NZ715889B2 - Benzothiazole compounds and their pharmaceutical use - Google Patents

Benzothiazole compounds and their pharmaceutical use Download PDF

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NZ715889B2
NZ715889B2 NZ715889A NZ71588912A NZ715889B2 NZ 715889 B2 NZ715889 B2 NZ 715889B2 NZ 715889 A NZ715889 A NZ 715889A NZ 71588912 A NZ71588912 A NZ 71588912A NZ 715889 B2 NZ715889 B2 NZ 715889B2
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alkyl
carbocycle
heterocycle
aryl
heteroaryl
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NZ715889A
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NZ715889A (en
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Kerim Babaoglu
Ryan Mcfadden
Michael L Mitchell
Paul A Roethle
Lianhong Xu
Hong Yang
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Gilead Sciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems

Abstract

Provided herein are compounds of formula I: or a salt thereof as described herein. Also provided are pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal using compounds of formula I. In one embodiment the compound is (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(4-methoxybenzylcarbamoyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid. reating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal using compounds of formula I. In one embodiment the compound is (S)-2-tert-butoxy-2-((S)-7-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(4-methoxybenzylcarbamoyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid.

Description

BENZOTHIAZOLE COMPOUNDS AND THEIR PHARMACEUTICAL USE Cross Reference to Related Application This patent application claims the benefit of priority ofUS. application serial No. 922, filed April 21, 2011, which ation is hereby incorporated by reference.
Background of the Invention Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV—1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
Although drugs targeting reverse transcriptase and se are in wide use and have shown iveness, ularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med. (1998) 3-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV. There is also a need for agents that are directed against alternate sites in the viral life cycle including agents that target the interaction of Lens Epithelial Derived Growth Factor (LEDGF/p75) and HIV-1 integrase.
Summm ofthe Invention The present invention provides compounds and methods for the treatment of an HIV infection. Accordingly, in one embodiment, the invention provides a compound of the invention which is a compound of a I: R4 R3 R3' G1 OH R5 m.” \GZ O wherein: G1 is S, G2 is N, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R5 is a single bond; or G1 is N, G2 is S, the dashed bond connected to G1 is a double bond, the dashed bond connected to G2 is a single bond, and the wavy bond connected to R5 is a single bond; or G1 is S, G2 is NR6, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a single bond, the wavy bond connected to R5 is a double bond and R5 is oxygen (e.g.“(wavy bond)-R5” is “=0”); R1 is R1:11 or Rlb; R2 is R2a or sz; R3 is R3a or R3b; R3, is R33, or R”; R4 is R43 or R4”; R5 is R5al or RSb; R6 is R681 or Réb; R1a is selected from: a) halo; b) R“, -C(=O)-R”, -C(=O)—O-R“, -o-R“, —s-R“, -S(O)-R“, -SOz-R“, -(C1-C6)alky1-R“, -(C1-C6)alkyl—C(=O)-R”, -(C1-C6)alky1-C(=O)-O-Rl1, 6)alkyl-O-R”, -(C1-C6)alkyl-S-R“, -(C1-C6)alkyl—S(O)—R“ and —(C1-C6)alkyl-SOZ—R“, wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or aryl are each ally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; and c) -N(R9)R1°, -N(R9)R1°, -O—C(=O)—N(R9)R1°, -SOz-N(R9)R1°, -(C1—C6)alkyl-N(R9)R1°, -(C1—C6)alkyl-C(=O)-N(R9)R1O, -(C1-C6)alky1-O-C(=O)—N(R9)R10 and -(C1-C6)alkyl-SOz-N(R9)R1°, wherein each R9 is independently selected from H, (C1—C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R”, -(C1—C6)alkyl—R“, -802— R“, -C(=O)—R“, —C(=O)OR“ and -C(=O)N(R9)R“, wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, )cycloalkyl, aryl, cycle and heteroaryl; Rlb is selected from: a) 6)alkyl-O-(C1-C6)alkyl-(C3-C7)carbocycle, —(C1-C6)alkyl—S-(C1- yl-(C3-C7) carbocycle, -(C1-C6)alkyl-S(O)-(C1-C6)alkyl-(C3-C6) carbocycle, -(Ci-C6)alkyl- SOz-(C1-C5)a1kyl-(C3—C7)carbocycle, -(C1-C6)alkyl-SOz-(C1—C6)alkyl-Zl3, —C(O)-(C1-C6)alkyl- z”, -O-(C1-C6)alkyl-Zl3, -S—(C1-C6)alkyl-Zl3, -S(O)-(C1-C6)alkyl-Zl3, —SOz-(C1-C6)alkyl—Zl3, -(C1-C6)alkyl-Zl4, -(C1-C6)alkyl-C(O)-(C1-C6)alkyl-Zl3, -(C1—C6)alkyl-C(O)-O(C1-C6)alkyl-Zl3, -(C1-C6)alkyl-O-(C1-C6)alkyl-Zl3, 6)alkyl-S-(C1-C6)alky1-Z13, -(C2- C6)alkenyl-(C1-C6)haloalkyl, -(C2-C6)alkynyl-(C1-C6)haloalkyl, - (C3-C7)halocarbocycle, -NRaSOzNRCRd, —NRaSOzO(C3-C7)carbocycle, -NRaSOZOaryl, -(C2-C6)alkenyl—(C3— C7)carbocycle, —(C2-C6)alkenyl-aryl, -(C2—C6)al'kenyl-heteroary1, -(C2-C6)alkenyl-heterocycle, -(C2—C5)alkynyl-(C3-C7)carbocycle, —(C2—C5)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl -(C2-C6)alkynyl-heterocycle, —(C3-C7)carbocycle-Z1 or -(C1-C6)haloalkyl-Z3, wherein'any (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl or heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle or d—bicyclic carbocycle is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups, or wherein two Z1 groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 ; c) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z2 groups and ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; d) C6)alkyl, -X(C1-C5)haloalkyl, -X(C2—C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein -X(C1-C6)alkyl and -X(C1-C6)haloalkyl are each independently substituted with one or more Z3 groups and optionally tuted with one or more Z1 groups, and wherein -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z4 groups and optionally substituted with one or more Zlgroups; e) aryl, heteroaryl, heterocycle, -Xaryl, roaryl eterocycle; wherein aryl heteroaryl and heterocycle, either alone or as part of a group, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more Zlgroups; 1) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl are each ndently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more Zlgroups; g) 'NReRf, -C(O)NReRr, -OC(O)NReRr, ch, ‘(CI'C6)alky1'NRch, -(C1-C5)alky1C(O)-NReRf, -(C1-C6)alkyl-O-C(O)-NReRf and -(C1—C6)alkyl-802NRch; wherein each (C1-C6)alkyl, as part of a group, is independently substituted with one or more (6. g. l, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more Zlgroups; and h) nitro and cyano; R221 is selected from: a) halo; b) R”, R“, -C(=O)-O-R“, -o—R“, -s-R“, -S(O)—R“, —SOz-Rll, -(C1-C6)alkyl-R“, -(C1-C6)alkyl-C(=O)-R“, -(C1-C6)alkyl-C(=O)—O—Rl1, -(C1—C6)alkyl-O-R“, 6)alkyl-S-R“, -(C1-C6)alkyl-S(O)-R“ and -(C1-C6)alkyl-SOZ-R”, wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl and heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more (e.g. l, 2 or 3) Z11 groups; and c) -N(R9)R1°, -N(R9)R10, -O-C(=O)-N(R9)R1°, -SOz—N(R9)R1°, (,)alkyl- N(R9)R1°, -(C1—C6)alkyl-C(=O)-N(R9)R10, -(C1-C6)alky1-O—C(=O)-N(R9)R10, and —(C1—C6)alkyl- SOz-N(R9)R10, wherein each R9 is independently ed from H, (C1-C5)alkyl and (C3- C7)cycloalkyl, wherein each R10 is independently selected from R”, -(C1—C6)alkyl-R“, -SOz-R“, -C(=O)-RI 1, -C(=O)OR11 and -C(=O)N(R9)R“, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; R2b is selected from: a) -(C1-C6)alkyl-O—(C1-C6)alkyl-(C3—C7)carbocycle, —(C1-C6)alkyl-S-(C1— C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl—S(O)-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1- C6)alkyl-SOz—(C1-C6)alky1-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -(C1—C6)alkyl-SOZ-(C1-C6)alkyl—Zl3, -C(O)—(C1-C6)a1kyl-Zl3, —o- )alky1-Z13, -S-(C1-C6)alkyl-Zl3, (C1-C6)alkyl-Zl3, -SOz-(C1—C6)alkyl-Zl3, -(C1-C6)alkyl—Zl4, -(C1-C6)alky1-C(O)-(C1-C6)alkyl-Z13, -(C1-C6)alkyl-C(O)-O(C1-C6)alkyl-Zl3, -(C1—C6)alky1—O-(C1-C6)alkyl—Zl3, -(C1-C6)alky1-S-(C1-C6)alkyl-Zl3, 7)halocarbocycle, -NRaSOzNRcRd, —NRaSOzO(C3-C7)carbocycle, -NRaSOZOaryl, -(C2-C6)alkenyl—(C3—C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C5)alkenyl-heteroaryl, -(Cz-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl—heteroaryl, —(C2-C6)alkynyl-heterocycle, —(C3-C7)carbocycle-Z1 or —(C1— C6)haloalkyl-Z3, wherein any )alkyl, -(C1-C6)haloalkyl, (C3—C7)carbocycle, (C2- C6)alkenyl, (C2-C6)alkynyl, aryl or heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z1groups; b) spiro-bicyclic carbocycle, bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, bicyclic carbocycle or bridged-bicyclic carbocycle is optionally substituted with one or more (6.g. 1, 2, 3, 4 or 5) Z1 groups, wherein two Zl groups er with the atom or atoms to which they are attached optionally form a (C3-C7)carbocycle or heterocycle wherein the (C3-C6)carbocycle or cycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; PCT/U82012/034593 c) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z1groups; d) -X(C1-C6)alkyl, -X(C1-C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3—C7)carbocycle, wherein -X(C1-C6)alkyl and X(C1-C6)haloalkyl are each independently tuted with one or more Z3 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups, and wherein -X(C2-C5)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z4 groups and optionally substituted with one or more Zlgroups; e) aryl, heteroaryl, heterocycle, -Xaryl, —Xheteroaryl and -Xheterocycle, wherein aryl heteroaryl and cycle, either alone or as part of a group, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; f) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally tuted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; g) ‘NRch, -C(O)NReRf, -0C(O)NRch, 'SOZNReRf, '(CI-C6)alkyl'NReRf, “(C1-C6)alkle(O)'NR.¢Rf, —(C1-C6)alkyl-O-C(O)-NReRf and -(C1-C6)alkyl—SOZNReRf, wherein each (C1-C6)alkyl, as part of a group, is ndently substituted with one or more (e.g. l, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; and h) nitro and cyano; or R1 and R2 together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are ally substituted with one or more Z1 groups; or R1 and R2 er with the atoms to which they are ed form a 5 or 6—membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7—membered heterocycle are each independently substituted with one or more (e.g. l, 2 or 3) Z7 or Z8 groups, or wherein when two Z7 groups are on same atom the two Z7 groups together with the atom to which they are attached optionally form a (C3-C7)carbocycle or 4, 5 or 3O 6-membered heterocycle; R311 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, )alkynyl, 6)alkyl-(C3-C7)cycloalkyl, -(C1-C6)alkyl-aryl, -(C1-C6)alkyl-heterocycle, -(C1-C6)alkyl- heteroaryl, -O(C1-C6)alkyl, -O(C1-C5)haloalkyl, -O(C2—C6)alkenyl, -O(C2—C6)alkynyl, -O(C3—C7)cycloalkyl, -Oaryl, -O(C1-C6)alkyl-(C3-C7)cycloalkyl, -O(C1-C(,)alkyl-aryl, -O(C1—C6)alkyl-heterocycle and C6)alkyl—heteroaryl, wherein any (C1—C6)alkyl, WO 45728 (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2—C6)alkynyl, -(C1-C6)alkyl-(C3—C7)cycloalkyl, -(C1-C6)alkyl-aryl, -(C1-C5)alkyl-heterocycle, -(C1-C6)alkyl—heteroaryl, —O(C1-C5)alkyl, -O(C1—C6)haloalkyl, —O(C2—C6)alkenyl, -O(C2—C6)alkynyl, -O(C3-C7)cycloalkyl, -Oaryl, C6)alkyl-(C3-C7)cycloalkyl, -O(C1-C6)alkyl-aryl, —O(C1-C6)alkyl-heterocycle or -O(C1-C6)alkyl-heteroaryl of R33 is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (C1-C6)alkyl, -O(C1—C6)alkyl, halo, oxo and -CN; and R33, is H; R3b is 7)carbocycle, aryl, heteroaryl, heterocycle, -(C1-C6)alkleH, -(C1-C6)alkyl- O—(Cl—C5)alkyl—Z12, -(C1-C6)alkyl-O-(Cz-C6)alkenyl-Zl2, -(C2-C6)alkyl-O-(Cz-C6)alkynyl-Z12, -(C1-C6)alkyl—S-(C1-C6)alkyl-ZIZ, —(C1-C6)alkyl-S-(Cz-C6)alkenyl-Z12, -(C2-C6)alkyl-S-(C2- CQalkynyl-le, -(C1-C6)alkyl-S(O)-(C1—C6)alkyl-ZIZ, -(C1-C(,)alkyl-S(O)—(C2-C6)alkenyl—Zu, 6)alkyl-S(O)-(C2-C6)alkynyl-le, 6)alkyl-SOZ-(C1—C6)alkyl-le, -(C1-C6)alkyl (C2-C6)alkenyl-Zn, -(C2-C6)alkyl-S02—(C2-C6)alkynyl-Z[2, -(C2-C(,)alkyl—NRaRb, -(C2-C6)alkleC(O)—NRcRd, -(C2-C5)alkyl-NRa-C(O)-0Rb, -(C2-C6)alkyl-NRa-C(O)-NRaRb, -(C1-C6)alkyl-SOZ(C1-C6)alkyl, -(C1-C6)alkyl-SOzNRcRd, -(C1-C6)alkyl-NRaSOzNRcRd, 6)alkyl-NRaS020(C3-C7)carbocycle, -(C1-C6)alkyl-NRaSOanryl, -(C1-C6)alkyl-NRa-SOZ-(C1—C6)alkyl, -(C1-C6)alkyl—NRa-Soz-(C1-C6)haloalkyl, -(C1-C5)alkyl-NRa-SOz—(Cz—C6)alkenyl, —(C1—C6)alkyl-NRa-SOz-(Cz-C5)alkynyl, -(C1-C6)alkyl—NRa-SOz-(Cg-C7)carbocycle, —(C1-C6)alkyl—NRa-SOz—(C3-C7)halocarbocycle, —(C1-C6)alkyl-NRa-SOz-aryl, -(C1-C6)alkyl-NRa-SOz—heteroaryl, -(C1-C6)alkyl—NRa—SOz-heterocycle, -O(C1-C6)alkyl-NRaRb, C6)alkleC(O)-NRcRd, - 0(C1-C6)alkyl—NRa-C(O)-0Rb, -O(C1-C6)alkyl-NRa-C(O)-NRaRb, -O(C1-C6)alkyl-NRa—SOz—(C1- C6)alkyl, -O(C1-C6)alkyl-NRa-SOz-(C1-C6)haloalkyl, C6)alkyl—NRa—SOz-(Cz-C6)alkenyl, -O(C1—C6)alkyl-NRa-SOz-(Cz-C6)alkynyl, —O(C1-C6)alkyl-NRa—SOZ-(C3-C7)carbocycle, -O(C1~C6)alkyl-NRa-SOz-(C3—C7)halocarbocycle, -O(C1—C6)alkyl-NRa-SOz-aryl, -O(C1-C6)alkyl-NRa-SOz-heteroaryl, -O(C1-C6)alkyl-NRa-S02-heterocycle, -O(C1-C6)alkyl-NRa-SOz-NRaRb, -O(C1-C6)alkyl-NRa-SOz-(C3-C7)carbocycle, -O(C1-C6)alkyl-NRa-SOz—(C3-C7)halocarbocycle, -O(C1-C5)alkyl-NRa—SOZ—aryl, -O(C1-C6)alkyl— NRaSOZNRcRd, -O(C1-C6)alkyl-NRaS020(C3—C7)carbocycle, -O(C1-C6)alkyl-NRaSOZOaryl, —Oheter0aryl, -Oheterocycle, —Sheteroaryl, -Sheterocycle, -S(O)heteroaryl, eterocycle, —SOzheteroaryl or -SOzheterocycle, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, (C3-C7)carbocycle, heteroaryl or heterocycle of R3b, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and R3“ is