 9.40 (br (1, J = 7.6 Hz, 1H), 9.27-9.16 (m, 2H), 6.85 (s, 1H), 4.54 (t, J: 112.4 Hz, 1H), 3.32 (d, J: 12.8 Hz, 1H), 3.08 (q, J= 8.81 Hz, 1H), 2.33 (s, 3H), 2.23-2.14 (m, 1H), 1.92-1.61 (m, 5H).
LCMS (ESI) m/Z 251.1 [M + H]+, 1R = 0.21 min.
HPLC tR = 2.35 min.
Intermediate A1: //S— / O 5 N N/ Cl NH N/ CI HATU,Et3N ,H HCI DMF N\ 048— HATU (1.37 g, 3.59 mmol) was added to a solution of 5-chloro(methylsulfonamido) benzoic acid (823 mg, 3.29 mmol) in DMF (15.0 mL), and the reaction mixture was stirred at room temperature. After 1 h, a solution of crude intermediate 5 (220 mg, 2.99 mmol) in DMF (1 mL) was added followed by the addition of triethylamine (2.00 mL, 14.3 mmol), and the on mixture was stirred at room temperature for 19 h. The reaction mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate solution (200 mL), and the layers were separated. The organic layer was washed with saturated s sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL), was dried over Na2SO4, and was concentrated under reduced pressure. The crude residue was purified Via Si02 column chromatography (12 g SiOz Combiflash HP Gold Column, 0—100% ethyl acetate/hexanes) to afford intermediate A1 (736.2 mg, 51% ps)) as a white solid. 1H NMR (CDC13, 400MHz): 5 10.05 (br s, 0.2H), 9.13 (br s, 1H), 8.95 (br s, 1H), 8.81 (br s, 0.2H), 7.70 (d, J: 8.8 Hz, 1H), 7.56 (d, J: 8.8 Hz, 0.2H), 7.40 (dd, J= 8.8, 2.4 Hz, 1H), 7.33 J= 2.4 Hz, 1H), 7.31 . (d, (d, J: 4.4 Hz, 0.2H), 6.45 (s, 1H), 6.40 (br s, 0.2H), 6.28 (br d, J= 4.4 Hz, 1H), 5.01 (br s, 0.2H), 4.54 (br d, J: 14.0 Hz, 0.2H), 3.35 (br d, J= 13.2 Hz, 1H), .03 (m, 1H), 2.92 (s, 3H), 2.39 (s, 3H), 2.13-1.98 (m, 1H), 1.90—1.59 (m, 2H), 1.59—1.31 (m, 3H). 13C NMR(CDC13, 100MHz):5167.09, 156.12, 153.13,147.86, 135.68, 131.79,131.66,131.38, , 125.91, 125.44, 117.08, 93.74, 47.65, 44.07, 39.81, 27.83, 25.47, 19.78, 16.90.
LCMS (ESI) m/z 482.1 [M + H]+, 1R = 2.79 min.
HPLC 1R (min), purity %: 5.438, 99%.
Rf= 0.47 (50% EtOAc/hexanes).
Chiral HPLC, 99%ee (Chiralpak IC 5 mM, 4.6 150 mm, 10 —95% MeCN/ H20, 0.05% trifluoroacetic acid r) (S)-isomer tR = 29.739 min, (R)-isomer tR = 29.495 min.
Example 5: Procedure for the preparation of intermediate B1.
Hh<::].7 NHBoc <::§%—<L/T:«:[fN \ \\ w/N\N\\ HCI / / / NH N N NH N CI EgN,MeOH To a solution of intermediate 5 (100.0 mg, 0.35 mmol) in MeOH (1.74 mL) was added (S)—tert-buty1 pyrrolidin-3—ylcarbamate (648 mg, 3.48 mmol) and triethylamine (970 uL, 6.96 mol) at room temperature, and the reaction mixture was heated to 70 0C. After 4 h, the reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The crude residue was purified by preparatory HPLC (5—100% MeCNflhO, 0.1% roacetic acid modifier) to afford intermediate B1.
LCMS (ESI) m/z 401.23 [M + H]+, tR = 1.86 min.
Example 6: Procedure for the preparation of ediate Cl.
Intermediate 7: Boc $06 §oc fi N N 3 Z C.C. (SiOZ) j z E Z NC OH NC OH NC OH cis trans A e of cis/ trans utyl 3-cyanohydroxypyrrolidine—l-carboxylate was separated on a silica column (200-300) eluting with ethyl acetate:petroleum ether=1 :10, ethyl acetate:petroleum ether =1 :5 to give intermediate 7 (earlier g peak, 30 g as white , 46%) solid.
TLC (Eluent: ethyl acetate:petroleum ether =1 :1): Starting material cis/ trans mixture (Rf = 0.4 and 0.45). 2012/071065 1H NMR: (400 MHz DMSO) 5 .48 (m, 1H), 3.8-3.65 (m, 1H),3.51-3.63 (m, 1H), 3.5—3.3 (m, 2H), 2.9—3.1 (m, 1H), 2.70 (s, 1H), 1.3-1.45 (s, 9H).
Intermediate 8: ?OC $oc N N j : TBDPSCI imidazole, DMF 3 Z NC OH NC OTBDPS cis cis To mixture of intermediate 7 (10 g, 0.047mol) and imidazole (6.4 g 0.094 mol) in DMF (100 ml) was added TBDPSCl (14.2 g 0.05 mol) dropwise and the mixture was stirred at room temperature overnight. 10% citric acid was added and extracted with ethyl acetate, dried and concentrated, purified by silica gel column chromatography(ethyl acetate: petroleum ether =1 :50 to 1:25) to give intermediate 8.
TLC Information t: eum ether: ethyl acetate =1 :1), starting material Rf = 0.40, product Rf = 0.90. 1H NMR (400 MHz DMSO) 8 7.74-7.62 (m, 4H),7.47-7.41(m,6H), 4.51 (m, 1H), 3.8-3.65 (m, 1H),3.51-3.63 (m, 1H), 3.5-3.3 (m, 2H), 2.9-3.1 (m, 1H), 13-145 (s, 9H).
Intermediates 9a and 9b “3°C E300 800 N | SFC (N7 N NC OTBDPS NC: ’bTBDPS NC OTBDPS 9a 9b ediate 8 was separated by chiral SFC (see below) to give intermediate 9a (earlier eluting) and intermediate 9b (later eluting). _ PCT/U82012/071065 Column: ChiralPak IC-H, 250 50mmI.D, mobile Phase: CO 2/ iPrOH (35% tic), retention time (93) 1.94 min, retention time (9b): 2.73 min.
Intermediate 10a: [1300 00c N TBAF N SJ, D.,, NC‘ ’OTBDPS 30mm NC‘ ’OH A solution of intermediate 93 (16.3g, 0.036 mol) in CH2C12 (200mL) at r.t was added TBAF (8.0 g, 0.025 mol). The reaction e was stirred at r.t for 30 min, then d with CH2C12 (500 mL), and washed with saturated aq. NH4C1 and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10:1 to 2:1) to afford intermediate 10a.
TLC Information (10a) (Eluent: petroleum ether: ethyl acetate =1 : 1). 1. Starting material (Rf: 0.90). 2. Reaction Mixture ct: Rf = 0.4). 1H NMR (10a): 400 MHz DMSO 8 4.60-4.58 (m, 1H), 3.87—3.79 (m, 1H),3.69-3.64 (m, 1H), 3.56-3.49 (m, 2H), 2.9-3.1 (m, 1H), 1.4-1.5 (s, 9H).
Intermediate C1 : / / / NH N/ MeOH C, NH CN WO 96681 A solution of intermediate 17 (Example 18: prepared from 1g BOC intermediate 10a) was dissolved in MeOH (10 ml), to the on was added intermediate 5 (944 mg, 3.76 mmol) and NEt3 (2 ml). The reaction mixture was heated at 700 overnight. The solvent was evaporated and the residue was purified with purified by combi—flash column chromatography (0—100% MeOH/DCM) to afford intermediate C1.
LCMS (m/z) 327.40[M + H]+ MW 326.19. e 7: Preparation of ate (-P(O)OH2) nd 192.
N\ N\ N POCI3 / N ‘P/OH N/ D-HOH N/ "Odd o o TEA, THF Cl NHSOzMe EN CI NHSOzMe EN D1 1 92 nd 192 can be prepared from intermediate D1(preparation described directly below) by treating a solution of D1 in THF at about 0°C with POCl3 and triethylamine. The reaction e can be stirred at about 0 0C for a period of time and quenched with triethylammonium bicarbonate buffer (1M). The mixture can then be concentrated and purified by HPLC to give the desired product.
Compound 192 can also be prepared by the following protocol.
OwN\N \/ / \ 2. Pyr, THF, one o 0” Duo, < Cl NH .2 93— CN 0’ “ NH O 43— 0 ‘6 Intermediate D1 (100mg, 0.18 mmol) was dissolved in THF (2 ml), and the reaction mixture was cooled to 0°C using an ice bath. To the above solution was added POC13 (110mg, 0.72 mmol) followed by pyridine (71mg, 0.9 mmol). The reaction mixture was stirred at 0°C for 30mins before it was quenched with saturated NaHCO3. Washed the aqueous layer with DCM twice (20 mL), the aqueous layer was lyopholized and the residue was then purified by prep HPLC (Gemini C18, 100 30 mm, 5 micron ) using a gradient of water/acetonitrile 0- 100 to afford the title nd 192.
LCMS (m/z) 638.12 [M+H], Tr = 2.87 min.
CALC. MW .
Accordingly one embodiment includes compound 192 and salts thereof, as well as methods and intermediates that are useful for the preparation of compound 192 and intermediate In a r manner the corresponding phosphate prodrugs (-P(O)OH2) of the compounds of formulas I, la, II, Ila, III, IIIa, IV and IVa can also be prepared. Accordingly, one embodiment includes the phosphate compounds (—P(O)OH2) of the compounds of formulas I, la, II, Ha, III, IIIa, IV and IVa and salts thereof.
Preparation of intermediate D1.
N 2‘0H /N\N \ N\N \ C / / / _____> N N N / / ,.....m0H N N Cl O CI N{l O Cl NH y S D1 \S¢O / §O / \o The starting chloride ediate A1 (0.92g, 1.9 mmol) was dissolved in iPrOH (10 mL) and treated with triethylamine (0.45 mL, 0.33 g) and the intermediate 17 (0.45 g) and then heated to a gentle reflux under nitrogen. After heating overnight the on was cooled and diluted with ethyl acetate and brine. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50—100% ethyl acetate in hexanes) to afford the product as a white solid (1.15 g). LCMS (ESI) m/Z 558.2 [M + H12 1‘}; = 2.17 min.
Using similar procedures the corresponding compounds 193, 194 and 195 can also be prepared. Accordingly, one ment includes compounds 193, 194 and 195 and salts thereof.
WO 96681 my Kyle“ Q—OCL Q t>40“ c: NHSOzMe CN Cl NHSOzMe CW“? 19194 CI NHSOzMe CN Example 8: Preparation of compound 196.
Compound 196 was prepared according to the general procedure cited below LCMS (m/z) 446.04 [M + H]+ MW 445.22 General Procedure / / / / A N NH N D. \OH HATU, TEA, DMF 16 h, rt In 50 mL, singled necked, round ed flask was placed intermediate C1 (1932 .90 mmol) and TEA (1.64 mL, 11.8 mmol) in DMF (13 mL). The ylic acid (0.040 mmol) was placed in a separate 2-ml Vial. Then, into the vial was dispensed a solution of intermediate C1 (0.037 mmol) followed by the addition ofHATU (15.2 mg, 0.04 mmol). The resulting reaction mixture was placed on an orbital shaker at room temperature for 16 h. Then, to the reaction mixture was added EtOAc (4 mL), washed with sat. NaHCO3 (2 mL x 2), and concentrated in Genevac. The crude residue was loaded onto the CUSIL column, washed with EtOAc2Hexane (1:1, 4 mL), eluted with MeOH:EtOAc (5:95, 3 mL), and concentrated in Genevac to give the final compound 196.
Example 9: Preparation of intermediate 11. @0/ Pd(OAc)2, Xanphos O , Dioxane, 100°C @0/ Br N To an oven dried 50 mL round-bottom flask, methyl 2-bromomethylbenzoate (352 mg, 1.54 mmol), sultam (236 mg, 1.95 mmol), cesium carbonate (732 mg, 2.25 mmol), ium acetate (40.4 mg, 0.18 mmol), and Xanphos (136 mg, 0.235 mmol) were added and flask was placed under argon. Reagents were suspended in 8 mL of anhydrous dioxane and mixture was heated at 100 °C overnight. After g to room temperature, reaction mixture was filtered, washing with ethyl acetate. Combined filtrate was concentrated under reduced pressure and resulting film was purified by silica gel column chromatography (ZS-100% Ethyl Acetate in Hexanes) to yield intermediate 11. lH-NMR (DMSO, 400 MHz): 5 7.75 (d, 1H), 7.44 (m, 1H), 7.35 (m, 1H), 3.89 (s, 3H), 3.81 (t, 2H), 3.28 (t, 2H), 2.55 (m, 2H), 2.39 (s, 3H).
LCMS m/z [M+H]+ NO4S requires: . Found 270.12.
Example 10: ation of intermediate 12.
UH)/ LiOH—HZO fiOH N3 0, 60 °C N3 o=,,S o=,,S O O Lithium hydroxide monohydrate (496 mg, 11.8 mmol) was added to a solution of intermediate 11 (316 mg, 1.17 mmol) in 22 mL of THF and 12 mL of water at room temperature. Reaction mixture was heated at 60 0C for two hours. After cooling to room temperature, reaction mixture was acidified with 40 mL of 1N HCl (aq) and extracted with ethyl e (3 x 30 mL). The combined organic layers were washed 50 mL of Brine, separated, dried (MgSO4), filtered, and concentrated under reduced pressure to yield intermediate 12. 1H-NMR (DMSO, 400 MHz): 5 12.9 (s, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.41-7.34 (m, 2H), 3.66 (t, J=6.8 Hz, 2H), 3.28 (m, 2H), 2.37 (m, 2H), 2.33 (s, 3H).