H, (C1—C6)alkyl or —O(C1—C6)alkyl; or R3b and R3” together with the carbon to which they are attached form a heterocycle or (C3-C7)carbocycle,which heterocycle or (C3-C7)carbocyc1e of R3b and R” together with the carbon to which they are ed is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R4a is ed from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl ofR4a is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (C1-C6)alkyl, (C2—C6)alkenyl, (C1—C6)haloalkyl, (C3-C7)cycloa1kyl, -(C1-C6)alkyl-(C3—C7)cycloalkyl, -OH, -O(C1-C6)alkyl, -SH, -S(C1-C6)alkyl, -NH2, -NH(C1-C6)alky1 and -N((C1-C6)alkyl)2, wherein (C1-C6)a]kyl is optionally tuted with hydroxy, -O(C1- yl, cyano or 0x0; R41) is selected from; a) (C1-C6)alkyl, )alkeny1 and (C2-C6)a1kynyl, wherein (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; b) (C3-C14)carbocycle, wherein (C3—C14)carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups, or wherein two Z1 groups together with the atom or atoms to which they are attached optionally form a )carbocycle or heterocycle; c) Spiro-heterocycle or bridged-heterocycle, wherein heterocycle or bridged-heterocycle is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups, or wherein two Z1 groups together with the atom or atoms to which they are attached optionally form a (C3-C7)carbocycle or heterocycle; and d) aryl, heteroaryl, spiro- heterocycle, fused- heterocycle, or bridged-heterocycle, wherein aryl, heteroaryl, spiro- heterocycle, fused- heterocycle and bridged-heterocycle are each independently substituted with one or more Z7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; or R4 and R3 together with the atoms to which they are ed form a macroheterocycle or a arbocycle, wherein any macroheterocycle or macrocarbocycle of R4 and R3 together with the atoms to which they are attached may be optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and R” is H or (C1—C6)alkyl, -O(C1-C6)alkyl; R5a is selected from: a) halo; b) R“, -C(=O)—R”, -C(=O)-O-R“, —o-R“, -S—R“, R“, -SOz-R“, -(cl— C6)alkyl-R“, -(C1-C6)alkyl-C(=O)-R”, -(C1-C5)alky1-C(=O)-O-R11, 6)alky1-O-R“, -(c1— C5)alkyl-S-R“, 6)alky1—S(O)-R“ and -(C1-C6)alkyl-SOZ-R“, wherein each R” is independently selected from H, (C1—C5)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C 1i-C6)haloalky1, (C3—C7)carbocycle, aryl, heterocycle and heteroaryl, wherein aryl, cycle and heteroaryl are each ally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; and c) -N(R9)R1°, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R1°, -SOz-N(R9)R1°, —(C1-C6)alkyl- N(R9)R1°, -(C1-C(,)a1ky1-C(=O)-N(R9)R10, -(Cx-C6)a1kyl-O-C(=O)-N(R9)R1°, and -(C1-C6)alkyl- R9)R1°, wherein each R9 is ndently selected from H, (C1-C6)alkyl and (C3- C7)cycloalkyl, and each R10 is independently selected from R“, 6)alkyl-R“, -SOz-R“, - C(=O)—R“, -C(=O)OR11 and -C(=O)N(R9)R“, wherein each R11 is independently selected from H, )alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; R5" is selected from: a) -(C1-C6)alkyl-O-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C5)alkyl-S-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyIS(O)—(C1-C6)alkyl-(C3-C6)carbocycle, -(C1-C6)alkyISOz(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl—(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, - (C3-C7)halocarbocycle, —NRaSOzNRCRd, —NRaSOZO(C3- C7)carbocycle, -NRaSOanryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2—C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2—C6)alkynyl-heteroaryl, -(C2—C6)a1kyny1-heterocycle, -(C3- C7)ca.rbocycle-Z1 or -(C1-C6)haloalkyl-Z3, wherein any (C1-C6)alkyl, (C1—C5)haloalkyl, (C3-C7)carbocycle, (C2-C5)alkenyl, (C2-C6)alkynyl, aryl or heteroaryl, either alone or as part of a group is optionally tuted with one or more(e.g. 1, 2, 3, 4 or 5) Z1 groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged—bicyclic ycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged—bicyclic carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups, or wherein two Z1 groups together with the atom or atoms to which they are ed optionally form a (C3- C7)carbocycle or cycle wherein the (C3-C7)carbocycle or heterocycle is ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; c) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z1groups; d) -X(C1-C6)alkyl,-X(C1-C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein —X(C1-C6)alkyl and -X(C1—C6)haloalkyl are each independently tuted with one or more Z3 groups and optionally substituted with one or more Zlgroups, and wherein -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and —X(C3-C7)carbocycle are each independently substituted with one or more (6.g. 1, 2, 3, 4 or 5) Z4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein aryl, heteroaryl and heterocycle, either alone or as part of a group, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or oups; f) )haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2—C6)alkynyl, wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; g) -NReRf, -C(0)NReRr, -0C(0)NReRf, -302NReRf, -(C1-C6)a1kyl-NReRf, -(C1-C6)alkle(O)-NRch, 6)alkyl-O-C(O)-NReRf and -(C1-C6)alkyl-SOZNReRf, wherein each (C1-C6)alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally tuted with one or more (e.g. 1, 2, 3, 4 or 5)Zlgroups; h) nitro and cyano; i) aryl, heteroaryl and cycle, wherein aryl, heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally tuted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; j) oxo; R6a is selected from: a) R“, —C(=O)-R”, -C(=O)—O-R“, -o-R“, -s-R“, -S(O)—R”, -SOz-R”, -(C1- C6)alkyl-R“, —(C1—C6)alkyl-C(=O)—R“, -(C1-C6)a1kyl-C(=O)-O-Rl1, -(C1-C5)alky1—O-R“, -(C1- C6)alkyl-S-R“, -(C1—C6)alkyl—S(O)-R” and -(C1—C6)alkyl-SOZ-R“, wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, 7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; and b) -C(=O)-N(R9)R1°, (R9)R‘°, -(C1-C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=O)- N(R9)R‘°, -(C1-C6)alkyl—O—C(=O)—N(R9)R10 and -(C1-C6)alkyl-Soz-N(R9)R1°, wherein each R9 is independently selected from H, (C1-C6)alkyl and )cycloalkyl, and each R10 is independently selected from R“, -(C1-C5)a1kyl-R“, “, -C(=O)-R“, -C(=O)OR“ and - C(=O)N(R9)Rl 1, wherein each R11 is independently selected from H, )alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, -(C1—C6)alkylaryl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z“ groups; R6b is selected from: 2012/034593 a) -(C1-C6)alkyl-SOz-(C1—C6)alkyl-Z13, —C(O)—(C1-C6)alkyl-Zl3, —O-(C1—C6)a1kyl—Zl3, -S-(C1-C6)alkyl-Zl3, -S(O)-(C1-C6)alkyl-Zl3, —SOz-(C1-C6)alkyl-Z13, -(C1—C6)alky1-Z14, —(c1— C6)alkyl-C(O)-(C1-C6)a1kyl-Z13, -(C1-C6)alky1-C(O)-O(C1-C6)a1kyl-Zl3, -(C1-C5)alkyl-O-(C1- C6)alkyl-Z13, -(C1-C6)alkyl-S-(C1-C6)alkyl-Zl3, —(C1-C6)alkyl-O—(C1-C6)alkyl—(C3-C7)carbocycle, 6)alkyl—S-(C1-C6)alkyl—(C3-C7)carbocycle, —(C1-C6)alkyl-S(O)-(C1- C6)alkyl-(C3-C7)carbocyc1e, -(C1-C6)alkyl-SOZ-(C1-C6)alkyl—(C3-C7)carbocycle, -(C2- C6)alkenyl-(C1-C6)haloalkyl, -(C2-C6)alkynyl-(C1-C6)haloalkyl, —(C3-C7)halocarbocycle, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C6)alkeny1—heteroaryl, -(C2-C6)alkenyl—heterocycle, —(C2—C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkyny1-aryl, 6)alkynyl—heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Zl, —(C1- C5)haloalkyl-Z3, -NRaSOZNRcRd, —NRaSOzO(C3-C7)carbocycle and —NRaSOZOary1, wherein any (C1-C6)a1kyl, (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)a1kenyl, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 ; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups, or wherein two Z1 groups together with the atom or atoms to which they are attached optionally form a (C3-C7)carbocycle or cycle wherein the (C3-C7)carbocyc1e or heterocycle is ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; c) (C1-C6)alkyl, wherein (C1-C5)alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; (1) -X(C1-C6)alkyl, -X(C1—C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and C7)carbocycle, wherein -X(C1-C6)alky and -X(C1-C6)haloalkyl, are each independently substituted with one or more (6.g. 1, 2, 3, 4 or 5) Z3 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups, and wherein —X(C2—C6)alkenyl, -X(C2—C6)alkynyl and -X(C3-C7)carbocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z4 groups and ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 ; 6) aryl, heteroaryl, cycle, -Xaryl, -Xheteroary1 and -Xheterocycle, wherein aryl, heteroaryl and heterocycle, either alone or as part of a group, are each independently substituted with one or more (6.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; i) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and )alkynyl are each independently PCT/U82012/034593 substituted with one or more (e.g. l, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 Or 5) Z1 groups; and g) 'C(O)NReRf, -302NRch, '(CI'C6)alkyl'NReRfa 6)alkle(O)-NReRf, -(C1—C6)alkyl—O-C(O)-NReRf and -(C1-C6)alkyl-SOZNReRf, wherein any (C1-C6)alkyl, as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; each X is independently selected from O, -C(O)—, -, -S-, -S(O)-, -SOz-, -(C1- C6)a1kle-, -(C1-C6)alkle(O)-, -(C1—C6)alkle(O)O-, -(C1-C6)alkylS-, -(C1-C6)alkylS(O)- and -(C1-C6)alkylSOZ-; each Z1 is independently selected from halo, -N02, -OH, =NORa, -SH, -CN, (C1- C6)alkyl, )alkenyl, (C2-C6)alkynyl, (C1—C6)haloalkyl, (C3-C7)carbocycle, (C3- C7)halocarbocycle, aryl, heteroaryl, heterocycle, -O(C1-C6)alkyl, -O(C2-C6)alkenyl, -O(C2- C5)alkynyl, -O(C1-C6)haloalkyl, -O(C3-C7)carbocycle, C7)halocarbocycle, —Oaryl, - Oheteroaryl, ~Oheterocycle, -S(C1-C6)alkyl, -S(C2-C6)alkenyl, C6)alkynyl, -S(C1- C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, —Saryl, -Sheteroaryl, - Sheterocycle, C1-C6)alkyl, -S(O)(C2-C6)alkenyl, C2-C6)alkynyl, -S(O)(C1- C6)haloalkyl, -S(O) (C3-C7)carbocycle, —S(O)(C3-C7)halocarbocycle, -SOZ(C1-C6)alkyl, — S(O)aryl, -S(O)carbocycle, -S(O)heteroaryl, -S(O)heterocycle, -SOz(C2-C6)alkenyl, —SOz(C2- C6)alkynyl, 1-C6)haloalkyl, -SOZ(C3-C7)carbocycle, -SOz(C3-C7)halocarbocycle, — SOzaryl, -SOzheteroaryl, -SOzheterocycle, -SOzNRcRd, -NRcRd, —NRaC(O)Ra, -NRaC(O)ORb, O)NRcRd -NRaSOZRb, -NRaSOzNRcRd, -NR38020(C3-C7)carbocycle, -NR38020aryl, —OS(O)2Ra, -C(O)Ra, -C(O)ORb, -C(O)NRcRd, and -OC(O)NRcRd, wherein any (C1-C6)alkyl, (C2-C5)alkenyl, )alkynyl, -(C3-C7)halocarbocycle, (C3-C7)carbocycle, (C3- C7)halocarbocycle, aryl, heteroaryl or heterocycle of Z1, either alone or as part of a group, is ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, —NRaC(O)2Rb, -heteroaryl, -heterocycle, —Oheteroaryl, -Oheterocycle, —NHheteroaryl, - NHheterocycle or -S(O)2NRcRd; each Z2 is independently selected from —N02, -CN, Spiro-heterocycle, bridge-heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NRaSOZ(C3-C7)carbocycle, Zaryl, —NRaS02heteroaryl, -NRaSOZNRcRd, -NRa8020(C3—C7)carbocycle and -NRaSOZOaryl; each Z3 is independently selected from -N02, -CN, -OH, 0x0, =NORa, thioxo, ary1,- heterocycle, heteroaryl, (C3-C7)halocarbocycle, —O(C1-C6)alkyl, -O(C3-C7)carbocycle, -O(C3- C7)halocarbocycle, -Oaryl, rocycle, -Oheteroaryl, -S(C1-C6)alkyl, -S(C3-C7)carbocycle, - 7)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(C1-C6)alkyl, -S(O)(C3-C7)carb0cycle, -S(O) (C3—C7)halocarbocycle, ryl, -S(O)heterocycle, - S(O)heteroaryl, -SOZ(C1—C5)alkyl, -SOz(C3—C7)carbocycle, -SOz(C3-C7)halocarbocycle, SOzaryl, WO 45728 -SOzheterocycle, ~SOzheteroaryl, ~NRaRb, —NRaC(O)Rb, -C(O)NRCRd, -S02NRcRd, -NRaSOzNRcRd, -NRaSOzO(C3-C7)carbocycle and -NRaSOanryl; each Z4 is independently selected from halogen, -(C1-C6)alkyl, (C3-C7)carbocycle, —(C1— C6)haloalkyl, -N02, —CN, -OH, oxo, =NORa, thioxo, -ary1, —heterocycle, -heteroaryl, —(C3- C7)halocarbocycle, -O(C1-C6)alkyl, -O(C3-C7)carbocycle, -O(C3-C7)halocarbocycle, -Oaryl, - Oheterocycle, -Oheteroaryl, -S(C1-C5)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, — Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(C1-C6)alkyl, C3-C7)carbocycle, -S(O)(C3— C7)halocarbocycle, -S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SOz(C1-C6)alkyl, —SOZ(C3— C7)carbocycle, 3-C7)halocarbocycle, SOzaryl, -SOzheterocycle, -SOzheteroaryl, —NRaRb, -NRaC(O)Ra, -C(O)NRcRd, -SOzNRcRd, -NRaSOzNRcRd, -NRaSOzO(C3-C7)carbocycle and -NRaSOanryl; each 25 is ndently selected from -N02, -CN, -NRaSOgNRcRd, -NRaSOzO(C3- C7)carbocycle, -NRaSOanryl, -NRaSOz(C1—C6)alkyl, -NRaSOz(C2-C6)alkenyl, -NRaSOz(C2— C6)alkynyl, -NRaS02(C3-C7)carbocycle, -NRaSOz(C3-C7)halocarbocycle, -NRaSOzaryl, -NRaSOzheteraryl, zheteroaryl, -NRaSOzheterocycle, -NRaC(O)alkyl, -NRaC(O)alkenyl, -NRaC(O)alkynyl, -NRaC(O) )carbocycle, -NRaC(O)(C3-C7)halocarbocycle, -NRaC(O)aryl, -NRaC(O)heteroaryl, -NRaC(O)heterocycle, -NRaC(O)NRcRd and -NRaC(O)ORb; each Z6 is independently selected from -N02, -CN, —NRaRa, NRaC(O)Rb,-C(O)NRcRd, (C3-C7)halocarbocycle, aryl, aryl, heterocycle, —Oaryl, -Oheteroaryl, -Oheterocycle, -O(C3-C7)halocarbocycle, -O(C1-C6)alkyl, -O(C3-C7)carbocycle, —O(C1-C6)haloalkyl, -Saryl, roaryl, —Sheterocycle, -S(C3-C7)halocarbocycle, —S(C1-C6)alkyl, —S(C3—C7)carbocycle, -S(C1—C6)haloalkyl, -S(O)aryl, —S(O)heteroaryl, —S(O)heterocycle, —S(O)(C3—C7)halocarbocycle, C1-C6)alkyl, -S(O)(C3-C7)carbocycle, -S(O)(C1-C6)haloalkyl, -SOzaryl, -SOzheteroaryl, -SOzheterocycle, -SOZ(C1—C6)alkyl, —SOZ(C1-C(,)haloalkyl, —SOz(C3-C7)carbocycle, -SOZ(C3- C7)halocarbocycle, —SOzNRcRd, —NRaS02(C3-C7)halocarbocycle, zaryl, -NRaSOzheteraryl, -NRaSOzheteroaryl, -NRaSOzNRCRd, -NRaSOzO(C3-C7)carbocycle and -NRaSOgOaryl, wherein any aryl, of Z6, either alone or as part of a group, is otionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) n, -OH, -O(C1-C6)alkyl, -CN or -(C1- 3O each Z7 is independently selected from -N02, =NORa, -CN, —(C1-C6)alkyl-le, -(C2— C6)alkenyl-le, -(C2—C6)alkenleH, -(C2-C6)alkynyl—Zl2, -(C2-C6)a1kynyl-OH, —(c1— C6)haloalkyl-le, -(C1—C6)haloalkleH, -(C3-C7)carbocycle-le, -(C3—C7)carbocycleOH, -(C3— C7)halocarbocycle, —(C1-C6)alkleRcRd, -(C1-C6)alkleRaC(O)Ra, 5)alkleRaSOzRa, aryl, heteroaryl, cycle, -O(C1-C6)alkyl-le, —O(C2-C6)alkenyl, -O(C2-C6)alkynyl, -O(C1- C6)haloalkyl, -O(C3—C7)carbocycle, -O(C3—C7)halocarbocycle, —Oaryl, -O(C1-C6)alkleR¢Rd, - 0(C1-C6)alkleRaC(O)Ra, -O(C1-C6)alkleRaSOZRa, -Oheteroaryl, -Oheterocycle, -S(C1- c6)a1ky1—z”, -S(C2—C6)alkenyl, -S(C2-C6)alkynyl, -S(C1-C6)haloalkyl, -S(C3-C7)carbocycle, C7)halocarbocycle, -S(C1-C6)alkleRcRd, -S(C1—C6)alkleRaC(O)Ra, —S(C1— C6)alkleR3802Ra, —Saryl, -Sheteroaryl, -Sheterocycle, -S(O)(C1-C6)alkyl, -S(O)(C2- C6)alkenyl, -S(O)(C2-C6)alkynyl, -S(O)(C1-C5)haloalkyl, -S(O)(C3-C7)carbocyle, -S(O)(C3- C7)halocarbocycle, -SOz(C1—C5)alkyl, -S(O)(C1—C6)alkleRcRd, -S(O)(C1-C6)alkleRaC(O)Ra, -S(O)(C1-C6)alkleRaSOzRa, ryl, -S(O)heteroaryl, eterocycle, -SO;(C1-C6)alkyl, 2—C6)alkenyl, -S02(C2—C6)alkynyl, 1-C6)haloalkyl, -SOz(C3-C7)carbocycle, -SOZ(C3-C7)halocarbocycle, —SOzaryl, -SOzheteroaryl, -SOzheterocycle, —SOZ(C1— C6)alkleRcRd, -SOZ(C1-C6)alkleRaC(O)Ra, 1-C6)alkleRaSO;zRa, -SOZNRcRd, -NRaC(O)ORb, -NRaC(O)NRcRd, -NRaSOZRb, -NRaSOzNRcRd, -NRaS020(C3—C7)carbocycle, — NRaSOzoaryl, -OS(O)2Ra, -C(O)NRcRd, and NRcRd, n any (C1—C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, (C3-C7)halocarbocycle, aryl, heteroaryl or heterocycle of Z7, either alone or as part of a group, is optionally substituted with one or more (e. g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, O)2Rb, aryl, heterocycle, —Oheteroaryl, -Oheterocycle, -NHheteroary1, -NHheterocycle or —S(O)2NRcRd_ each 28 is independently selected from -N02 or —CN; each Z10 is independently selected from i) halo, oxo, thioxo, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -OH, —O(C1- C6)alkyl, -O(C1-C6)haloalkyl, -SH, -S(C1-C6)alkyl, -SO(C1- , C6)alkyl, -SOZ(C1-C6)alkyl, —NH2, -NH(C1-C6)alkyl and -N((C1—C6)alkyl)2; ii) (C1-C6)alkyl optionally tuted with -OH, -O—(C1—C6)haloalkyl, or —O- (C1-C6)alkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C1-C6)alkyl or COOH; each 2“ is independently selected from z“), -C(=O)—NH2, -C(=O)—NH(C1-C4)alkyl, -C(=O)-N((C1—C4)alkyl)2, -C(=O)-aryl, —C(=O)-heterocycle and -C(=O)-heteroaryl; each 212 is independently selected from -N02, =NORa, thioxo, aryl, heterocycle, heteroaryl, (C3-C7)halocarbocycle, (C3-C7)carbocycle, -O(C3-C7)carbocycle, -O(C3- ocarbocyle, -Oaryl, -Oheterocycle, -Oheteroaryl, —S(C1-C6)alkyl, -S(C3-C7)carbocyle, -S(C3-C7)halocarbocyle, -Saryl, —Sheterocycle, —Sheteroaryl, —S(O)(C1—C6)alkyl, -S(O)(C3-C7)carbocyle, -S(O)(C3-C7)halocarbocycle, -S(O)aryl, -S(O)heterocycle, —S(O)heteroaryl, 1-C6)alkyl, —SOz(C3-C7)carbocycle, -SOz(C3-C7)halocarbocycle, terocycle, -SOzheteroaryl, -NRaRa, -NRaC(O)Rb, -C(O)NRcRd, -SOzNRcRd, - NRaSOZNRcRd, -NRaS020(C3-C7)carbocyle and -NRaSOanryl; each Z13 is independently selected from -N02, -OH, =NORa, —SH, —CN, (C3- C7)halocarbocycle, -O(C1-C6)alkyl, C5)alkenyl, -O(C2-C6)alkynyl, -O(C1-C6)haloalkyl, - 0(C3-C7)carbocycle, -O(C3-C7)halocarbocycle, —Oaryl, -Oheteroaryl, -Oheterocycle, -S(C1— C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C1-C6)haloalkyl, -S(C3—C7)carbocycle, -S(C3— C7)halocarbocycle, —Saryl, -Sheteroaryl, rocycle, -S(O)(C1-C5)alkyl, -S(O)(C2-C6)alkenyl, -S(O)(C2-C6)alkynyl, -S(O)(C1-C6)haloalkyl, -S(O)(C3—C7)carbocycle, -S(O)(C3- C7)halocarbocycle, —S(O)aryl, -S(O)heteroaryl, -S(O)heterocycle, 1-C6)alkyl, 2- C6)alkenyl, -SOZ(C2-C6)alkynyl, 1-C6)haloalkyl, -SOz(C3-C7)carbocycle, —SOz(C3- C7)halocarbocycle, —S02aryl, -SOzheteroaryl, -SOzheterocycle, cRd, -NRcRd, —NRaC(O)Ra, -NRaC(O)ORb, —NRaC(O)NRcRd -NRaSOsz, -NRaSOzNRcRd, -NRaSOzO(C3- C7)carbocycle, -NRaSOanryl, -OS(O)2Ra, -C(O)Ra, -C(O)0Rb, -C(O)NRcRd, and - OC(O)NRcRd, n any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, aryl, heteroaryl or heterocycle of Z”, either alone or as part of a group, is optionally substituted with one or more (6.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NRaC(O)2Rb, -heteroaryl, -heterocycle, roaryl, - Oheterocycle, —NHheteroaryl, -NHheterocycle, or -S(O)2NRcRd; each Z14 is independently selected from -N02, =NORa, -CN, -(C3-C7)halocarbocycle, — O(C3-C7)halocarbocycle, -S(C3-C7)halocarbocycle, -S(O)(C3-C7)halocarbocycle, -SOZ(C3- C7)halocarbocycle, -NRaSOZNRcRd, -NRaS020(C3-C7)carbocycle, -NRaSOanryl, -OS(O)2Ra, wherein any 7)halocarbocycle of Z”, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NR3C(O)2Rb, - heteroaryl, -heterocycle, roaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or 'S(O)2NRcRd; each Z15 is independently selected from aryl, heteroaryl, heterocycle, -Oaryl, —Oheteroaryl, —Oheterocycle, —O(C1—C6)alkyl—aryl, -O(C1-C6)a1kyl-heteroaryl, -O(C1- C6)alkyl-heterocycle, n aryl, heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z16 groups and ally subsituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 , and wherein any -Oary1, -Oheteroaryl, -Oheterocycle, -O(C1-C6)alkyl-aryl, -O(C1-C6)alkyl-heteroaryl or -O(C1-C6)alkyl-heter0cycle is optionally subsituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; each 2‘6 is independently selected from -N02, -OH, =NORa, -SH, -CN, )alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)carbocycle, (C3-C7)halocarbocycle, aryl, heteroaryl, heterocycle, -O(C1-C6)alkyl, -O(C2—C6)alkenyl, -O(C2-C6)alkynyl, -O(C1-C6)haloalkyl, —O(C3- 2012/034593 C7)carbocycle, -O(C3-C7)halocarbocycle, —Oary1, -Oheteroaryl, —Oheterocycle, —S(C1-C6)alkyl, —S(C2-C6)alkenyl, -S(C2—C6)alkynyl, -S(C1-C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3— C7)halocarbocycle, —Saryl, —Sheteroaryl, -Sheterocycle, -S(O)(C1-C6)alkyl, C2-C6)alkenyl, -S(O)(C2-C6)alkynyl, -S(O)(C1—C6)haloalkyl, -S(O) (C3—C7)carbocycle, —S(O)(C3- C7)halocarbocycle, -SOZ(C1-C6)alkyl, —S(O)aryl, -S(O)carbocycle, -S(O)heteroary1, —S(O)heterocycle, 2-C6)alkenyl, -SOZ(C2-C6)alkynyl, -SOz(C1-C6)haloalkyl, -SOz(C3- C7)carbocycle, -SOz(C3-C7)halocarbocycle, —SOzaryl, -SOzheteroaryl, —SOzheterocycle, -SOgNRcRd, -NRcRd, -NRaC(O)Ra, O)ORb, -NRaC(O)NRcRd —NRaSOZRb, -NRaSOZNRcRd, -NRaSOZO(C3—C7)carbocycle, 20aryl, -OS(O)2Ra, -C(O)Ra, -C(O)ORb, -C(O)NRcRd, and -OC(O)NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, aryl, heteroaryl or heterocycle of 216, either alone or as part of a group, is optionally tuted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, (C1-C6)a1kyl, -OH, -ORb, -CN, -NRaC(O)2Rb, heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -S(O)2NRcRd; each Ra is independently H, )alkyl, )alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, aryl(C1-C6)a1kyl-, heteroaryl or heteroaryl(C1-C6)alkyl-, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, or heteroaryl of Ra, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, OH or cyano; each Rb is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkyny1, (C3-C7)carbocycle, heterocycle, aryl, ary1(C1-C6)alkyl—, heteroaryl or heteroaryl(C1—C6)alkyl-, wherein any (C1-C5)alkyl, (C2-C6)alkenyl, (C2—C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, or heteroaryl of Rh, either alone or as part of a group, is optionally tuted with one or more (e.g. 1, 2, 3, 4 or 5) n, OH and cyano; Rc and Rd are each ndently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, aryl, aryl(C1—C6)alky1-, heterocycle, heteroaryl or heteroaryl(C1-C6)alkyl-, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3—C7)carbocycle, cycle, aryl, or aryl of R0 or Rd, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, OH or cyano; or RC and Rd together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle of Rc and Rd together with the nitrogen to which they are attached is ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, OH or cyano; each R6 is independently selected from -ORa, (C1—C6)alkyl or (C3-C7)carbocycle, wherein (C1—C6)alkyl and (C3-C7)carbocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; (C2-C6)haloalkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein any (C2—C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and aryl, heterocycle and heteroaryl wherein aryl, heterocycle and aryl are each ndently substituted with one or more (6.g. 1, 2, 3, 4 or 5) Z5 groups; each Rf is independently selected from -Rg, -OR& -(C1-C6)alkyl-Z6, -SOzRg, -C(O)Rg, C(O)ORg and &Rg; and each Rg is ndently selected from (C1-C6)alkyl, (C3-C7)carbocycle (C1-C6)haloa1kyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, wherein any (C1-C6)alkyl, (C3—C7)carbocycle -(C1—C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle or heteroaryl of Rg is optionally tuted with one or more (6.g. 1, 2, 3, 4 or 5) Z1 swim; or a salt thereof.
The invention also provides a pharmaceutical composition comprising a compound of a I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also es a method for ng (e.g. preventing, mediating or inhibiting) the proliferation of the HIV Virus, treating AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g. a human), comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the mammal.
The invention also provides a method of treating an HIV infection in a mammal (e.g. a human) comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the mammal.
The invention also provides a method for treating an HIV infection in a mammal (e.g. a human) comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional eutic agents selected from the group consisting HIV protease inhibiting nds, HIV non- side inhibitors of reverse transcriptase, HIV nucleoside inhibitors of e transcriptase, HIV nucleotide inhibitors of reverse riptase, HIV integrase inhibitors, gp4l inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization tors, and other drug for treating HIV, and combinations thereof.
The invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g. for use in treating (e.g. preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human)).
The invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g. for use in treating (e.g. preventing, mediating or inhibiting) an HIV infection in a mammal (e.g. a human)).
The invention also provides a compound of formula I, or a pharrnaceutically acceptable salt thereof for use in the manufacture of a medicament for treating (e.g. ting, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human).
The invention also provides a nd of a I, or a ceutically able salt thereof, for use in the prophylactic or therapeutic treatment (e.g. prevention, mediation or inhibiting) of the proliferation of the HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset ofAIDS or ARC symptoms.
The invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV infection in a mammal (e.g. a human).
The invention also provides a compound of a I or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection in a mammal (e.g. a .
The invention also provides processes and intermediates disclosed herein that are usefiil for preparing compounds of a I or salts thereof.
Detailed Description of the Invention Definitions Unless stated otherwise, the following terms and s as used herein are intended to have the following gs.
When trade names are used , applicants intend to independently include the ame product and the active pharmaceutical ingredient(s) of the tradename t.
“Alkyl” is hydrocarbon containing normal, secondary or tertiary atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e, (Cl-Cgo)alkyl), l to 10 carbon atoms (i.e., (C1- C10)alkyl), 1 to 8 carbon atoms (i. e., (C1-C3)alkyl)or 1 to 6 carbon atoms (i.e., (C1-C6 alkyl). 3O Examples of suitable alkyl groups include, but are not d to, methyl (Me, —CH3), ethyl (Et, —CH2CH3), 1-propyl (n-Pr, r_1—propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1- butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1—propyl (i-Bu, i-butyl, —CH2CH(CH3)2), 2-buty1 (s—Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl—2-propyl (t-Bu, t-butyl, —C(CH3)3), 1- pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methylbutyl (—C(CH3)2CH2CH3), 3-methylbutyl (-CH(CH3)CH(CH3)2), 3-methylbutyl (~CH2CH2CH(CH3)2), 2—methylbutyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2—hexy1 (-CH(CH3)CH2CH2CH2CH3), 3-hexy1 (-CH(CH2CH3)(CH2CH2CH3)), yl-2—pentyl 3)2CH2CH2CH3), 3-methy1—2-pentyl H3)CH(CH3)CH2CH3), 4—methyl—2-pentyl (-CH(CH3)CH2CH(CH3)2), 3—methy1—3-pentyl (-C(CH3)(CH2CH3)2), 2-methylpentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethylbutyl (—C(CH3)2CH(CH3)2), 3,3—dimethylbutyl (— CH(CH3)C(CH3)3, and octyl (—(CH2)7CH3), “Alkyl” also refers to a saturated, branched or straight chain hydrocarbon radical having two lent radical centers derived by the removal oftwo en atoms from the same or two different carbon atoms of a parent alkane. For example, an alkyl group can have 1 to 10 carbon atoms (i. e. or 1 to 6 carbon atoms , (Cl-Clo)alkyl), (1’. e. , (C1- C6)alkyl) or 1-3 carbon atoms (i. e. , )alkyl). Typical alkyl radicals include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (~CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propy1 (-CH2CH(CH3)—), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl H2CH2CH2—), and the like.