LCMS m/z [M+H]' C11H13NO4S requires: 254.06. Found 254.18.
Example 11: Preparation of compound 197.
)N‘N \ N 04% Mi ‘H D-MOH HATU,TEA, DMF, rt 0 QMOH L’\\ \N N/j i\\ 4?, N HATU (70 mg, 0.185 mmol) was added to a solution of intermediate 12 (40 mg, 0.16 mmol) in 3 mL of anhydrous DMF at room ature. After 60 minutes of stirring, intermediate C1 (40 mg, 0.123 mmol) was added followed immediately by triethylamine (0.030 mL, 0.213 mmol). Reaction mixture stirred at room temperature overnight under argon.
Mixture was then poured into 30 mL of H20 and extracted three times with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL brine, dried (MgSO4), filtered, and concentrated under d pressure leaving a residue. Product was purified by prep HPLC (1 5-100% Acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) to yield compound 197 as a trifluoroacetic acid salt, after lyophilization.
LCMS m/z [M+H]+ C23H33N7O4S requires: 564.23. Found 564.13.
HPLC Tr (min), purity %: 5.33, 99% Example 12: Preparation of intermediate 13.
O 0 Cl Cl 0 1) NaN3, DMF, rt OH 2) LiOH-HZO MeOH/THF/HZO, rt Br N3 Step 1: Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2— (bromomethyl)—5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL ofDMF at room ature.
After ng overnight, on mixture was quenched with 25 mL of water. Aqueous was extracted with ethyl acetate (3x30 mL) and combined organics were washed with water (2x40 mL) and 50 mL of brine. Organics were dried (NazSO4), filtered, and concentrated under reduced pressure to yield methyl 2-(azidomethyl)chlorobenzoate which was used in the next step without further purification.
Step 2: Lithium hydroxide drate (794 mg, 18.9 mmol) was added to a solution of methyl 2-(azidomethyl)-5—chlorobenzoate (426 mg, 1.88 mmol), from the previous step, in 27 mL of 1:1 :1 THFzmethanolzwater at room temperature. After stirring overnight, reaction mixture was quenched with 20 mL of 2N HCl(aq), and extracted with ethyl acetate (3x30 mL).
Combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to yield intermediate 13. 1H-NMR (DMSO, 400 MHz): 7.88 (m, 1H), .65 (m, 1H), 7.54 (m, 1H), 4.78 (s, 2H).
Example 13: ation of compound 198.
N\ N\ / / / / N\ ”\OH HATU,TEA, DMF, rt N i\\ or i\\ N N Following the procedure for the synthesis of compound 197, beginning with intermediate 13 (36.2 mg, 0.171 mmol) and intermediate C1 (40 mg, 0.123 mmol), compound 198 was synthesized as a trifluoroacetic acid salt after lization.
LCMS m/z [M+H]+ C25H26C1N902 requires: 520.19. Found 520.03.
HPLC Tr (min), purity %: 6.34, 97%.
Example 14: Preparation of intermediate 14.
O 0 Br / MESOZCI, CHzciz Br O / Pyridine, rt 0 - NHz NHSOzMe To a solution of methyl 2-aminobromobenzoate (7.38 g, 32.0 mmol) and pyridine (6.3 mL, 81.5 mmol) in 100 mL of anhydrous CH2C12, was added slowly methane sulfonlehloride (6.5 mL, 79.9 mmol). After stirring overnight, reaction mixture was quenched with 100 mL of 1N HCl (aq). Aqueous mixture was extracted with ethyl acetate (3x120 mL) and combined organic layers were washed 200 mL brine. Organics were dried (MgSO4), filtered, and concentrated under reduced re to yield ediate 14. Silica gel column tography (0—30% Ethyl Acetate in Hexanes), yielded intermediate 14. 1H-NMR(CDC13, 300 MHz): 5 10.4 (s, 1H), 8.22 (s, 1H), 7.63 (s, 2H), 3.96 (s, 3H), 3.05 (s, 3H) LCMS m/z [M+H]+ C9H10BrNO4S requires: 307.95. Found .
Example 15: Preparation of intermediate 15.
O 0 Br@0/ NaOH(aq), THF, rt NHSOzMe Br\©EU\OH A 2.65 M solution ofNaOH in water (2.65 mL, 7.02 mmol) was added to a solution of intermediate 14 in 9 mL of THF with strong stirring. The reaction mixture was stirred at room temperature over night. The mixture was then acidified with 10 mL of 1N HCl and extracted with ethyl e (3 x 20 mL). The combined organic layers were washed 30 mL of brine, separated, dried (MgSO4), filtered, and trated under reduced pressure to yield intermediate 15. 1H-NMR (DMSO, 300 MHz): 8 10.6 (s, 1H), 8.05 (s, 1H), 7.79 (d, 1H), 7.55 (d, 1H), 3.18 (s, 3H).
LCMS m/z [M+H]' CgHgBI'NO4S requires: 291.94. Found 291.90.
Example 16: Preparation of compound 199.
/ / N‘H IDMOH N N N EA,DMF,rt o DMOH §\\ Br NH \\\ ing the procedure for the synthesis of compound 197, beginning with intermediate 15 (47 mg, 0.160 mmol) and intermediate C1 (40 mg, 0.123 mmol), compound 199 was synthesized as a trifluoroacetic acid salt, after lyophilization .
LCMS m/z [M+H]+ C25H23BrN7O4S requires: 602.11. Found 602.78 HPLC Tr (min), purity %: 6.52, 80% Example 17: Preparation of intermediate 16.
HO CI oxalyl chloride 0 DMF, CHZCIZ, rt N.“ NH O/” ‘8.— O/’II 0 o DMF (0.070 mL, 0.908 mmol) was added slowly to a suspension of 5—methyl-2— (methylsulfonamido)benzoic acid (1.01 g, 4.59 mmol) and oxalyl chloride (1.6 mL, 18.3 mmol) in 11 mL of anhydrous dichloromethane. After 3 hours, reaction mixture was concentrated and dried in-vacuo to yield intermediate 16 which was used in the next step without further purification. lH-NMR(CDC13, 400 MHz): 5 10.2 (s, 1H), 7.92 (s, 1H), 7.64 (m, 1H), 7.39 (m, 1H), 3.03 (s, 3H), 2.35 (s, 3H).
Example 18: Preparation of intermediate 17.
BOC\D“‘O’H HCOOH HDMO’H a 40°C a \\\ \\\ N N The BOC pyrollidine intermediate 10a (1 g, 4.7 mmol) was added to HCOOH (5 ml) and was heated at 40°C for 2h. The solvent was evaporated under d pressure and ted IPA ) was added to dissolve the residue, white precipitate formed after the IPA solution cooled down. The product was filtered and washed with IPA to give intermediate 17 that was used without further purification in uent reactions.
Example 19: Preparation of intermediate 18.
HCI 0 Ctort O O/II Triethylamine (0.58 mL, 4.16 mmol) was added slowly to a mixture of intermediate 17 (479 mg, 2.01 mmol) and intermediate 5 (573 mg, 2.00 mmol) in 10 mL of dichloromethane under argon at 0 0C. After 3 hours, LC/MS indicated full conversion to desired product. The reaction mixture was concentrated and dried in-vacuo to yield intermediate 18 that was used in the next steps without further purification.
LCMS m/z [M+H]+ C1N503S es: 462.13. Found 462.32.
Example 20: Preparation of compound 200.
N‘H N‘H \\\ 0’8” N TEA, MeOH, 75°C Ogfi‘” o o Triethylamine (0.100 mL, 0.717 mmol) was added to a mixture of intermediate 18 (102 mg, 0.221 mmol) and intermediate 17 (50 mg, 0.316 mmol) in 3 mL of methanol at room ature. After heating at 75 0C overnight, reaction mixture was cooled to room temperature and concentrated under reduced re. The remaining residue was purified by silica gel column chromatography (IO-75% ethyl acetate in hexanes) to yield compound 200.
LCMS m/Z [M+H]+ C26H31N7O4S requires: . Found 538.01.
HPLC Tr (min), purity %: 6.10, 97%.
Example 21: Preparation of compound 201.
/N\N \ CI /N‘N \ 0\ / / N N N / / .nOH NH N N 0 HATU, NEt3. DMF -. 3 CI 0 \\\ 2-Methoxychlorobenzoic acid (29mg, 0.17 mmol) and HATU (76mg, 0.2 mmol) were dissolved in DMF (2 ml). The reaction e was stirred at room temperature for 10mins. To the above on was added intermediate C1 (3 5mg, 0.1 mmol) and NEt3 (55 pl). The reaction was d at room temperature for 30mins and was quenched with brine (10 ml) and then extracted with EtOAc (20 ml). The organic layer was washed with brine twice (10 ml) and then was evaporated under reduced pressure. T he residue was purified with prep HPLC (0—100% H20) to afford compound 201.
LCMS (m/z) 495.17 [M + H]+.
MW 493.97.
Example 22: Preparation of compound 202.
WN\/ / N N O DI‘\OH c. <\\ N The title compound was prepared according to the procedure for compound 201 starting from intermediate C1 and 2-methylchlorobenzoic acid.
LCMS (m/z) 479.20 [M + Hr.
MW 477.97.
Example 23: Preparation of intermediate 19. 0 OH ’/ ’/ NH N“ on N N/ C: HATU,NEg,DMF 2- Amino—5-methylbenzoic acid (316 mg, 2.09 mmol), HATU (992mg, 2.61 mmol) were dissolved in anhydrous DMF (2 ml). After activation for 1 hour, intermediate 5 (500 mg, 1.74 mmol) and triethylamine (0.7 ml) was added to the above solution. The reaction was stirred under nitrogen for 2 hours. ts were removed by rotary evaporation. The e was d with silica gel column chromatography to provide intermediate 19.
LCMS m/z [M+H]+ C20H22C1N50 requires: 384.15. Found 383.99.
HPLC Tr (min), purity %: 2.00, 98%.
Example 24: Preparation of intermediate 20. o N- \\ W A WCI / / / / N N Cl N N Cl 0 0 ne NH2 ):0 Intermediate 19 , 0.84mmol) was dissolved in pyridine (2 ml). Then acetyl chloride (78mg, 1.0 mmol) was added to the above solution. The reaction was stirred under nitrogen for 30mins. Solvents were removed by rotary evaporation. The residue was purified with silica gel column chromatography to provide intermediate 20.
LCMS m/z [M+H]+ C22H24C1N502 requires: 426.16. Found 425.89.
HPLC Tr (min), purity %: 2.40, 98%.
Example 25: Preparation of compound 203.
N N/ [H l‘Q/ZN The title compound was prepared in 25% yield according to the procedure for compound 201 ng from intermediate 20 and the cis and trans mixture of 3—cyano hydroxypyrrolidine. Compound 203 was obtained as a e of all 4 isomers at the pyrrolidine.
LCMS (m/Z) 501.87 [M + H]+.
MW 500.58.
Example 26: Preparation of compound 204.
Wig:’FH CI NO Intermediate D1 (Example 7) (0.100g) was dissolved in DMF (2 ml) and Boc—L-valine (0. 075g), DMAP (0.02g) and HATU (0. 096g) added with stirring at room temperature. After 5 h, the solution was diluted with MeCN (2 ml) and water (4 ml) and was d with preparatory HPLC to yield the corresponding ester. The ester was dissolved in dioxane (2 ml) and HCl (4M in dioxane, 2 ml) was added with ng. After 2h, volatiles were removed at room temperature and the crude product was purified with preparatory HPLC to yield compound 204.
LCMS (m/z) 657.23, Tr = 1.64 min.
MW 657.18.
Example 27: Preparation of compound 205.
MYN\ H O N / / N N N Hj O Q. I \O H 3 Cl N' 0 The title compound was prepared in an analogous way as described for compound 204 above utilizing proline to afford the product nd 205.
LCMS (m/z) , Tr = 1.58 min.
CALC. MW 655.17.
Example 28: Preparation of compound 206.
/ / NHBoc TFA N N/ N N N N . J} ...OH ’ ’ 0 o Q-‘o ., NH2 2, EDCI, DMAP, DCM EN ON c: Cl N.“ N:— o‘SB— 0’ b lnterrnediate D1 (Example 7) (200mg, 0.36 mmol) was dissolved in DCM (2 ml), to the above solution was added Boc-Glycine (90mg, 0.6 mmol) and EDCI (111mg, 0.58 mmol) followed by DMAP (23mg, 0.18 mmol). The reaction mixture was stirred at room ature for 3 hours. To the above reaction mixture was added TFA (0.1 m1) and d at room temperature for 1 h. The solvent was evaporated under reduced pressure and purified with prep HPLC (Gemini C18, 100 30 mm, 5 micron column) using a gradient of water/acetonitrile 0- 100 to afford the title compound 206.
LCMS (m/z) 615.24 [M+H], Tr = 2.67 min.
CALC. MW 615.22.
Example 29: Preparation of compound 207.
MarN-/ / N N N Cl OH 028— Into oven-dried, argon purged flask were placed intermediate D1 (Example 7) (140 mg, 0.25 mmol), succinic anhydride (55 mg, 0.55 mmol) and catalytic amount (1 mg) of 4— dimethylaminopyridine. The flask was sealed with septa and ed with argon three times.