The term “halo” or en” as used herein refers to fluoro, chloro, bromo and iodo.
The term “haloalkyl” as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent. For example, a (C1-C6)haloalkyl is a (C1-C6)alky1 wherein one or more of the hydrogen atoms have been replaced by a halo substituent. Such a range includes one halo substituent on the alkyl group t to complete halogenation of the alkyl group.
The term “aryl” as used herein refers to a single ic ring or a bicyclic or multicyclic ring. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl es a phenyl radical or an ortho-fused bicyclic or multicyclic radical having about 9 to 14 atoms in which at least one ring is aromatic (e.g. an aryl fused to one or more aryl or carbocycle). Such bicyclic or multicyclic rings may be optionally substituted with one or more (e.g. 1, 2 or 3) 0x0 groups on any carbocycle portion of the bicyclic or multicyclic ring. It is to be understood that the point of attachment of a ic or multicyclic radical, as defined above, can be at any position of the ring including an aryl or a carbocycle portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
“Arylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl l as described herein (i.e., an aryl-alkyl- moiety). The alkyl group of the “arylalkyl” is typically 1 to 6 carbon atoms (i.e. aryl(C1-C6)alkyl). Arylalkyl groups include, but are not limited to, benzyl, ylethan—1-yl, l-phenylpropan-l-yl, naphthylmethyl, 2-naphthylethanyl and the like.
The term “heteroaryl” as used herein refers to a single aromatic ring or a le condensed ring. The term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 atoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
The term also includes multiple condensed ring systems (e.g. ring s comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, can be fused with one or more heteroaryls (e.g. yridinyl), carbocycles (e.g. 5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a le condensed ring. Such multiple condensed rings may be optionally substituted with one or more (6.g. 1, 2 or 3) oxo groups on the carbocycle portions of the condensed ring. It is to be understood that the point of attachment of a heteroaryl multiple condensed ring, as defined above, can be at any position of the ring including a heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, dinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, olyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.
The term “heterocyclyl” or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring or a multiple condensed ring. The term includes single saturated or partially unsaturated ring (e.g. 3, 4, 5, 6 or 7-membered ring) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be tuted with one or more (e.g. 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their ed forms. Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl. The term also includes multiple condensed ring systems (e.g. ring s comprising 2 or 3 rings) wherein a heterocycle group (as defined above) can be connected to two adjacent atoms (fused cycle) with one or more cycles (e.g. decahydronapthyridinyl ), heteroaryls (e.g. 3O l,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g. droquinolyl) or aryls. It is to be understood that the point of attachment of a heterocycle multiple condensed ring, as defined above, can be at any position of the ring including a cyle, heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, l,2,3,4— ydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1,3-benzodioxolyl and nzodioxanyl.
The term “bridged-heterocycle” as used herein refers to a 4, 5, 6, 7 or 8-membered heterocycle as defined herein connected at two non-adjacent atoms of the 4, 5, 6, 7 or 8- membered heterocycle with one or more (e.g. 1 or 2) 3, 4, 5 or 6-membered heterocycles or (C3- C7)carbocycles as defined herein. Such bridged-heterocycles include bicyclic and tricyclic ring systems (e.g. icyclo[2.2.1]heptane and 4-azatricyclo[4.3.1.13’8] undecane).
The term “Spiro-heterocycle” as used herein refers to a 3, 4, 5, 6, 7 or 8-membered heterocycle as defined herein connected to one or more (6.g. 1 or 2) single atoms of the 3, 4, 5, 6, 7 or 8-membered heterocycle with one or more (e.g. 1 or 2) 3, 4, 5, 6-membered heterocycles or a (C3-C7)carbocycles as defined . Such Spiro-heterocycles include bicyclic and tricyclic ring systems (e.g. oxaspiro[4.5]decenyl).
The term “macroheterocycle” as used herein refers to a saturated or partially unsaturated 8, 9, 10, 11 or 12-membered ring comprising about 5 to 11 carbon atoms and about 1 to 3 atoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring which may be ally fiised at two adjacent atoms of the macroheterocycle to one or more (e.g. l, 2 or 3) aryls, carbocycles, heteroaryls or heterocycles. The macroheterocycle may be substituted with one or more (e.g. l, 2 or 3) 0x0 groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
“Heteroarylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl radical as described herein (i.e., a heteroaryl-alkyl- moiety). The alkyl group of the “heteroarylalkyl” is typically 1 to 6 carbon atoms (i. e. aryl(C1-C6)alkyl). Heteroarylalkyl groups include, but are not d to heteroaryl-CH2-, heteroaryl-CH(CH3)-, heteroaryl-CHZCH2—, 2-(heteroaryl)ethanyl, and the like, wherein the “heteroaryl” n includes any of the heteroaryl groups described above. One skilled in the art will also understand that the heteroaryl group can be attached to the alkyl n of the heteroarylalkyl by means of a carbon-carbon bond or a carbon- heteroatom bond, with the proviso that the resulting group is chemically stable. Examples of heteroarylalkyls e by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heteroaryls such as thiazolylmethyl, 2-thiazolylethan-1—yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6—membered sulfur, oxygen, and/or nitrogen containing heteroaryls such pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc. ocyclylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl radical as described herein (i. e., a heterocyclyl—alkyl- moiety). The alkyl group of the “heterocyclylalkyl” is typically 1 to 6 carbon atoms (i. e. heterocyclyl(C1—C6)alkyl). Typical heterocyclylalkyl groups include, but are not limited to heterocyclyl-CH2-, heterocyclyl-CH(CH3)-, heterocyclyl- CH2CH2-, 2-(heterocyclyl)ethan-1—yl, and the like, wherein the “heterocyclyl” n includes any of the heterocyclyl groups described above. One skilled in the art will also tand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically . Examples of heterocyclylalkyls include by way of example and not limitation -membered sulfur, oxygen, and/or nitrogen containing heterocycles such tetrahydrofilranylmethyl and pyrroldinylmethyl, etc., and 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, etc.
The term “carbocycle” or cyclyl” refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocycle or a mutlicyclic ring system. In one embodiment the carbocycle is a monocycle comprising 3-6 ring carbons (i.e. (C3-C6)carbocycle). Carbocycle includes multicyclic carbocyles having 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle ed that the t single ring of a multicyclic carbocycle is 7 carbon atoms.
The term “Spiro-bicyclic carbocycle” refers to a ycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to a single carbon atom (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc). The term “fused—bicyclic carbocycle” refers to a carbocycle bicyclic ring system n the rings of the bicyclic ring system are connected to two adjacent carbon atoms such as as a o [4,5], [5,5], [5,6] or [6,6] , or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane). The term “bridged-bicyclic carbocycle” refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to two non—adjacent carbon (e.g. norbornane, bicyclo[2.2.2]octane, etc). The “carbocycle” or “carbocyclyl” may be optionally substituted with one or more (e.g. 1, 2 or 3) 0x0 groups. Non-limiting es of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, l—cyclopent-l-enyl, 1-cyclopent—2- enyl, 1—cyclopentenyl, cyclohexyl, 1-cyclohex-l -enyl, 1-cyclohexenyl and 1—cyclohex enyl.
The term “halocarbocycle” as used herein refers to a carbocycle as defined herein, wherein one or more en atoms are each replaced by a halo substituent. For example, (C3— C7)halocarbocycle is a (C3-C7)carbocycle n one or more of the hydrogen atoms have been replaced by a halo substituent. Such a range includes one halo substituent on the carbocycle group to complete halogentation of the carbocycle group.
The term carbocycle” as used herein refers to a saturated or partially unsaturated 8, 9, 10, 11 or bered ring comprising 8 to 12 carbon atoms which may be optionally fused at two adjacent atoms of the macrocarbocycle to one or more (6g. 1, 2 or 3) aryls, ycles, heteroaryls or heterocycles. The macrocarbocycle may be substituted with one or more (6g. 1, 2 or 3) 0x0 groups.
“Carbocyclylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein (lie. a carbocyclyl-alkyl— ). The alkyl group ofthe cyclylalkyl” is typically 1 to 6 carbon atoms (i. e. carbocyclyl(C1-C6)alkyl). Typical carbocyclyl alkyl groups include, but are not d to carbocyclyl-CH2—, carbocyclyl-CH(CH3)-, carbocyclyl—CHZCH2-, 2- (carbocyclyl)ethan-1—yl, and the like, wherein the “carbocyclyl” portion includes any of the carbocyclyl groups described above.
It is to be understood that when a le is substituted, for example, as described by the phrase “(C1-C6)alkyl, either alone or as part of a group, is optionally substituted ”, the phrase means that the variable (C1-C6)alkyl can be substituted when it is alone and that it can also be substituted when the variable “(C1-C6)alkyl” is part of a larger group such as for example an aryl(C1-C6)alkyl or a -( C1—C6)alkyl—SOZ-(C1-C6)alkyl-(C3-C7)carbocycle group. Similarly, 2O when stated, other variables (e.g. )alkenyl, (C1-C6)alkynyl, aryl, heteroaryl, cycle, etc.) can also be substituted “either alone or as part of a group.” It is to be understood that certain variables of formula I that connect two chemical groups may be oriented in either direction. Thus, for the X group of formula I (e. g. 0, -C(O)-, -C(O)O-, -S—, -S(O)—, —SOz_, —(C1~C6)alkle-, —(C1-C6)alkle(O)-, —(C1-C6)alkle(O)O-, -(C1— C6)alkylS—, -(C1-C6)alkylS(O)- and -(C1-C6)alky1802-) certain values ofX that are not symmetric can be ed in either direction. For example, the -C(O)O—, can be oriented as either -C(O)O- or -OC(O)-, relative to the groups it connects.
It is to be understood that the nitrogen that is included in the core of the compound of formula I can be present in an ed form. For example, the thiazole nitrogen of either G1 or G2 of formula I can be an N—oxide. Accordingly, the invention includes a nd of formula I (as defined in the summary of the invention) or a salt or N—oxide thereof.
One skilled in the art will recognize that substituents 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 usefill compound which can be formulated into an acceptably stable pharmaceutical ition. Compounds of formula I which have such stability are contemplated as g within the scope of the present invention.
The modifier “about” used in tion 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 “chira ” refers to molecules which have the property of perimposability ofthe mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
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 or axes of chirality and whose molecules are not mirror images of one another. Diastereomers typically have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities.
Mixtures of diastereomers may te under high resolution analytical ures such as electrophoresis and chromatography.
“Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
Certain compounds of the ion can exist as atropisomers. For example, it has been ered that atropisomers exist for certain substituents at the R4 position of formula I as marked by an asterisk in the formula below.
R4 R3 R3' ,G1 OH R5 w: \GZ O The chirality that results from the somers at the asterisk position is a e of certain compounds of the invention. Accordingly, the ion includes all atropisomers of compounds of the invention including mixtures of atropisomers and well as mixtures that are enriched in an atropisomer as well as single atropisomers, which mixtures or nds possess the useful properties described herein.
In one embodiment, the compounds ofthe invention of formula I are greater than 50% a single atropisomer for the R4 substituent at the sk position. In one embodiment, the compounds of the invention of formula I are at least 60% a single atropisomer for the R4 substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 70% a single atropisomer for the R4 substituent at the sk position. In another embodiment, the compounds of the invention of formula I are at least 80% a single atropisomer for the R4 substituent at the sk position. In another embodiment, the compounds of the invention of a I are at least 90% a single atropisomer for the R4 substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 95% a single atropisomer for the R4 substituent at the asterisk position. In one embodiment the stereochemistry for the R4 substituent at the carbon marked with an asterisk as shown above for Formula I is the (R) stereochemistry. In another embodiment the chemistry for the R4 substituent at the carbon marked with an asterisk as shown above for Formula I is the (S) stereochemistry.
For certain compounds of the invention the stereochemistry at the carbon bearing the R3 substituent of formula I as marked by an asterisk in the formula below is another aspect of the invention.
R4 R3 G1 OH R5 NW, \G2 0 In one embodiment the stereochemistry at the carbon marked with an asterisk as shown above for Formula I is the (S) stereochemistry. In another embodiment the stereochemistry at the carbon marked with an asterisk as shown above for Formula I is the (R) stereochemistry.
In one embodiment, the compounds of the ion of formula I are greater than 50% a isomer for the carbon at the asterisk position. In r embodiment, the compounds of the invention of formula I are at least 60% a single isomer for the carbon at the asterisk on. In another embodiment, the compounds of the invention of formula I are at least 70% a single stereoisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of a I are at least 80% a single stereoisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 90% a single steroisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 95% a single stereoisomer for the carbon at the asterisk position The term “treatment” or “treating,” to the extent it s to a disease or condition includes ting the disease or condition from occurring, inhibiting the disease or condition, 2012/034593 eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw—Hill Dictionary of Chemical Terms (1984) McGraw—Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistg of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i. e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes (D and L) or (R and S) are used to denote the absolute configuration of the le about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the nd is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer 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 mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or s. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
Protecting Groups In the t of the present ion, protecting groups include prodrug moieties and chemical protecting groups.
“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. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g. Protective Groups in Organic tg, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991.
Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the ncy of desired chemical reactions, e. g. and breaking chemical bonds in an , making d and planned fashion. Protection of fimctional groups of a compound alters other physical properties besides the vity of the protected flmctional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may lves be biologically active or inactive. ted compounds may also exhibit altered, and in some cases, zed properties in vitro and in viva, such as passage through cellular nes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as gs. r function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess r 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 ection, e.g. , alcohols, be physiologically acceptable, although in general it is more desirable if the products are cologiCally innocuous.
Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic ures, i. e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dependent upon the chemistry of the on to be protected against (e. g. , acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, yl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan. s functional groups ofthe compounds ofthe invention may be protected. For example, protecting groups for —OH groups (whether yl, carboxylic acid, onic acid, or other functions) include “ether— or ester-forming groups”. Ether- or ester-forming groups are capable of oning as chemical protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester- forrning groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Smthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0 62301-6) (“Greene”). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag art, New York, 1994), which is incorporated by reference in its entirety herein. In particular r 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, 2012/034593 Carboxyl Protecting Groups, pages 118-154, r 5, Carbonyl Protecting Groups, pages 155- 184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below.
Stereoisomers The compounds of the invention may have chiral centers, e.g. chiral carbon or phosphorus atoms. The compounds of the ion thus include c mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In on, 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 ions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers ed or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures can be separated into their individual, substantially optically pure isomers h well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active ts, e.g. , acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
The nds of the invention can also exist as tautomeric isomers in certain cases.
Although only one delocalized resonance structure may be ed, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible eric forms are within the scope of the invention.
Salts and Hydrates Examples ofpharmaceutically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, ), an alkaline earth metal (for example, magnesium), ammonium and NX4+ (wherein X is C1—C4 alkyl). Pharmaceutically acceptable salts of a hydrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, c, lactic, fumaric, ic, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, oric and sulfamic acids.
Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said PCT/U82012/034593 nd in combination with a suitable cation such as Na+ and NX4+ (wherein X is independently selected from H or a C1—C4 alkyl .
For therapeutic use, salts of active ingredients of the compounds of the invention will typically be pharmaceutically acceptable, i. e. they will be salts d from a physiologically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula I or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
In on, salts may be formed from acid on of certain organic and inorganic acids, e.g, HCl, HBr, H2804, H3PO4 or c sulfonic acids, to basic centers, typically amines, or to acidic groups. y, it is to be understood that the compositions herein comprise compounds ofthe invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the natural or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one g a side chain with a basic or acidic group, 6.g. or , lysine, arginine glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, cine, or Specific values listed below for radicals, substituents, and ranges in the ments of the invention are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Isotopes It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more es such as, but not limited to, deuterium (2H or D). As a non-limiting example, a -CH3 group may be substituted with —CD3.
Compounds of formula I.
A c group of compounds of formula I are compounds of formula la: R4 R3 R3 S OH R —<\5 N R2 or a salt f.
Another specific group of compounds of formula I are compounds of formula Ib: R4 R3 R3.
N CH R5—</ 0 S R2 or a salt thereof.
Another specific group of compounds of formula I are compounds of formula 10: R4 R3 S OH R —<\5 N R2 Ic wherein R3 is-O(C1—C(,)alkyl or a salt f.
Another specific group of compounds of formula I are compounds of formula Ic’: wherein R3 is-O(C1-C6)alkyl or a salt thereof. 2012/034593 Another specific group of compounds of formula I are compounds of a Id: R4 R3 N OH R5—</ 0 S R2 wherein R3 is-O(C1-C6)alkyl, or a salt thereof.
Another specific group of compounds of formula I are compounds of formula Id’: wherein R3 is-O(C1-C6)alkyl, or a salt thereof. r specific group of compounds of formula I are compounds of formula 16: R4 R3 S OH 03/ 0 N R2 or a salt thereof.
Another specific group of compounds of formula I are compounds of formula Ie’: R4 R3 s OH O:*< N R2 R6 Ie 9 or a salt thereof.
Another specific group of compounds of formula I are compounds of formula If: R4 R3 s OH O:< 0 N R2 wherein R3 is-O(C1-C6)alkyl, or a salt thereof.
Another specific group of compounds of formula I are compounds of a If: wherein R3 is—O(C1-C5)alkyl, or a salt thereof.
Another specific group of compounds of a I are nds of formula Ig: R4 R3 R3 s OH R5NV\/ \GZ O wherein: G2 is N, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R5 is a single bond; or G2 is NR6, the dashed bond connected to G2 is a single bond, the wavy bond connected to R5 is a double bond and R5 is oxygen (e.g.“(wavy bond)-R5” is “=0”).
Another specific group of compounds of formula I are compounds of formula Ig’: wherein: G2 is N, the dashed bond ted to G2 is a double bond, and the wavy bond connected to R5 is a single bond; or G2 is NR6, the dashed bond connected to G2 is a single bond, the wavy bond ted to R5 is a double bond and R5 is oxygen (e.g.“(wavy bond)-R5” is “=0”).
Another specific group of compounds of formula I are compounds of formula 111: R4 R3 s OH R5 m1\\/ \Gz 0 lb wherein: G2 is N, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R5 is a single bond; or G2 is NR6, the dashed bond connected to G2 is a single bond, the wavy bond connected to R5 is a double bond and R5 is oxygen (e.g.“(wavy bond)-R5” is “=0”).
Another specific group of compounds of formula I are compounds of formula Ih’: R4 R3 wherein: PCT/U82012/034593 G2 is N, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R5 is a single bond; or G2 is NR6, the dashed bond connected to G2 is a single bond, the wavy bond ted to R5 is a double bond and R5 is oxygen (e.g.“(wavy bond)-R5” is “=0”).
Another specific group of compounds of formula I are compounds of formula Ii: R4 R3 R3.
R5——<" wherein: G1 is S; G2 is N; the dashed bond connected to G1 is a single bond and the dashed bond connected to G2 is a double bond; or G1 is N; G2 is S; the dashed bond ted to G1 is a double bond and the dashed bond ted to G2 is a single bond; or a salt thereof.
Another specific group of compounds of formula I are compounds of formula Ij: R4 R3 G1 OH R5 1m: \\G2 or a salt f.
Specific embodiments of the invention (e.g. embodiments) and specific values listed below are embodiments and values for compounds of formula I including all of the compounds of sub-fomulas of formula I (e.g. the compounds of formulas Ia, Ib, Ic, Ic’, Id, Id’, Ie, Ie,’ If, If’ Ig, Ig’, Ih, Ih’ and IalOO-Ia145) A specific group of compounds of formula I are compounds wherein at least one of R1, R2, R3, R3,, R4 or R5 is selected from R“: RZb, R3", R3”, R"b or RSb.
Another specific group of compounds of formula I are compounds wherein at least two of R1, R2, R3, R3’ , R4 or R5 is selected from R1b , R2b , R3b , R3b’ , R4b or R5b .
Another ic group of compounds of formula I are nds wherein at least three of R1, R2, R3, R3’ , R4 or R5 is selected from R1b , R2b , R3b , R3b’ , R4b or R5b .
Another specific group of compounds of formula I are compounds wherein at least four of R1, R2, R3, R3’ , R4 or R5 is selected from R1b , R2b , R3b , R3b’ , R4b or R5b .
Another specific group of compounds of formula I are compounds wherein at least five of R1, R2, R3, R3’ , R4 or R5 is selected from R1b , R2b , R3b , R3b’ , R4b or R5b .
Another specific group of compounds of formula I are compounds wherein at R1, R2, R3, R3’ , R4 and R5 are R1b , R2b , R3b , R3b’ , R4b and R5b .
A specific value for R1 is H.
Another specific value for R1 is H or halo.
Another specific value for R1 is H or F.
A specific value for R3’ is H.
A specific value for R3 is R3b .
A specific value for R3b is -OC(CH3)2CH 2OH, -OC(CH3)2CH 2OH, -O(C1-C6)alkyl-O- C(O)-NH 2, C6)alkyl-O-C(O)-N(CH 3)2 or -O(C 1-C6)alkyl-O-C(O)-NH(phenyl).
Another specific value for R3b is -(C1-C6)alkylOH or -O(C1-C6)alkyl-O-C(O)-NR cRd.
Another ic value for R3 is R3a .
A ic value for R3a is )alkyl, (C2-C6)alkenyl or -O(C1-C6)alkyl wherein any (C 3a 1-C6)alkyl or )alkenyl of R is optionally substituted with one or more groups selected from -O(C1-C6)alkyl, halo, oxo and -CN.
Another specific value for R3a is -OC(CH3)3.
A specific value for R3’ is R3b’ .
A specific value for R3b’ is (C1-C6)alkyl or -O(C1-C6)alkyl.
A specific value for R3’ is R3a’ .
A specific value for R3a’ is H.
A specific value for R3 is (C1-C6)alkyl, (C2-C6)alkenyl or -O(C1-C6)alkyl, wherein any (C 3a 1-C6)alkyl or (C2-C6)alkenyl of R is optionally tuted with one or more groups selected from -O(C1-C6)alkyl, halo, oxo and -CN.
A specific value for R3 is -OC(CH3)3.
A specific group of compounds of fomula I are compounds wherein the compounds of formula I are compounds of formula Ih: R4 R3 R5 lW‘\/ \Gz 0 wherein: G2 is N, the dashed bond connected to G2 is a double bond, and the wavy bond ted to R5 is a single bond; or G2 is NR6, the dashed bond connected to G2 is a single bond, the wavy bond ted to R5 is a double bond and R5 is .
A specific group of nds of fomula I are compounds n R3b and R3b’ together with the carbon to which they are attached form a (C3-C7)carbocycle or heterocycle; wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more Zl groups.
Another specific group of compounds of fomula I are compounds wherein R3b and R3b’ together with the carbon to which they are attached form a (C3-C7)carbocycle or a 4, 5 or 6- membered heterocycle; wherein the (C3-C6)carbocycle or the 4, 5 or 6—membered heterocycle is optionally substituted with one or more Zl groups.
Another specific group of compounds of fomula I are compounds wherein R3b and R3” together with the carbon to which they are attached form a (C4—C6)carbocycle or a 5 or 6- membered heterocycle; wherein the (C4-C6)carbocycle or the 5 or ered heterocycle is ally substituted with one or more Z1 groups.
Another specific group of compounds of fomula I are compounds wherein R31) and R3” together with the carbon to which they are attached form a 5 or 6-membered heterocycle; wherein the 5 or 6-membered heterocycle is optionally substituted with one or more Z1 groups.
Another specific group of compounds of fomula I are compounds wherein R31) and R31), together with the carbon to which they are attached form a tetrahydropyran or tetrahydrofuran optionally substituted with one or more Z1 groups.
Another specific group of compounds of fomula I are compounds wherein R3b and R3b, together with the carbon to which they are attached form: Q or View “22w each of which is optionally substituted with one or more Z1 groups; and wherein ‘6 9’ denotes the point of attachment to the carbon of the compound of formula I.
A specific value for R4 is R“.
A specific value for R“ is (C1-C5)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein (C1-C6)alky1, (C2-C5)alkenyl or (C2-C6)alkyny1 are each optionally tuted with one or more Z1 groups.
Another specific value for R41) is: optionally substituted with one or more Z1 groups.
Another specific value for R4b is (C3-C7)carbocycle; wherein (C3-C7)carbocycle is optionally substituted with one or more Z1 groups; or wherein two Z1 groups together with the atom or atoms to which they are attached ally form a (C3-C6)carbocycle or 5membered heterocycle.
Another c value for R41) is: oo [0 ,NW’ © or0 each of which is optionally substituted with one or more Z1 .
Another specific value for R4b is aryl, heterocycle or aryl; n aryl, heterocycle and heteroaryl are each independently substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
Another specific value for R4b is: OCFs O OCF F 3 oer:3 r specific value for R4 is R“.
A specific value for R4a is: CFa F I} '\ / or? \N .— O <’l::|N (1 HW’ NW, Another specific value for R4a is: 0 o C' ' \N ’ ' C' NW m, NW NW Another c value for R48 is: NW .NW N A specific value for R4 is selected from: a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and aryl ofR4 is optionally substituted with one or more (6.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (C1—C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalky1, 6)a1kyl-(C3-C7)cycloalkyl, -OH, -O(C1-C6)alkyl, -SH, C6)a1kyl, —NH2, -NH(C1—C6)alkyl and -N((C1-C(,)alkyl)2, wherein (C1-C5)alkyl is optionally substituted with hydroxy, -O(C1- C6)alkyl, cyano or oxo; and b) aryl, heteroaryl, spiro—, fused-, or bridged-heterocycle; wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are each independently substituted with one or more Z7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups.
Another specific value for R4 is selected from: PCT/U82012/034593 a) aryl, cycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl ofR4 is optionally substituted with one or more (6.g. 1, 2, 3, 4 or 5) groups each ndently selected from halo, (C1—C6)alkyl, (C2—C5)a1kenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, -(C1-C6)alkyl-(C3-C7)cycloalkyl, -OH, -O(C1-C6)alkyl, -SH, -S(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl and -N((C1-C6)alky1)2, wherein (C1-C6)alkyl is optionally substituted with y, -O(C1- C6)alkyl, cyano or 0x0; and b) aryl and heteroaryl, n aryl and heteroaryl are each ndently substituted with one or more Z7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups.
Another specific value for R4 is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl OfR4 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or ) groups each independently selected from halo, (C1-C6)alkyl, (C2-C5)alkenyl, (C1-C5)haloalkyl, (C3-C7)cycloalkyl, -(C1-C6)alkyl-(C3-C7)cycloalkyl, -OH, -O(C1-C6)alkyl, -SH, -S(C1-C6)alkyl, - NH2, -C6)alkyl and -N((C1-C6)alkyl)2, wherein (C1-C6)alkyl is optionally substituted with hydroxy, —O(C1-C6)alkyl, cyano or 0x0.
Another specific value for R4 is: Cl 0 f0 N CI vaV NW NW NW Another specific value for R4 is: CI 0 f0 N . CI 0 (\o F O 0 A specific group of compounds of a I are compounds wherein R4 and R3 together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R4 and R3 together with the atoms to which they are ed may be ally substituted with one or more Z1 groups; and R3’ is H, (C1-C6)alky1 or —O(C1-C6)alkyl.
Another specific group of compounds of formula I are compounds wherein R4 and R3 together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R4 and R3 together with the atoms to which they are attached may be optionally substituted with one or more Z1 groups; and R3, is H.
Another specific group of compounds of formula I are compounds wherein R4 and R3 together with the atoms to which they are attached form the macroheterocycle or a macrocarbocycle which is further fused to a Z group; wherein: Z is aryl, heteroaryl or (C3-C6)carbocycle; n3 is 2, 3 or 4; W1 and W2 are each independently O, NH or CH2; and wherein “*” denotes the R4 point of attachment of the eterocycle or macrocarbocycle to the compound of formula I and “n” denotes the R3 point of attachment of the macroheterocycle or macrocarbocycle to the compound of formula I; and wherein the macroheterocycle or a macrocarbocycle is optionally substituted with one or more Z1 groups. r specific group of nds of formula I are compounds wherein, R4 and R3 together with the atoms to which they are attached form the macroheterocycle: wherein: n1 is 3 or 4; n2 is 2, 3 or 4; n3 is 2, 3 or 4; W is O, NH or N(C1—C4)alkyl; and wherein “*” denotes the R4 point of ment of the macroheterocycle to the compound of formula I and “n” denotes the R3 point offattachment of the eterocycle to the compound of formula I; and wherein the macroheterocycle or a macrocarbocycle is optionally substituted with one or more Z1 groups A specific value for R2 is RZb.
Another specific value R2 is R23.
A specific value for Rza is H, halo or -CH3.
Another specific value for R23 is Cl.
A specific value for R2 is halo, H or )alkyl.
Another specific value for R2 is halo, H or —CH3.
Another specific value for R2 is H or -CH3.
Another c value for R2 is H or (C1-C5)alkyl.
Another specific value for R2 is (C1—C6)alkyl.
Another specific value for R2 is -CH3.
Another specific value for R5 is R53. r specific value for R521 is H, )alkyl, (C3-C7)carbocycle, -(C1-C6)alkyl-R“, - C(=O)-Rl 1, -N(R9)R10, -C(=O)-N(R9)R1°, heterocycle or heteroaryl, wherein heteroaryl is optionally substituted with one or more Z11 groups.
Another specific value for R53 is H, (C1-C6)alkyl, (C3-C7)carbocycle, —C(=O)-R1 1, - 1°, -C(=O)-N(R9)R1° or heterocycle. r specific value for R521 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl or -(C1-C6)alkyl—R“.
A specific value for R11 is aryl.
Another specific value for R11 is carbocycle or aryl.
Another specific value for R11 is carbocycle.
Another specific value for R521 is -N(R9)R10.
A specific value for R9 is H or (C1-C6)alky1.
A specific value for R10 is H or (C1-C6)alkyl.
Another specific value for R9 is H, (C1-C6)alkyl or -C(=O)-R“. r specific value for R10 is H, (C1-C6)alkyl or —C(=O)-R11.
A value for Z9 is “each 29 is independently selected from -(C1-C(,)alkyl, -O(C1-C6)alkyl”.
A specific value for R5a is: D—E \ N—§ \—§. CN—E , g;' or °>\—§ —§ \_§ H—§ O g >\ g CN—E , or A specific value for R5 is RSb.
Another specific value for R5b is-(Cz-C6)alkynyl-(C3-C7)carbocycle.
Another specific value for R5b is: A specific value for R5 is H, (C1-C6)alkyl, (C3-C7)carbocycle, -R“, —N(R9)R10, - C(=O)-N(R9)R10, heterocycle or -(C2-C6)alkynyl-(C3-C7)carbocycle.
A specific value for R5 is: 2012/034593 D—é Mg y; I: _ — E \ \ o\ \ K)»; )SvofiN—E ‘ , [:HN g 0 \N—E V /o—§ 0—;_ or > l C HO>—é . < , (bl—E ' ~< eNH HNH Mfg 0%; > or y C d A specific value for R5 is selected from: a) R“, -C(=O)-R”, -C(=O)-O-R“, -o-R“, —S-R”, -S(O)-R“, -SOz-R11, -(C1-C6)alkyl-R“, -(C1-C6)alkyl-C(=O)-R“, -(C1—C6)alkyl-C(=O)—O—R11, -(C1-C5)alkyl-O-R“, — (C1-C6)alkyl—S-R”, -(C1-C6)alky1-S(O)-R“ and -(C1-C6)a1kyl-SOZ-R“, wherein each R“ is independently selected from H, (C1-C5)alkyl, (C2—C6)alkenyl, (C2-C5)alkynyl, (C1-C6)haloalkyl, (C3-C7)carbocycle, aryl, heterocycle and heteroaryl, n aryl, heterocycle and heteroaryl are each ally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) —N(R9)R1°, -C(=O)-N(R9)R1°, -O-C(=O)—N(R9)R1°, -SOz-N(R9)R1°, -(C1-C6)alkyl- N(R9)R‘°, -(C1-C5)alky1—C(=O)-N(R9)R’0, -(C1-C6)alkyl-O-C(=O)-N(R9)Rl0, and 6)alkyl- R9)R10; wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3- C7)cycloalkyl; and each R10 is independently selected from R”, -(C1-C6)a1kyl-R”, “, — C(=O)—R11, -C(=O)OR11 and -C(=O)N(R9)R“, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, )cycloalkyl, aryl, heterocycle and heteroaryl; c) -(C1-C6)alkyl-O-(C1-C6)alkyl—(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyIS(O)-(C1-C6)alkyl-(C3-C6)carbocyc1e, 6)alkylSOZ(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl—(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, - (C3—C7)halocarbocycle, -NRaSOzNRcRd, -NRaSOZO(C3- C7)carbocycle, -NRa8020aryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, -(C2—C5)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C5)alkynyl—heterocycle, -(C3- bocycle-Zl or -(C1-C6)haloalkyl-Z3, wherein any (C1-C6)alky1, (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl or heteroaryl, either alone or as part of a group, is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z1 groups; (1) 'NReRf, ‘C(O)NReRf, 'OC(O)NReRf, ‘SOZNReRf, -(C1-C6)alky1-NReRf, —(C1-C6)alky1C(O)-NReRf, -(C1-C6)alkyl-O-C(O)-NReRf and -(C1-C6)alky1—SOZNRch, wherein each (C1-C6)alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and ally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z1groups; and e) oxo.