Dry tetrahydrofuran (20 mL) was added into the on mixture via syringe, followed by diisopropylethylamine (72 mg, 0.56 mmol). This reaction mixture was heated for 14 hours at 70 0C to e the full conversion. The solvent was evaporated, the residue was dissolved in ethyl acetate (30 mL) and this solution was washed twice with 10% solution of citric acid (30 mL), brine (30 mL), dried over ium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using gradient of dichloromethane/methanol (from 10/0 to 9/ l) to afford the title compound 207.
TLC Rf = 0.49 (10% methanol in dichloromethane, silica gel).
LCMS (m/z) 658.2 (100%) and 660.2 (44%) [M + H]+; 655.8 (100%) and 657.9 (40%) [M - H]+, Tr = 3.96 min., purity >99%.
For C29H32C1N7O7S Calc. MW 657.2 (100%) and 659.2 (37%). 1H-NMR(CDC13, 400 MHz): 9.19 (s, 1H), 8.73 (s, 1H), 7.61 (d, J= 8.8 Hz, 1H), 7.31 (d, J: 8.8 Hz, 1H), 7.25 (s, 1H), 6.14 (s, 1H), 6.03 (s, 1H), 5.51 (s, 1H), 5.23 (s,.lH), 4.04 (m, 3H), 3.75 (m, 1H), 3.34 (m, 1H), 3.19 (m, 1H), 3.06 (m, 1H), 2.84 (m, 2H), 2.66 (m, 3H), 2.29 (m, 3H), 2.00-1.22 (m, 6H).
Example 30: Preparation of compound 208.
MYN\/ N N/ Du‘O /N CI NH 025*— 2012/071065 Into oven-dried, argon purged flask were placed intermediate D1 (Example 7) (56 mg, 0.1 mmol), niacin (19 mg, 0.15 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol). The flask was sealed with septa and repurged with argon three times. Dry dichloromethane (20 mL) was added into the reaction mixture via syringe, followed by 1-ethyl-3 ~(3- dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.3 mmol). This reaction mixture was ed with argon three times and stirred at room temperature for 10 minutes to achieve the full sion. The solvent was evaporated, the residue was dissolved in ethyl e (30 mL) and this solution was washed twice with 5% solution of citric acid (30 mL), saturated solution O3 (30 mL), water (30 mL), brine (30 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using gradient of dichloromethane/methanol (from 10/0 to 95/5) to afford the title compound.
TLC Rf = 0.78 (5% methanol in dichloromethane, silica gel).
LCMS (m/z) 663.3 (100%) and 665.2 (43%) [M + H]+; 661.2 (100%) and 663.2 (38%) [M - H]+, = 4.19 min., purity >99%.
For C31H31C1N805S Calc. MW 662.2 (100%) and 664.2 (38%). lH-NMR (CDC13, 400 MHz): 9.21 (s, 1H), 8.77 (d, J: 4.2 Hz, 1H), 8.74 (s, 1H), 8.31 (d, J= 7.9 Hz, 1H), 7.61 (d, J: 8.8 Hz, 1H), 7.39 (dd, J= 7.9 Hz, J= 4.2 Hz, 1H), 7.31 (d, J= 8.8 Hz, 1H), 7.24 (s, 1H), 6.14 (m, 1H), 6.02 (s, 1H), 5.73 (m, 1H), 4.16 (m, 4H), 3.88 (m, 1H), 3.47 (m, 1H), 3.00 (s, 1H), 3.06 (m, 1H), 2.82 (s, 3H), 2.31 (s, 3H), 1.60-1.22 (m, 6H).
Example 31: Preparation of Compound 209.
MYN-/ / N N N .. o 0 GM CI NH 02‘8“— S WO 96681 Into oven-dried, argon purged flask were placed compound 207 (123 mg, 0.19 mmol) and 2-morpholinoethanamine (27 mg, 0.21 mmol). The flask was sealed with septa and repurged with argon three times. Reaction flask was placed in an ice-bath. 6 mL of dry acetonitrile were added into the reaction mixture via syringe, followed by diisopropylethylamine (97 mg, 0.75 mmol) and 0—(7-azabenzotriazol—1-yl)—N,N,N’,N-tetramethyluronium hexafluorophosphate (107 mg, 0.28 mmol). This reaction mixture was repurged three times with argon, the ice-bath was removed and the reaction e was stirred at room ature for 5 minutes to achieve the fill conversion. The solvent was evaporated and the residue was purified by silica gel chromatography (triethylamine neutralized silica gel) using gradient of dichloromethane/methanol (from 10/0 to 9/1) to afford the title compound 209.
TLC Rf = 0.57 (10% methanol in dichloromethane, silica gel).
LCMS (m/z) 770.3 (100%) and 772.2 (51%) [M + H]+; 768.2 (100%) and 770.1 (43%) [M - H]+,Tr = 2.95 min., purity >99%.
For C35H44C1N907S Calc. MW 769.3 (100%) 771.3 (37%). lH-NMR (CDC13, 400 MHz): 9.23 (s, 1H), 8.72 (s, 1H), 7.62 (d, J: 8.7 Hz, 1H), 7.31 (d, J= 8.7 Hz, 1H), 7.25 (m, 1H), 6.14 (m, 1H), 6.00 (s, 2H), 5.51 (m, 1H), 5.23 (s, 2H), 4.03 (m, 1H), 3.75 (m, 1H), 3.64 (m, 6H), 3.26 (m, 2H), 3.19 (m, 1H), 3.06 (m, 2H), 2.80 (s, 3H), 2.73 (m, 2H), 2.45 (m, 2H), 2.38 (m, 3H), 2.28 (s, 3H), 1.94—1.22 (m, 4H).
Example 32. Preparation of intermediate 32.
A pyridine CI CCI3 EtO \ OEt 2) NaOEt, EtOH A solution of xy-propene (5.1 mL, 46 mmol) in ne (3.4 mL) was added slowly Via addition funnel (~1 drop/sec) to neat trichloroacetyl chloride (4.7 mL, 42 mmol) at —10 °C under an argon atmosphere. The reaction e was then allowed to slowly warm to 23 °C. After 20 h, the reaction mixture was diluted with dichloromethane (50 mL) and the resulting mixture was washed with 0.01N HCl (3 50 mL) and brine (50 m L), was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. To the crude e was added sodium ethoxide (21 wt% in ethanol, 7.1 g, 44 mmol) slowly via syringe. After 30 min, the reaction mixture was ioned between dichloromethane (500 mL) and water (500 mL). The phases were split and the aqueous layer was extracted with romethane (500 mL). The combined organic extracts were dried over ous sodium sulfate, and were concentrated to afford intermediate 32. 1H-NMR (CDC13, 400 MHz): 7.28 (app 5, 1H), 4.09 (q, .1: 7.1 Hz, 2H), 3.96 (q, J: 7.1 Hz, 2H), 1.66 (s, 3H), 1.25 (t, J= 7.1 Hz, 3H), 1.20 (t, J= 7.1 Hz, 3H).
Antiviral Activity Another ment relates to methods of inhibiting viral infections, comprising the step of treating a sample or subject ted of needing such inhibition with a composition of the invention.