Another specific value for R5 is selected from: a) R“, -C(=O)-R1 1, -C(=O)-O-R” and on“; wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3- C7)carbocycle, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) -N(R9)R10 and -C(=O)—N(R9)R10; wherein each R9 is independently selected from H, (C1—C6)alkyl and (C3-C7)cycloalkyl; and each R10 is independently selected from R“, -(C1- C6)alkyl-R”, -SOz-R”, —C(=0)-R“, OR“ and -C(=O)N(R9.)R”, wherein each R” is independently selected from H, (C1-C6)alkyl, )alkenyl, )alkynyl, )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and aryl; c) -(C2—C6)alkynyl-(C3—C7)carbocycle, wherein -(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one or more(e.g. l, 2, 3, 4 or 5) Z1 groups; d) 'NReRf and-C(O)NRch; and e) oxo.
Another specific value for R5 is selected from: a) R“, -C(=0)—R“, -C(=O)-O-R“ and -O-R“; wherein each R“ is independently selected from H, (C1-C5)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3- C7)carbocycle, aryl, heterocycle and aryl, wherein aryl, heterocycle and heteroaryl are each optionally tuted with one or more (e.g. 1, 2 or 3) Z11 groups; 2012/034593 b) R10 and -C(=O)—N(R9)R10; n each R9 is independently selected from H, (C1-C6)alkyl and (C3-C7)cycloalkyl; and each R10 is independently selected from R“, -(C1- yl-R“, -SOz-R“, -C(=O)—R“, —C(=O)OR” and -C(=O)N(R9)R”, wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; c) —(C2-C5)alkynyl-(C3—C7)carbocycle, wherein -(C2—C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z1 groups; and (1) -NRch and-C(O)NReRf.
Another specific value for R5 is selected from: a) H, (C1-C6)alkyl, (Cl-C6)haloalkyl, (C3-C7)carbocycle, heterocycle, —R”, - C(=O)—O-R11 and -O-R“, n heterocycle is optionally substituted with one or more (e.g. l, 2 or 3) Z11 groups and wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2- C6)a1kenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)carbocycle, aryl, heterocycle and aryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) -N(R9)R10 and -C(=O)-N(R9)Rl°; wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3-C7)cycloalkyl; and each R10 is independently selected from R1 1, -(C1- C6)alkyl-R“, -SOz-R11, —C(=O)—R“, -C(=O)OR“ and -C(=O)N(R9)R“, wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2—C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; c) -(C2-C6)alkynyl-(C3-C7)carbocycle, wherein -(C2-C6)alkynyl-(C3-C7)carbocycle is ally substituted with one or more(e.g. l, 2, 3, 4 or 5) Z1 groups; and d) ‘NReRf and-C(O)NRch.
Another specific value for R5 is selected from: PCT/U52012/034593 HOH \ N—§ <N_ \N—§ \N—§ , ( < , —g, fi' @N—E :3 N-§ [OWN—E H 0 ' O —N\ Q4”; O \N—§ 0— E >4 0—: o—fig g m ‘NH HN NH 02,—; > or ‘ S d A specifc group of compounds of formula I are compounds wherein R5 is oxo and R6 is selected from R11 and -(C1-C6)alkyl-R“, n each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, n aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups.
Another specifc group of compounds of formula I are compounds wherein R5 is oxo and R6 is selected from: 7., “Nu ""‘m “‘44, ""vv F F F F F A specific group of compounds of formula I are nds wherein R4b is selected from; 21) (C1-C6)alkyl, (C2—C6)alkenyl and (C2-C6)alkynyl, wherein any (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; b) (C3-C14)carbocycle, wherein (C3-C14)carbocycle is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 ; c) Spiro-heterocycle or bridged-heterocycle, wherein Spiro-heterocycle or bridged-heteroocycle is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 ; d) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z7 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4" is selected from; a) (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein any (C1—C6)alkyl, )alkenyl or (C2-C6)alkynyl is optionally tuted with one or more (e.g. l, 2, 3, 4 or 5) Z1 ; b) (C3-C14)carbocycle, wherein (C3-C14)carbocycle is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups; wherein two Z1 groups together with the atom or atoms to which they are attached optionally form a (C3-C7)carbocycle or heterocycle; and c) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each ndently substituted with one or more (e.g. l, 2, 3, 4 or 5) Z7 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4b is selected from; a) (C1-C6)alkyl, )alkenyl and (C2—C6)alkynyl, wherein any )alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups; b) (C3-C14)carbocycle, wherein (C3—C14)carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and c) aryl, cycle and heteroaryl, n aryl, heterocycle and heteroaryl are each independently substituted with one or more (e.g. l, 2, 3, 4 or 5) Z7 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups.
In another embodiment, the invention provides a nd of the invention which is a compound of formula I: R4 R3 R3 G1 OH R5—<:/ ' \Gz O wherein: G1 is S; G2 is N; the dashed bond connected to G1 is a single bond and the dashed bond connected to G2 is a double bond; or G1 is N; G2 is S; the dashed bond connected to G1 is a double bond and the dashed bond connected to G2 is a single bond; R1 is Rla or R"); R2 is R221 or RZb; R3 is R33 or R3b; R3, is R35 or R3”; R4 is R43 or K”; R5 is R5a or RSb; R1"1 is selected from: a) halo; b) R”, -C(=O)-R“, -C(=O)-O-R”, -o-R“, -s-R”, -S(O)-R“, -SOz-R”, -(C1-C6)alky1-R”, -(C1-C6)alkyl-C(=O)-R“, -(C1-C6)a1kyl-C(=O)-O-R11, -(C1-C6)alkyl—O-R“, - (C1-C6)alky1-S-Rl 1, —(C1-C6)alky1-S(O)-R“ and -(C1-C6)alkyl—SOZ-R“; wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2—C6)alkenyl, (C2-C6)alkynyl, )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; and c) —N(R9)R‘°, -C(=O)-N(R9)R1°, -O-C(=O)-N(R9)R1°, -SOz-N(R9)R1°, -(C1-C6)alkyl-N(R9)R1°, -(C1-C6)alkyl-C(=O)-N(R9)R1°; -(C1-C6)alky1-O-C(=O)-N(R9)R10 and - )alkyl-SOZ-N(R9)Rl°; wherein each R9 is independently ed from H, (C1-C6)alkyl and (C3-C7)cycloalkyl; and each R10 is independently selected from R“, -(C1-C6)alkyl-R“, — SOz-R“, -C(=O)-R”, OR” and -C(=O)N(R9)R”, wherein each R“ is independently ed from H, )alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3- C7)cycloa1ky1, aryl, heterocycle and heteroaryl; R11) is selected from: a) -(C1-C6)alkyl-O-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alky1-(C3-C7) carbocycle, -(C1—C6)alkyl-S(O)-(C1-C6)alky1—(C3-C6) carbocycle, -(C1-C6)alkyl- SOz—(C1—C6)alky1-(C3-C7)carbocycle, -(C1-C6)alkyl-SOZ-(C1-C6)alkyl-Z13, -C(O)-(C1-C6)alkyl- z”, —O-(C1-C6)a1kyl-Zl3, -S-(C1-C6)alkyl-Z13, (C1-C6)alkyl-Z13, -SOz—(C1-C6)alkyl—Z13, —(C1-C6)alkyl-Z14, —(C1—C6)alkyl-C(O)-(C1-C6)alkyl-Zl3, -(C1-C6)alkyl-C(O)-O(C1-C6)alkyl-Zl3, -(C1-C6)alkyl-O—(C1—C6)alkyl-Zl3, 6)alkyl-S—(C1-C6)alkyl-Z13, -(c2— C6)alkenyl-(C1—C6)haloalkyl, -(C2-C6)alkynyl-(C1-C6)haloalkyl, — (C3-C7)halocarbocycle,- NRaSOzNRcRd, -NRa8020(C3-C7)carbocycle, -NRaSOZOaryl, -(C2-C6)alkenyl-(C3- C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)a1kenyl—heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl—heteroaryl -(Cz-C6)alkynyl-heterocycle, —(C3—C7)carbocycle-Z1 or -halo(C1-C6)alkyl-Z3; wherein (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2—C6)alkenyl, (C2-C6)alkynyl, aryl or heteroaryl are each optionally substituted with one or more (6.g. 1, 2, 3, 4 or 5) Z1 groups; b) spiro-bicyclic ycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic ycle are optionally substituted with one or more (6.g. l, 2, 3, 4 or 5) Z1 groups; wherein two Z1 groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; c) (C1-C6)alkyl; n (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; d) C6)alkyl, C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle; wherein (C1—C6)alkyl and (C1—C6)haloalkyl are each substituted with one or more Z3 groups and optionally substituted with one or more Zlgroups; and wherein (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C7)carbocycle are each substituted with one or more (e. g. l, 2, 3, 4 or 5) Z4groups and optionally substituted with one or more Zlgroups; e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl eterocycle; n aryl aryl and heterocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more Zlgroups; f) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl; n (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl are each substituted with one or more (e.g. l, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more Zlgroups; g) 'NReRfa -C(O)NReRr, -OC(O)NReRf, ‘SOZNReRf: 6)alky1'NReRf, —(C1-C6)alkle(O)-NReRf, -(C1-C6)alkyl-O-C(O)-NRch and “(C1-C6)al.ky1'SOZNReRf; wherein each )alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more Zlgroups; and WO 45728 h) nitro and cyano R2a is selected from: a) halo; b) R“, C(=O)-R“, -C(=O)-O-R“, -o-R”, -s-R“, -S(O)—R“, -SOz-R“, -(C1—C6)alkyl-R“, —(C1—C6)alkyl-C(=O)-R“, -(C1—C6)alkyl-C(=O)-O-R11, -(C1-C6)alkyl-O-R“, — (C1—C5)alkyl-S-R“, -(C1-C5)alky1-S(O)-R” and -(C1-C6)alkyl-S02-R”; wherein each R“ is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl and heterocycle and heteroaryl, wherein aryl, cycle or aryl are each optionally substituted with one or more (e.g. l, 2 or 3) Z11 groups; and c) -N(R9)R1°, -C(=O)—N(R9)R1°, -O-C(=O)-N(R9)R1°, -SOz-N(R9)R1°, -(C1-C6)alkyl— N(R9)R‘°, -(C1-C5)alkyl-C(=O)-N(R9)R1°, -(C1-C6)alkyl-O-C(=O)-N(R9)Rl0, and -(C1—C6)alkyl- SOz—N(R9)R1°, wherein each R9 is independently selected from H, (C1-C5)alkyl and (C3- C7)cycloalkyl; each R10 is ndently selected from R“, —(C1—C6)alkyl—R“, —SOz—R“, —C(=O)—R“, - C(=O)OR11 and -C(=O)N(R9)R“; wherein each R11 is independently selected from H, (C1- yl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; R21) is selected from: a) -(C1-C6)alkyl-O-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- yl-(C3-C7)carbocycle, -(C1-C6)alkyl—S(O)-(C1—C6)alkyl—(C3-C7)carbocycle, -(C1— C6)alkyl(C1—C6)alkyl-(C3-C7)carbocycle, 6)alkenyl-(C1-C6)haloalkyl, -(C2- ynyl-(C1—C6)haloalkyl, -(C1-C6)alkyl-SOz—(C1-C6)alkyl-Z13, —C(O)-(C1-C6)alkyl-Z13, -o- (C1-C6)alkyl-Z13, -S-(C1-C6)alkyl-Z13, -S(O)-(C1-C6)alkyl-Zl3, -SOz-(C1-C6)alkyl-Zl3, -(C1—C6)alkyl-Zl4, -(C1—C6)alky1-C(O)-(C1-C6)alkyl-Z13, -(C1-C6)alkyl-C(O)-O(C1-C6)alkyl—Z13, -(C1-C5)alkyl-O-(C1-C6)alkyl-Zl3, -(C1-C6)alkyl-S-(C1—C6)alkyl-Zl3, -(C3-C7)halocarbocycle,- NRaSOzNRcRd, -NRaS020(C3-C7)carbocycle, -NRaSOanryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, 6)a1kenyl-heterocycle, -(C2-C5)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, —(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, —(C3—C7)carbocycle-Z1 or —halo(C1- 3O C6)alkyl-Z3; wherein (C1-C5)alkyl, -(C1-C6)haloalkyl, (C3-C7)carbocycle, )alkenyl, (C2- C5)alkynyl, aryl or aryl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or ) Zlgroups; b) spiro-bicyclic carbocycle, fused—bicyclic carbocycle and bridged—bicyclic carbocycle; wherein spiro-bicyclic ycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups; wherein PCT/U82012/034593 two Z1 groups together with the atom or atoms to which they are ed optionally form a (C3-C7)carbocycle or heterocycle wherein the (C3-C6)carbocycle or heterocycle is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups; c) (C1—C6)alkyl; n )alkyl is substituted with one or more Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; d) -X(C1-C6)alkyl, X(C1-C6)haloalkyl, X(C2—C6)alkenyl, -X(C2—C6)alkynyl and -X(C3—C7)carbocycle; n (C1-C6)alkyl and (C1-C6)haloalkyl are each substituted with one or more Z3 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; and wherein (C2-C6)alkenyl, )alkynyl and (C3-C7)carbocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z4groups and optionally substituted with one or more ps; e) aryl, heteroaryl, heterocycle, , —Xheteroaryl and -Xheterocycle; n aryl heteroaryl and heterocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; f) (C1-C6)haloalkyl, (C3—C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl; wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; g) 'NReRr, “C(O)NReRfa -OC(O)NReRf, 'SOZNRch, '(Cl-C6)alkyl'NReRr, —(C1—C6)alkle(O)—NReRf, -(C1-C6)alkyl—O-C(O)-NReRf and '(CI'C6)alkyl‘S02NReRf; wherein each (C1—C6)alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; and h) nitro and cyano; R321 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, )alkynyl, -(C1-C6)alkyl-(C3-C7)cycloalkyl, -(C1-C6)alkyl-aryl, -(C1-C6)alkyl-heterocycle, -(C1—C6)alkyl- heteroaryl, -O(C1-C5)alkyl, -O(C1-C6)haloalkyl, -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, -O(C3-C7)cycloalkyl, -Oaryl, -O(C1-C6)alkyl-(C3-C7)cycloalkyl, -O(C1—C6)alkyl-aryl, -O(C1-C6)alkyl-heterocycle and -O(C1-C6)alkyl—heteroaryl; n any (C1-C6)alkyl, )haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C1-C6)alkyl-(C3-C7)cycloalky1, -(C1-C5)alkyl-aryl, -(C1-C6)alkyl-heterocycle, -(C1-C6)alkyl-heteroaryl, -O(C1-C6)alkyl, -O(C1-C6)haloalkyl, —O(C2—C6)alkenyl, —O(C2-C6)alkynyl, -O(C3-C7)cycloalkyl, -Oary1, —O(C1-C6)alkyl-(C3-C7)cycloalkyl, -O(C1-C6)alkyl—aryl, —O(C1—C6)alkyl-heterocycle or -O(C1-C6)alkyl-heteroaryl of R321 is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (C1-C6)alkyl, -O(C1-C6)alkyl, halo, 0x0 and —CN; and R33, is H; R31) is -(C3-C7)carbocycle, ary1,heteroaryl, heterocycle, 6)alky10H, -(C1—C6)alkyl- O-(Cl-C6)alkyl-Z12, -(C1-C6)alky1—O-(C2-C6)alkenyl—Z12, -(C2—C6)alkyl—O-(C2-C5)alkynyl-Z12, - (C1-C6)alkyl-S-(C1-C6)alkyl-Z12, -(C1-C6)alkyl-S-(Cz-C6)alkenyl-Z12, -(C2—C6)alkyl—S-(C2- C6)alkynyl-Z12, —(C1-C6)alkyl-S(O)-(C1-C6)alkyl-Z12, 6)alkyl-S(O)-(C2-C6)alkenyl—Z12, — (C2-C6)alkyl-S(O)-(C2-C6)alkynyl-Z12, -(C1-C5)alkyl-SOZ—(C1-C6)alkyl-Z12, -(C1-C6)a1kyl-SOZ- (C2-C6)alkenyl-Z12, -(C2-C6)alkyl-SOz-(C2-C6)alkynyl-Z12, -(C2-C6)a1kyl-NRaRb, -(C2-C6)alkleC(O)—NRcRd, -(C2-C5)alkyl-NRa-C(O)-0Rb, -(C2—C6)alkyl-NRa—C(O)-NRaRb, - (C1'C6)alky1'SOZ(C1'C6)alky1a '(Cl‘C6)alky1‘SOZNRcRda '(CI'C6)alkyl'NRaSOZNRcRd= -(C1-C6)alkyl—NRaS020(C3-C7)carbocycle, -(C1-C6)alkyl-NRaSOanryl, -(C1-C6)alkyl-NRa-SOZ-(C1-C6)alkyl, -(C1-C5)alkyl-NRa-SOZ-halo(C1—C6)alkyl, —(C1-C6)alkyl-NRa-SOz-(Cz-C6)alkenyl, -(C1-C6)alky1-NRa-SOz-(Cz-C6)alkyny1, -(C1-C6)alkyl-NR3-SOz-(C3-C7)carbocycle, -(C1-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -(C1-C6)alkyl-NRa-SOZ-aryl, -(C1-C5)alkyl-NR3-SOz-heteroaryl, -(C1-C6)a1kyl—NRa-SOz-heterocycle, -O(C1-C6)alkyl-NRaRb, -O(C1-C6)alky10C(O)-NRcRd, - O(C1-C6)a1kyl-NRa-C(O)-0Rb, -O(C1—C6)alkyl—NRa—C(O)—NRaRb, -O(C1-C6)alky1-NRa-SOZ-(C1- C6)alky1, -O(C1-C6)alkyl—NRahalo(C1-C6)alkyl, —O(C1-C6)alkyl-NRa-SOz-(Cz-C6)alkenyl, -O(C1-C6)alkyl-NRa-SOz-(Cz-C6)alkynyl, -O(C1-C6)alkyl—NR3-SOz-(Cg-C7)carbocycle, —O(C1-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -O(C1—C(,)alkyl-NRa-Soz-aryl, -O(C1—C6)alkyl-NRa-SOz-heteroaryl, -O(C1-C6)alkyl-NRa-SOz-heterocycle, -O(C1—C6)alkyl—NRa-SOZ-NRaRb, C6)a1kyl-NRa-SOz-(C3-C7)carbocycle, -O(C1-C6)alkyl-NRa-SOz-halo(C3-C7)carbocycle, -O(C1-C5)alkyl-NRaaryl, C6)alkyl- NRaSOzNRcRd, C6)alkyl-NRaS020(C3—C7)carbocycle, -O(C1—C6)alkyl—NRaSOanryl, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle, —S(O)heteroaryl, -S(O)heterocycle, — SOzheteroaryl or -S02heterocycle; wherein any (C1-C6)alkyl, aryl, (C3—C7)carbocycle, heteroaryl or heterocycle of R3b is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R3” is H, (C1-C5)alkyl or -O(C1-C6)alkyl; or R3b and R3b’ er with the carbon to which they are attached form a heterocycle or (C3-C7)carbocyc1e which cycle or )carbocycle of R3b and R3b’ together with the 3O carbon to which they are attached is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R4a is selected from aryl, cycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R4a is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, -(C1-C5)alky1-(C3-C7)cycloalkyl, -OH, -O(C1-C6)alkyl, -SH, —S(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl and -N((C1-C6)alkyl)2; wherein (C1—C6)alky1 is optionally tuted with hydroxy, -O(C1- C6)alkyl, cyano or 0x0; R4b is selected from; a) (C1—C6)alky1, (C2-C6)alkenyl and (C2-C6)alkynyl; wherein (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl are each ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; b) (C3-C14)carbocycle; wherein (C3—C14)carbocycle is optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups; wherein two Zl groups together with the atom or atoms to which they are attached optionally form a (C3—C7)carbocycle or heterocycle; c) Spiro-heterocycle or bridged-heterocycle; n Spiro-heterocycle or bridged—heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; or wherein two Z1 groups together with the atom or atoms to which they are attached optionally form a (C3-C7)carbocycle or heterocycle; and d) aryl, heteroaryl, spiro-, fused-, or bridged—heterocycle; wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are each independently substituted with one or more Z7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; or R4 and R3 together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R4 and R3 together with the atoms to which they are attached may be optionally substituted with one or more (6.g. 1, 2, 3, 4 or 5) 21 groups; and R3” is H or (C1-C6)alkyl, C6)alkyl.
R5a is ed from: a) halo; b) R“, -C(=O)-R“, -C(=O)-O-R“, —o—R“, -s—R“, -S(O)-R“, -SOz-R“, —(c1— C6)alkyl-R”, -(C1-C6)alkyl-C(=O)-R”, -(C1-C6)alkyl-C(=O)-O-R11, -(C1-C6)alkyl-O-R“, -(C1- yl-S-R“, —(C1-C6)alkyl-S(O)-R“ and -(C1-C6)a1kyl-SOZ-R“; wherein each R“ is independently ed from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, )carbocycle, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; and c) -N(R9)R1°, -C(=O)-N(R9)R1°, -O-C(=O)—N(R9)R1°,-SOz-N(R9)R1°,-(C1-C6)alky1- 3O N(R9)R1°, -(C1—C6)alky1-C(=O)-N(R9)R10, -(C1-C6)alkyl-O-C(=O)-N(R9)R10, and 6)alkyl— SOz-N(R9)R10; wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3- C7)cycloalky1; and each R10 is independently selected from R1 1, —(C1-C6)alkyl-R“, “, - C(=O)-R1 1, -C(=O)OR11 and N(R9)R”; n each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkeny1, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloa1kyl, aryl, heterocycle and heteroaryl; R5" is selected from: a) 6)alkyl-O-(C1-C6)alkyl-(C3—C7)carbocycle, —(C1-C6)alkyl-S-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkylS(O)-(C1-C6)alkyl-(C3-C6)carbocycle, -(C1-C6)alkylSOp,(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, - (C3-C7)halocarbocycle, -NRaSOZNRcRd, -NRa8020(C3- C7)carbocycle, -NR38020aryl, 6)alkeny1-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle, 5)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, 6)alkynyl-heteroaryl, —(C2-C6)alkynyl-heterocycle, -(C3- C7)carbocycle-Z1 or -halo(C1-C6)alkyl-Z3; wherein (C1-C6)alkyl, (C1—C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl or heteroaryl are each optionally substituted with one or more(e.g. l, 2, 3, 4 or 5) Z1 groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle, bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; wherein two Zl groups together with the atom or atoms to which they are attached optionally form a (C3- bocycle or heterocycle wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; c) (C1-C5)alkyl; wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; d) -X(C1-C6)alkyl,-X(C1-C6)haloalkyl, -X(C2—C6)alkenyl, C6)alkynyl and -X(C3-C7)carbocycle; wherein (C1-C6)alkyl or (C1-C6)haloalkyl are each substituted with one or more Z3 groups and optionally substituted with one or more Zlgroups; and wherein (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C7)carbocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z4 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Zlgroups; e) aryl, heteroaryl, heterocycle, -Xaryl, roaryl and —Xheterocycle; wherein aryl aryl are heterocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; 3O 0 (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl; where )haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and ally substituted with one or more (e.g. l, 2, 3, 4 or 5) Zlgroups; g) a -C(O)NReRf, -OC(O)NReRf, ‘SOZNReRf: ‘(CI'C6)alkyl'NRch> '(Cl-C6)alkle(O)'NReRf, -(C1-C6)alkyl—O—C(O)-NReRf and '(Cl'C6)a1kyl‘SOZNReRf; wherein each (C1—C6)alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; and h) nitro and cyano; or R1 and R2 together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle; n the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are each ndently substituted with one or more (e.g. 1, 2 or 3) Z7 or Z8 groups; wherein when two Z7 groups are on same atom the two Z7 groups er with the atom to which they are attached optionally form a )carbocycle or 4, 5 or ered heterocycle; X is independently selected from O, -C(O)-, —C(O)O—, -S-, -S(O)—, -SOz_, -(C1— le-, -(C1-C6)alky1C(O)—, -(C1-C6)alky1C(O)O-, -(C1-C6)alkylS-, -(C1-C6)alkylS(O)-, "(C1-C6)alk}’1502-; each Z1 is independently selected from halo, -N02, -OH, =NORa, -SH, —CN, -(C1- C6)alky1, -(C2-C6)alkenyl, —(C2-C6)alkynyl, -(C1-C6)haloalkyl, (C3-C7)carbocycle, - (C3- C7)halocarbocycle, —aryl, -heteroaryl, -heterocycle, -O(C1-C5)alkyl, -O(C2-C6)alkenyl, -O(C2- C6)alkynyl, -O(C1-C6)haloalkyl, —O(C3-C7)carbocycle, -O(C3-C7)halocarbocycle, —Oaryl, - Oheteroaryl, rocycle, -S(C1-C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, —S(C1- C6)haloalkyl, I-S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, —Saryl, -Sheteroaryl, - Sheterocycle, —S(O)(C1—C(,)alkyl, -S(O)(C2-C6)alkenyl, -S(O)(C2-C5)alkynyl, -S(O)(C1- C6)haloalkyl, -S(O) (C3-C7)ca.rbocycle, C3—C7)halocarbocycle, —SOz(C1-C6)alkyl, -S(O)aryl, -S(O)carbocycle, -S(O)heteroaryl, -S(O)heterocycle, 2-C6)alkenyl, -SOZ(C2— C6)alkynyl, -SOZ(C1—C6)haloalkyl, -SOz(C3—C7)carbocycle, -SOZ(C3-C7)halocarbocycle, -SOzaryl, -SOzheteroaryl, -SOzheterocycle, -SOzNRcRd, -NRcRd, -NRaC(O)Ra, -NRaC(O)ORb, -NRaC(O)NRCRd -NRaSOZRb, -NRaS02NRcRd, ZO(C3-C7)carbocycle, -NRaSOZOaryl, -OS(O)2Ra, -C(O)Ra, -C(O)0Rb, -C(O)NRcRd, and -OC(O)NRcRd, wherein any (C1—C6)alkyl, (C2—C6)alkenyl, (C2-C6)alkynyl, -(C3-C7)halocarbocycle, (C3-C7)carbocycle, (C3- C7)halocarbocycle, aryl, heteroaryl or heterocycle of Z1 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -0Rb, -CN, -NRaC(O)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or NRcRd; each Z2 is independently selected from -N02, -CN, spiro- heterocycle, bridge- heterocycle, spiro-bicyclic carbocycle, bridged—bicyclic carbocycle, (C3-C7)carbocycle, -NRaSOZaryl, -NR3802heteroaryl, ZNRcRd, -NRaSOZO(C3-C7)carbocycle and — NRaSOanryl; WO 45728 each Z3 is independently selected from -N02, -CN, -OH, 0x0, =NORa, thioxo, aryl, heterocycle, oaryl, —(C3-C7)haloca.rbocycle, -O(C1-C6)alkyl, -O(C3-C7)carb0cycle, -Ohalo(C3-C7)carbocycle, -Oaryl, -Oheterocycle, —Oheteroaryl, -S(C1-C6)alkyl, —S(C3- C7)carbocyc1e, -S(C3-C7)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(C1-C6)alkyl, -S(O)(C3-C7)carbocycle, —S(O) (C3-C7)halocarbocycle, —S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SOz(C1-C6)alkyl, —SOz(C3—C7)carbocycle, -SOZ(C3-C7)halocarbocycle, SOzaryl, -SOzheterocycle, —SOzheteroaryl, -NRaRb, -NRaC(O)R4,, -C(O)NRcRd, -SOzNRcRd, -NRaSOzNRcRd, -NRa8020(C3-C7)carbocycle and -NRaSOZOaryl; each Z4 is independently selected from halogen, -(C1-C6)alkyl, (C3-C7)carbocycle, -halo(C1-C6)alkyl, -N02, —CN, —OH, oxo, =NORa, thioxo, -ary1, —heterocycle, -heteroaryl, —(C3- C7)halocarbocycle, -O(C1-C5)alkyl, -O(C3—C7)carbocycle, -O(C3-C7)halocaIbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, C6)alkyl, -S(C3—C7)carbocycle, -S(C3-C7)halocarbocycle, , rocycle, -Sheteroaryl, -S(O)(C1-C5)alkyl, -S(O)(C3—C7)carbocycle, —S(O)(C3- ocarbocycle, -S(O)ary1, -S(O)heterocycle, -S(O)heter0aryl, —SOz(C1-C6)alkyl, -S02(C3- b0cycle, -S02(C3-C7)halocarbocycle, SOzaryl, —SOzheterocycle, teroaryl, -NRaRb, -NRaC(O)Ra, RcRd, -SOzNRcRd, -NR3802NRcRd, -NRaSOZO(C3-C7)carbocycle and — NRaSOZOaryI; each 25 is independently selected from -N02, -CN, -NRa802NRcRd, -NRaSOZO(C3- C7)carb0cycle, -NRaSOanryl, -NRaSOZ(C1-C6)alkyl, -NRaSOz(C2-C6)alkenyl, -NRaS02(C2- C6)alkynyl, -NRaSOZ(C3-C7)carbocycle, -NRaS02(C3-C7)halocarbocycle, -NR3802aryl, -NRaSOZheteraryl, -NRaSOZheteroaryl, -NR3802heterocycle, O)alkyl, -NRaC(O)alkenyl, —NRaC(O)alkynyl, -NRaC(O) (C3-C7)carbocycle, -NRaC(O)(C3-C7)halocarbocycle, -NRaC(O)aryl, -NRaC(O)heteroaryl, -NRaC(O)heterocycle, -NRaC(O)NRcRd and -NRaC(O)ORb; each Z6 is independently selected from -N02, -CN, -NRaRa, NRaC(O)Rb,-C(O)NRcRd, -(C3-C7)halocarbocycle, -aryl, —heteroaryl, -heterocycle, -Oary1, roaryl, -Oheterocycle, —O(C3—C7)halocarbocycle, -O(C1-C6)alkyl, -O(C3-C7)carbocycle, -Ohalo(C1-C6)alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C3—C7)halocarbocycle, -S(C1—C6)alkyl, —S(C3-C7)carbocycle, C6)haloalkyl, ryl, -S(O)heteroaryl, -S(O)heterocycle, -S(O)(C3-C7)halocarbocycle, -S(O)(C1-C6)alkyl, -S(O)(C3-C7)carbocycle, -S(O)halo(C1—C6)alkyl, -SOzary1, -S02heteroaryl, 3O -SOzheterocycle, -SOz(C1-C6)alkyl, -SOzhalo(C1-C6)alkyl, -SOz(C3—C7)carbocycle, -SOz(C3- ocarbocycle, -SOzNRcRd, -NRaSOZ(C3-C7)halocarbocycle, 2aryl, -NRaSOZheteraryl, -NRaSOzheteroaryl, -NRaSOzNRcRd, -NRa8020(C3-C7)carbocycle and —NRaSOgOaIyl. each Z7 is independently selected from -N02, =NORa, -CN, -(C1-C6)alkyl-Z12, —(C2- C5)alkenyl-le, -(C2—C6)alkenleH, -(C2-C6)alkynyl—Z12, —(C2-C6)alkynyl-OH, —(c1— lkyl-le, -(C1-C6)haloalkleH, —(C3—C7)carbocycle-Z12, —(C3-C7)carbocycleOH, -(C3- C7)halocarbocycle, -(C1-C6)alkleRcRd, 