Samples suspected of containing a virus include l or man-made materials such as living organisms; tissue or cell cultures; biological samples such aspbiological material s , serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing an organism which induces a viral infection, frequently a pathogenic organism such as a tumor virus. s can be contained in any medium including water and organic solvent\water mixtures. Samples include living organisms such as humans, and manmade materials such as cell cultures.
If desired, the anti-virus activity of a compound described herein after application of the composition can be observed by any method ing direct and indirect methods of ing such activity. Quantitative, qualitative, and semi-quantitative methods of ining such activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
The antiviral activity of a compound described herein can be measured using standard screening protocols that are known. For example, the ral activity of a compound can be measured using the following general protocols.
WO 96681 Respiratory syncytial virus (RSV) antiviral activity and cytotoxicity assays Anti-RSV activity Antiviral activity against RSV was determined using an in Vitro cytoprotection assay in Hep2 cells. In this assay, compounds inhibiting the virus replication exhibit cytoprotective effect against the virus-induced cell g were quantified using a cell viability t. The method used was similar to s previously described in published literature (Chapman ct al., Antimicrob Agents Chemother. 2007, 51(9):3346-53.) Hep2 cells were obtained from ATCC (Manassas, VI) and maintained in MEM media supplemented with 10% fetal bovine serum and penicillin/streptomycin. Cells were passaged twice a week and kept at subconfluent stage. Commercial stock ofRSV strain AZ ced Biotechnologies, Columbia, MD) was titered before compound testing to determine the appropriate dilution of the Virus stock that generated desirable cytopathic effect in Hep2 cells.
For ral tests, Hep2 cells were seeded into l plates 24 hours before the assay at a density of 3,000 cells/well. On a separate 96well plate, compounds to be tested were serially diluted in cell culture media. Eight concentrations in 3-fold serial dilution increments were prepared for each tested compound and 100 uL/well of each dilution was transferred in duplicate onto plates with seeded Hep2 cells. Subsequently, appropriate dilution of Virus stock previously determined by titration was prepared in cell culture media and 100 uL/well was added to test plates containing cells and serially diluted compounds. Each plate included three wells of infected untreated cells and three wells of uninfected cells that served as 0% and 100% virus inhibition control, tively. Following the infection with RSV, testing plates were ted for 4 days in a tissue culture tor. After the incubation, RSV-induced cytopathic effect was determined using a Cell TiterGlo reagent ga, Madison, WI) followed by a luminescence read-out. The percentage inhibition was calculated for each tested concentration relative to the 0% and 100% tion controls and the EC50 value for each compound was determined by non-linear regression as a tration inhibiting the RSV-induced cytopathic effect by 50%. Ribavirin (purchased from Sigma, St. Louis, MO) was used as a positive control for antiviral activity.
Compounds were also tested for antiviral ty against RSV in Hep2 cells using a 384 well format. Compounds were diluted in DMSO using a p serial on in 3-fold increments via automation in 4 adjacent replicates each. Eight compounds were tested per dilution plate. 0.4uL of diluted compounds were then stamped via Biomek into 384—well plates (Nunc 142761 or 164730 w/lid 264616) containing 20uL of media (Mediatech Inc. MEM mented with Glutamine, 10% FBS and Pen/Strep). DMSO and a le positive control compound, such as 80 uM GS-329467 or 10 uM 427346 was used for the 100% and 0% cell killing controls, respectively.
Hep2 cells (1.0 x 105 cells/ml) were prepared as above in batch to at least 40 mls excess of the number of sample plates (8 mls cell mix per plate) and ed with vendor supplied (ABI) RSV strain A2 to arrive at an MOI of 1:1000 (viruszcell #) or 123000 (vol virus: cell vol).
Immediately after addition of virus, the RSV infected Hep2 cell suspension was added to each stamped 384-well plate at 20 ul per well using a uFlow dispenser, giving a final volume of 40 uL/well, each with 2000 infected cells. The plates were then incubated for 5 days at 37°C and % C02. Following incubation, the plates were equilibrated to room temperature in a biosafety cabinet hood for 1.5 hrs and 40uL of Cell-Titer Glo viability reagent (Promega) was added to each well via uFlow. Following a10-20 minute incubation, the plates were read using an on or Victor Luminescence plate reader (Perkin-Elmer). The data was then uploaded and analyzed on the Bioinformatics portal under the RSV Cell ivity and 8-plate EC50-Hep2- 384 or 8-plate EC50-Hep2-Envision protocols.
Multiple point data generated in the assay was analysed using Pipeline Pilot (Accelrys, Inc., n 7.0) to generate a dose response curve based on least squares fit to a 4—parameter curve. The generated formula for the curve was then used to calculate the % inhibition at a given tration. The % inhibition reported in the table was then adjusted based on the normalization of the bottom and top of the curve % inhibition values to 0% and 100% respectively.
Representative activities for the compounds of the invention against RSV-induced cytopathic effects are shown in the Table below.
WO 96681 Compound Percent inhibition formula at 0.5 uM Compound Percent inhibition formula at 0.5 [AM O\O\O\O\O\O\O\O\O\U1U‘IUIU‘IUIUIUIUIUlUi-b-P-b-b-b-b-P F—‘OKOOGQONUI-bWNHOOOOflONUI-RWNt—‘OKDOONONUILW 88 1 00 H L11 N\] Uiv—A UIONHOOU.‘NHUJ-b 72 100 73 99 74 100 75 100 76 99 77 100 78 100 79 100 80 14 81 96 82 100 83 99 84 100 Compound Percent tion formula at 0.5 pM 89 100 90 100 91 100 95 21 99 100 WO 96681 Compound t inhibition 1 87 1 00 1 93 n.d 196 96 (n.d. not determined) WO 96681 Cytotoxicity Cytotoxicity of tested compounds was determined in uninfected Hep2 cells in parallel with the antiviral activity using the cell viability t in a similar fashion as described before for other cell types (Cihlar et al., Antimicrob Agents Chemother. 2008,52(2):655-65.). The same protocol as for the determination of antiviral activity was used for the measurement of compound cytotoxicity except that the cells were not infected with RSV. d, fresh cell culture media (100 uL/well) without the virus was added to tested plates with cells and prediluted nds. Cells were then incubated for 4 days followed by a cell viability test using CellTiter Glo t and a luminescence read-out. Untreated cell and cells treated with 50 ug/mL puromycin (Sigma, St. Louis, M0) were used as 100% and 0% cell viability control, respectively. The percent of cell viability was calculated for each tested compound concentration relative to the 0% and 100% controls and the CC50 value was determined by non- linear regression as a nd concentration reducing the cell viability by 50%.
To test for compound cytotoxicity in Hep2 cells using a 384 well format, compounds were diluted in DMSO using a lO-step serial dilution in 3-fold increments Via automation in 4 adjacent replicates each. Eight compounds were tested per dilution plate. 0.4uL of d compounds were then d Via Biomek into 384-well plates (Nunc 142761 or 164730 w/lid 264616) containing 20uL of media (Mediatech Inc. MEM supplemented with Glutamine, 10% FBS and Pen/Strep). 50 ug/mL puromycin and DMSO were used for the 100% and 0% cytotoxicity controls, respectively.
Hep2 cells (1.0 X 105 ml) were added to each stamped plate at 20 ul per well to give a total of 2000 cells/well and a final volume of 40 uL/well. Usually, the cells were batch prediluted to 1.0 X 105 mL in excess of the number of sample plates and added at 20 ul per well into each assay plate using a uFlow dispenser. The plates were then incubated for 4 days at 37°C and 5% C02. Following incubation, the plates were equilibrated to room temperature in a biosafety cabinet hood for 1.5 hrs and 40uL of Cell—Titer G10 viability reagent (Promega) was added to each well via uFlow. Following a 10-20 minute incubation, the plates were read using an EnVision or Victor Luminescence plate reader (Perkin-Elmer). The data was then uploaded and analyzed on the Bioinformatics portal (Pipeline Pilot) under the Cytotoxicity assay using the 8—plate CC50-Hep2 or e ep2 Envision protocols. Compounds tested for Anti-RSV activity were also tested in this cyctotoxicity assay. l 00 1 406004 All publications, patents, and patent documents cited herein above are incorporated by reference herein, as though dually incorporated by reference.
The invention has been described with reference to various specific and preferred embodiments and techniques. However, one skilled in the art will understand that many variations and modifications may be made while remaining within the spirit and scope of the invention.
Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general dge in New d or any otherjurisdiction.

Claims (13)

What is claimed is
1. A nd of formula I: 10 or a salt or ester, thereof; wherein: A is —(C(R4)2)n- wherein any one C(R4)2 of said —(C(R4)2)n- may be ally replaced with -O-, -S-, -S(O)p-, NH or NR3; nis 3,4, 5 or6; 15 eachpis 1 or 2; Ar is a C2—C20 cyclyl group or a C6-C20 aryl group, wherein the C2—C20 heterocyclyl group or the C6-C20 aryl group is ally substituted with 1, 2, 3, 4 or 5 R6; each R3, R4 or R6 is independently H, oxo, 0R“, NRIIR‘Z, NR“C(0)R“, NR“C(O)OR“, NR“C(0)NR“R”, N3, CN, N02, SR“, 3(0),,Ra, NR“S(O)pRa, -C(=O)R“, —C(=0)0R“, — 20 C(=O)NR“R12, —C(=O)SR“, -S(O)p(OR”), —SOZNR“R12, —NR“S(O)p(OR“), —NR“sopNR“R12, NR“C(=NR‘ 1)NR“R12, halogen, (C1—C3)alkyl, (C2—C3)alkenyl, (C2—C8)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, )cycloalkyl or (C4~Cg)carbocyclylalkyl; or two R4 on adjacent carbon atoms, when taken together, may optionally form a double 25 bond n the two carbons to which they are attached or may form a (C3-C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by -O-, —S—, -S(O)p-, -NH- or -NRa—; or four R4 on adjacent carbon atoms, when taken together, may optionally form an optionally substituted C6 aryl ring; or two R4 on the same carbon atom, when taken together, may optionally form a (C3- C7)cycloalkyl ring wherein one carbon atom of said (C3—C7)cycloalkyl ring may be optionally replaced by -O-, -S-, -S(O)p-, -NH- or —NRa-; or two R6 on adjacent carbon atoms, when taken er, may optionally form a (C3— C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be ally 10 replaced by -O-, -S-, -S(O)p-, -NH— or —NRa—; each Ra is independently (C1-C3)alkyl, )haloalkyl, (C2-C8)alkenyl, (C2-Cg)alkynyl, aryl(C1-Cg)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or )carbocyclylalkyl wherein any (C1—C3)alkyl, )haloalkyl, (C2-Cg)alkenyl or (C2- Cg)alkynyl of Ra is optionally substituted with one or more OH, NH2,‘ CO2H, C2—C20 15 heterocyclyl, and wherein any aryl(C1—Cg)alkyl, C5—C20 aryl, C2—C20 heterocyclyl, (C3- C7)cycloalkyl or (C4—Cg)carbocyclylalkyl of R3 is ally substituted with one or more OH, NH2, CO2H, C2—C20 heterocyclyl or (C1-C3)alkyl; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, aryl(C1-C3)alkyl, C6—C2o aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl, )carbocyclylalkyl, 2O -C(=O)Ra, -S(O)pRa or ary1(C1-Cg)alkyl; or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S—, -S(O)p—, -NH-, -NRa- or -C(O)—; and wherein each (C1-C8)alkyl, (C2—Cg)alkenyl, (C2-Cg)alkynyl, aryl(C1—Cg)alkyl, C6—C20 25 aryl, C2—C20 cyclyl, )cycloalkyl or (C4—Cg)carbocyclylalkyl of each R6, R11 or R12 is, independently, optionally tuted with one or more oxo, halogen, y, NH2, CN, N3, N(Ra 2, NHR“, SH, SR3, S(O)pRa, ORa, (C1-C8)alkyl, (C1—C3)haloalkyl, -C(O)Ra, -C(O)H, -C(=O)OR3, -C(=O)OH, -C(=O)N(Ra 2 , -C(=O)NHRa , -C(=O)NH2 , NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, 30 NRaC(O)N(Ra)2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra 2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NRaS(O) pN(Ra 2, NRaS(O) pNH2, NHS(O) pNHRa, NHS(O) pN(Ra)2, NHS(O) pNH2, -OC(=O)Ra, —OP(O)(OH)2 or Ra; provided the compound is not: 1001406004 CI NH \\}\1 O/('3l
2. The compound of claim 1 or a salt or ester, thereof; . 3 wherein each R . IS H.
3. The compound oi’claim l or claim 2 or a salt or ester, thereof; wherein n is 3.
4. The compound of any one ofclaims 1—3 or a salt or ester, thereof; . 4 wherein each R . IS H.
5. The compound of any one of claims 1—4 or a salt or ester, thereof; wherein A is -(Cl~12)3—.
6. The nd of claim 1 wherein the compound of formula I is a compound of formula Ia: M“!N\/ N N/ N F0 “OH Ia . Ar 2 or a salt or ester, thereof.
7. The compound of any one of claims 1-6 or a salt or ester, thereof; wherein Ar is phenyl, pyridyl, l,2,3,4—tetrahydronaphthyl, indazolyl, phthyridyl, 2,3,- dihydroindanyl, quinolyl, l, 4H-benzo][d][1,3]dioxanyl, pyrazolo[l,5-a]pyridinyl, imidazo[1,2—a]pyridiny1, 1, 2,3,4-tetrahydroquinolyl, benzo[d][l,3]dioxolyl, quinoxalyl, isoquinolyl, naphthyl, thiophenyl, pyrazolyl, 4,5,6,7-tetrahydrobenzothiophenyl or pyrazolo[3,4,b]pyridiny1, l 001 406004 wherein any , pyridyl, l,2,3,4—tetrahydronaphthyl, lyl, 1,6—naphthyridyl, 2,3,- oindanyl, quinolyl, indolyl, 4H-benzo][d][l,3]dioxanyl, pyrazolo[l,5-a]pyridinyl, imidazo[l,2—a]pyridinyl, l, 2,3,4-tetrahydr0quinolyl, benzo[d][l,3]di0xolyl, quinoxalyl, isoquinolyl, naphthyl, thiophenyl, pyrazolyl, 4,5,6,7—tetrahydr0benzothiophenyl or pyrazolo[3,4,b]pyridinyl of A is optionally substituted with l to 5 R6.
8. The compound of any one of claims 1—7 or a salt or ester, thereof; wherein each R6 is independently OR“, CN, S(O)pRa, halogen, (C1-Cg)alkyl, C6~C20 aryl, C2-C20 heterocyclyl, (C3—C7)cycloalkyl, (C4—Cg)carbocyclylalkyl, NR1 “ or NR1 ,Ra, wherein any (C1~Cg)alkyl, C6—C20 aryl, C2~C20 cyclyl, (C3~C7)cycloalkyl or )carbocyclylall<yl ofR6 is optionally substituted with one or more 0x0, halogen, hydroxy, NH2, CN, N3, N(Ra)2, NHRa, 81-], SR'“, S(O),,R”, OR“, (C1—C8)alkyl, (C1— Cg)haloalkyl, —C(O)Ra, -C(O)H, —C(=O)OR3, -C(=O)Ol~l, —C(=O)N(Ra)2 , —C(=O)NHRa , —C(:O)Nl-[2 , NHS(O)pR”, NR"S(O)pRa, NHC(O)Ra, NR“C(O)R8, NHC(O)OR“, NR“C(O)OR“, NR“C(O)NHR“, NR“C(O)N(R“)2, NRaC(O)NH2, Nl—IC(O)NHRa, NHC(O)N(R’°‘)2, NHC(O)NI~12, =Nl—l, :NOH, =NOR“, NR“S(O)pNHRa, NR“S(O) pN(Ra)2, O) pNHg, NHS(O) pNHRH, NHS(O) )2, NHS(O) pNHz, —OC(:O)R“1, —OP(O)(OH)2 or R”.
9. The compound of any one of claims 1—7 or a salt or ester, thereof; wherein each R6 is independently ORl 1, CN, S(O)I,Ra, halogen, (C1—C8)alkyl, C6—C20 aryl, C2—C20 heterocyclyl, (C3-C7)cycloalkyl or (C4—Cg)carbocyclylalkyl, wherein any (C1—C8)alkyl, C6~C20 aryl, C2~C20 heterocyclyl, (C3-C7)cycloall<yl or (C4—Cg)carbocyclylalkyl of R6 is optionally substituted with one or more 0x0, halogen, hydroxy, NHz, CN, N3, N(Ra)2, NHRaj SH, SR3, a, 0R3, (C1— Cg)alkyl, (C1—C8)haloalkyl, -C(O)Ra, ~C(O)H, —C(=O)ORa, ~C(=O)OH, N(Ra)2 , —C(=O)NHRa , -C(:O)NH2 , NHS(O)pRa, NRaS(O)pRa, R3, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ra)2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra)2, NHC(O)NH2, =NH, =NOH, =NORa, NRaS(O)pNHRa, NRaS(O) pN(Ra)2, NRaS(O) pNHz, NHS(O) pNHRa, NHS(O) pN(Ra)2, NHS(O) le-l2, —OC(=O)Ra, ~OP(O)(OH)2 or Ra.
10. The compound ofclaim 1 selected from: WO 96681 MN\/N WO 96681 \ N\ / / / / / N / N N N N N NO ‘OH N N OH 0 0 F i\\ / \ 2’\ F L’\\’ N _N \\N, \N WO 96681 WN\/ / N N N 0 O0H L; , O \\ —§ \\ N I | N S F 2012/071065 CI \OHHOWJO/N:96\\\ . QVOHl \\N , \N /'|\H/j\/ M“LN/Y /l\H/\I N N NQ N N M0H N N .uOH N N _. ‘0H O O O N\ N\ / / / / WO 96681 N NO N N N N _I‘0“ _,\0” o 0 Q..lIOH o N \\ Cl \\N / \N\\ \ o / / / / N N N N N / ...QH N N/ N 0 Q DMOH 0 , QMOH ’ S / \\\’ / / / / / / N N NO N N N N N . OH .OH .OH 0 0 0 \ O ID N ’ F , \ \\ / \ i\\ F \\\ N /N/D‘0H N /N/N... N /N/N.0H o o o w o / 0 N i\\ 3\ r 3\ \\N ' / F Cl N /N \\N / / N N/ N w/ N N/ N Cl 0 O‘OH N N D ‘OH F ‘0“ 0 F%/\N O Cl O : —— 3 \\ ' F I \ ’\ \ N \\ N / N and \ \ N/ \ O | N— A "’OH and salts and esters, f.
11. The compound of claim 1 selected from: WO 96681 '3 \\ Br \ C' \\\ N‘H N N — N /,S\\ 3 O O NH \\ \\ o‘fi \ N Cl \\ . N’ \\ CI NH H ; CI N 0 ,H CN ‘éo 0' ”‘00 / ' s=o / O / / N /N\N/j\/ N N 3 NH2 O 0 0” DINO CI Nj-l -,I W 04%“ CN 0“ Cl NH 0 ' ozs— {flagN OW{QEENQ'WW Cl NH 028— 2 5 Q and salts and esters, f.
12. A compound of formula: MYN \/N N/ w CI NgL/O O// \ wherein W is: l H H TN” H NH | 571/N H H NH NH \NH J: H gr HN ’3‘” NW W'w N H ITI "01,1, 'fi NH *3 / IfN HNare X?/‘23. w” \ A ' {1% . wtA or a salt, or iscmer thereof.
13. The compound of claim 12 selected from:
NZ625737A 2011-12-22 2012-12-20 Pyrazolo[1,5-a]pyrimidines as antiviral agents NZ625737B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161579625P 2011-12-22 2011-12-22
US61/579,625 2011-12-22
US201261618510P 2012-03-30 2012-03-30
US61/618,510 2012-03-30
PCT/US2012/071065 WO2013096681A1 (en) 2011-12-22 2012-12-20 Pyrazolo[1,5-a]pyrimidines as antiviral agents

Publications (2)

Publication Number Publication Date
NZ625737A NZ625737A (en) 2016-04-29
NZ625737B2 true NZ625737B2 (en) 2016-08-02

Family

ID=

Similar Documents

Publication Publication Date Title
JP6122868B2 (en) Pyrazolo [1,5-A] pyrimidine as an antiviral agent
US10174038B2 (en) Compounds and methods for antiviral treatment
US9957275B2 (en) Pyrazolo[1,5-A]pyrimidines for antiviral treatment
NZ625737B2 (en) Pyrazolo[1,5-a]pyrimidines as antiviral agents
OA16278A (en) Pyrazolo [1,5-A] pyrimidines as antiviral agents.