6)alkleRaC(O)Ra, —(C1—C6)alkleRaSOzRa, aryl, -heteroaIyl, -heterocycle, -O(C1-C6)alkyl-le, -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, -O(C1- C6)haloalkyl, C7)carbocycle, -O(C3-C7)halocarbocycle, —Oaryl, -O(C1-C6)alkleRcRd, C6)alkleRaC(O)Ra, -O(C1-C6)alkleRaSOgRa, -Oheteroaryl, -Oheterocycle, -S(C1— C6)alky1-le, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C1-C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S(C1-C6)alkleRcRd, C6)alkleRaC(O)Ra, -S(C1- C6)alkleRaSOzRa, —Saryl, -Sheteroaryl, —Sheterocycle, -S(O)(C1-C6)alkyl, -S(O)(C2- C6)alkenyl, -S(O)(C2-C6)alkynyl, -S(O)(C1—C6)haloalkyl, —S(O)(C3—C7)carbocyle, -S(O)(C3— C7)halocarbocycle, -SOZ(C1-C6)alkyl, -S(O)(C1-C6)alkleRcRd, -S(O)(C1~C6)alkleRaC(O)Ra, — S(O)(C1-C6)alkleRaSOzRa, —S(O)aryl, -S(O)heteroaryl, eterocycle, -SOz(C1-C6)alkyl, -SOz(C2-C6)alkenyl, -SOz(C2—C6)alkynyl, —SOz(C1-C(,)haloalkyl, -SOz(C3—C7)carbocycle, - SOz(C3-C7)halocarbocycle, -SOzaryl, -SOzheteroaryl, -SOzheterocycle, -SOZ(C1-C6)alkleRcRd, -SOg(C1-C5)alkleRaC(O)Ra, -SOZ(C1—C6)alkleRaSOzRa, -SOzNRcRd, —NRaC(O)ORb, -NRaC(O)NRcRd, 2Rb, -NRaSOzNRcRd, -NRaS020(C3-C7)carbocycle, -NRaSOanryl, -OS(O)2Ra, -C(O)NRCRd, and -OC(O)NRCRd, n any (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3—C7)carbocycle, (C3-C7)halocarbocycle, aryl, heteroaryl or heterocycle of Z7 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, —NRaC(O)2Rb, —heteroaryl, ocycle, -Oheteroaryl, -Oheterocycle, eroaryl, —NHheterocycle, or —S(O)2NRcRd. each 28 is independently selected from -N02 or —CN; each 29 is independently selected from -(C1-C6)alkyl, -O(C1-C6)alkyl; each Z10 is independently selected from i) halo, oxo, thioxo, (C2-C6)alkenyl, (C1—C6)haloalkyl, (C3- C7)cycloalkyl, )cycloalkyl-(C1-C6)alkyl-, —OH, -O(C1- C6)alkyl, -O(C1—C6)haloalkyl, -SH, -S(C1-C6)alkyl, -SO(C1— C6)alkyl, 1-C6)alkyl, -NH2, -NH(C1-C6)alkyl and -N((C1—C6)alkyl)2; ii) (C1-C6)alkyl optionally substituted with ~OH, -O-(C1-C6)haloalkyl, or -O- (C1—C6)alkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, cycle and heteroaryl is optionally substituted with halo, (C1—C6)alkyl or COOH; each 2“ is independently selected from 2‘0, -C(=O)-NH2, —C(=O)-NH(C1—C4)alkyl, -C(=O)-N((C1-C4)alkyl)2, —C(=O)—aryl, -C(=O)-heterocycle and -C(=O)—heteroaryl; PCT/U82012/034593 each Z12 is independently selected from —N02, =NORa, thioxo, -aryl, -heterocycle, —heteroaryl, -(C3-C7)halocarbocycle, —(C3—C7)carbocycle, -O(C3-C7)carbocycle, -Ohalo(C3- bocyle, -Oaryl, —Oheterocycle, -Oheteroaryl, —S(C1-C6)alkyl, -S(C3—C7)ca.rbocyle, -Shalo(C3—C7)carbocyle, —Saryl, -Sheterocycle, —Sheteroaryl, -S(O)(C1-C6)alkyl, C3—C7)carbocyle, -S(O)halo(C3-C7)carbocycle, -S(O)ary1, -S(O)heterocycle, -S(O)heteroaryl, -SOz(C1-C6)alkyl, -SOz(C3-C7)carbocycle, -SOz(C3-C7)halocarbocycle, SOzaryl, terocycle, -SOzheteroaryl, -NRaRa, -NRaC(Q)Rb, -C(O)NRcRd, -SOzNRcRd, -NR3S02NRcRd, -NRaSOzO(C3-C7)carbocyle and -NRaSOanry1; each Z13 is independently selected from -N02, -OH, =NORa, -SH, —CN, -(C3- C7)halocarbocycle, -O(C1-C5)alkyl, -O(C2—C6)alkenyl, -O(C2-C5)alkynyl, —O(C1—C6)haloalkyl, C7)carbocycle, -O(C3-C7)halocarbocycle, , -Oheteroaryl, -Oheterocycle, -S(C1- C6)alkyl, C6)alkenyl, -S(C2-C6)alkynyl, —S(C1-C(,)haloalkyl, -S(C3-C7)carbocycle, -S(C3- C7)halocarbocycle, —Saryl, -Sheteroaryl, -Sheterocycle, -S(O)(C1-C6)alkyl, -S(O)(C2-C6)alkenyl, -S(O)(C2-C6)alkynyl, C1-C6)haloalkyl, -S(O)(C3—C7)carbocycle, -S(O)(C3- C7)halocarbocycle, -S(O)ary1, -S(O)heteroaryl, —S(O)heterocycle, 1-C6)alkyl, -SOz(C2- C6)alkenyl, 2-C6)alkynyl, -SOz(C1-C6)haloalkyl, -SOZ(C3-C7)carbocycle, -SOz(C3- C7)halocarbocycle, —SOzaryl, -SOzheteroaryl, terocycle, —SOzNRcRd, -NRcRd, —NRaC(O)Ra, -NRaC(O)ORb, -NRaC(O)NRcRd -NRaSOsz, -NRaSOZNRcRd, -NRaSOzO(C3- C7)carbocycle, -NRaSOanryl, -OS(O)2Ra, -C(O)Ra, -C(O)0Rb, -C(O)NRcRd, and -OC(O)NRcRd; wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3- C7)halocarbocycle, (C3-C7)carbocycle, (C3—C7)halocarbocycle, aryl, heteroaryl or heterocycle of Z13 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NRaC(O)2Rb, oaryl, —heterocycle, -Oheteroaryl, —Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(O)2NRcRd; each Z14 is independently selected from -N02, =NORa, -CN, -(C3-C7)halocarbocycle, -O(C3-C7)halocarbocycle, -S(C3-C7)halocarbocycle, -S(O)(C3—C7)halocarbocycle, -SOZ(C3- C7)halocarbocycle, -NRaSOzNRcRd, -NR38020(C3~C7)carbocycle, -NRaSOanryl, —OS(O)2Ra; wherein any -(C3-C7)halocarbocycle of Z14 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NRaC(O)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, rocycle, -NHheteroaryl, -NHheterocycle, or -S(O)2NRcRd; each R2, is independently H, (C1-C6)alkyl, -(C2-C6)alkenyl, —(C2—C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, aryl(C1-C5)alkyl-, heteroaryl or heteroaryl(C1-C5)alkyl-; wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, )carbocycle, heterocycle, aryl, or heteroaryl of Ra is optionally substituted by halogen, OH and cyano; WO 45728 each Rb is independently -(C1-C6)alky1, —(C2-C6)alkenyl, -(C2-C5)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, ary1(C1-C(,)alkyl-, heteroaryl or heteroaryl(C1-C6)alkyl—; wherein any (C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, or heteroaryl of Rb is optionally substituted by halogen, OH and cyano; Rc and Rd are each ndently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, aryl, ary1(C1—C6)alkyl-, heterocycle, heteroaryl or heteroaryl(C1—C6)alkyl- wherein any (C1-C6)alkyl, ~(C2-C5)alkenyl, -(C2-C6)a1kynyl, )carbocycle, heterocycle, aryl, or heteroaryl of R0 or Rd is optionally substituted by halogen, OH and cyano; or Rc and Rd together with the nitrogen to which they are attached form a heterocycle; wherein any hetereocycle of Rc and R4 together with the nitrogen to which they are attached is ally substituted by halogen, OH or cyano; each R3 is independently selected from -ORa, (C1-C6)alky1 or )carbocycle wherein (C1-C6)alky1 or (C3-C7)carbocycle is substituted by one or more Z6 and optionally substituted with one or more Z1; -(C2-C6)haloalkyl, -(C2-C(,)alkenyl, or -(C2-C6)alkyny1 wherein any haloalkyl, alkenyl or alkynyl is optionally substituted with one or more Z1; aryl, heterocycle or heteroaryl wherein aryl, heterocycle or heteroaryl is substituted by one or more Zs; each Rf is independently selected from -R& -ORa, —(C1—C6)alkyl-Z6, -SOzRg, g, C(O)ORg, or -C(O)NReRg; and each Rg is independently selected from (C1-C6)alkyl, )carbocycle )haloalkyl, (C2-C6)alkenyl, (C2-C6)a1kynyl, aryl, heterocycle or heteroaryl n any (C1-C6)alkyl, (C3-C7)carbocycle -(C1-C6)haloalky1, (C2-C6)alkenyl, )alkynyl, aryl, heterocycle or heteroaryl of Rg is optionally substituted with one or more 21 groups; or a salt thereof.
In one embodiment, the compounds of formula I are selected from: and salts thereof.
In one embodiment, the compounds of a I are selected from: WO 45728 WO 45728 WO 45728 WO 45728 and salts thereof.
In one ment, the compounds of formula I are selected from: WO 45728 WO 45728 WO 45728 WO 45728 WO 45728 WO 45728 and salts thereof.
In another embodiment, the compounds of formula I are ed from: and salts thereof.
General S nthetic Procedures Schemes 1, 2, 3, 4, 5, 6 and 7 are provided as further embodiments of the invention and illustrate general methods which were used to prepare compounds of formula I and which can be used to prepare additional compounds of formula I.
Scheme 1 °\ KSCNv Br2v S O\ HZN—<\ 1 ‘ H PO NaNO 8 0\ 3 4| 2 HOAC' rt N <\ H2N R2 2. HZPOZ N R2 R1 R1 R1 1A ‘ X—R4 BBr3, <\S Brz, » 0“ Pd PPh K CO DCM N <3\ R2 HOAC , , 2 3 N R2 E/H:)6 R1 HCI “3 15 (X = boronic acid, halogen) 4 4 R R R4 Bu3Sn/\ s 0H szo, s OTf s \ <\ <\ PdCl2(PPh3)2 <\ N R2 Pyr, DCM N R2 DMF, 120 °C N R2 R1 R1 R1 ‘BuOAc HCIO4 CF03, H5|05 ___—.—————-.> wet ACN Scheme 2 S O\ R —X - - S O\ H2N—<\ t-butyInItrIte, Br—<\ N R2 CuBrz, ACN N R2 K3PO4, PdCIzdppf R1 R1 dioxane (X = boronic acid, n) S 0\ R5—<\ N R2 23 2C The benzothiazole intermediate 2B can be converted to the final compound 2C by the methods used to convert 1C to IM as outlined in Scheme 1.
Scheme 3 3 O\ NBS S O\ R4—x H2N—<\ ’ H2N—<\ N R2 st04 N R2 Pd(PPh3)4. K2003, R1 R‘ 13 3A DME/Hzo (X = boronic acid, halogen) R4 R4 S O\ t-butylnitrite S O\ RS'X HZN—<\ ’ Br—<\ N R2 CuBrz, MeCN N R2 K3PO4, PdC|2(dppf), R1 R1 DME/HZO 3B 3C (X = boronic acid. halogen) S 0\ R5—<\ ________, N R2 3E 2C The benzothiazole ediate 3E can be converted to the final nd 2C by the methods used to convert 1C to 1D and IF to IM as outlined in Scheme 1.
Scheme 4 R4 R4 S 0\ HNRR S O\ S Br—<\ RRN—(x —> RRN—<\ N R2 N R2 N R R1 3C 4A The benzothiazole intermediate 4A can be converted to the final nd 4B by the methods used to convert 1C to 1D and IF to 1M as outlined in Scheme 1 wherein HNRR represents an HNR9R10, HNRchor a heterocycle (when R and R taken together with the nitrogen to which they are attached form a ring).
Scheme 5 2012/034593 Br Br R KOt—Bu S R3 1. BnOH, NaH S 3 , Cl—<\ H0—<\ 2. H2, Pd/C N N R2 R2 Rex R1 R1 Br R4 S R3 R43(0H)2 S 3 o=< 0—1/ N Pd<PPh3)4. K2003 .N R2 6 R6 R R1 Scheme6 Br Br Br OH szo OTf fiengua 3' \ ADM” 9H _, _, . OH OZN R2 33” OZN R2 Pd°.LiCI. OZN R2 R1 R1 DMF R1 OZN R2 46 4H Br Br _ 9H QJ< PvaI - 0in tBuOAc OPiv H2 : OPiv KSCN Py HCIO4 Pt/C 02N R2 HOAc, Br2 HZN R2 R1 R1 Br OJ< ' OP” 3—3' N NO Cl—-<\S 0in l 1.BnOH,NaH cuor2 N 2. H2, Pd/C KOt-Bu, R4B(OH)2 Rex 3)4, cho3 The benzothiazoline intermediate 4S can be converted to the final compound 4T by the methods used to convert 1C to IM as outlined in Scheme 1. 2012/034593 Scheme 7 Pd°, K2CO3 —> R5_<\S | R5B(OH)2 Pd°, K2003 s R5—<\ | R4B(OH)2 N The benzothiazoline intermediate 4V can be converted to the final compound 4W by the methods used to convert 1C to IM as outlined in Scheme 1.
A specific value for R5 is selected from: a) aryl, heterocycle and aryl, wherein aryl, heterocycle and aryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. l, 2, 3, 4 0r 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and c) aryl, heteroaryl and cycle, wherein aryl, heteroaryl and heterocycle, are each independently tuted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups.
A specific group of compounds of formula I are compounds wherein: R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. l, 2 or 3) Z11 groups; b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl are cycle, are each independently tuted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups; and c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R3, is H.
Another specific group of compounds of formula I are compounds wherein: R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) aryl, heteroaryl and heterocycle, n aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; and c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. l, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; Ry is H; R1 is H; and R2 is H or (C1-C5)alkyl.
Another specific group of compounds of formula I are compounds wherein: R5 is ed from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. l, 2 or 3) Z11 ; b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally tuted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups; R3, is H; R1 is H; R2 is H or )alkyl; and R3 is -O(C1-C6)alkyl.
A specific value for R5 is ed from: a) aryl, heterocycle and heteroaryl, n aryl, cycle and heteroaryl are each optionally tuted with one or more (e.g. 1, 2 or 3) Z11 groups; and b) aryl, heteroaryl and heterocycle, n aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Z1 groups.
A specific group of compounds of formula I are compounds wherein: R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; and b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and cycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R3, is H.
Another specific group of nds of formula I are compounds wherein: R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and aryl are each optionally substituted with one or more (e.g. l, 2 or 3) Z11 groups; and b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. l, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5)Z1groups; R3, is H; R1 is H; and R2 is H or (C1-C6)alkyl.
Another c group of compounds of formula I are nds wherein: R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; and b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R3, is H; R1 is H; R2 is H or (C1-C6)alkyl; and R3 is C5)alkyl.
Another specific value for R5 is aryl, heteroaryl, heterocycle, wherein aryl, heteroaryl and cycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. l, 2, 3, 4 or 5) Zlgroups; Another specific group of compounds of formula I are compounds wherein: R5 is selected from aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and cycle, are each independently substituted with one or more (e.g. l, 2, 3, 4 or 5) Z15 groups and ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; and R3, is H.
Another specific group of compounds of formula I are compounds wherein: PCT/U82012/034593 R5 is ed from aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; R3, is H; R1 is H; and R2 is H or (C1-C6)alkyl.
Another specific group of compounds of formula I are compounds wherein R5 is selected from aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R3, is H; R1 is H; R2 is H or (C1-C6)a1kyl; and R3 is —O(C1-C6)alkyl.
Another specific value for R5 is selected from: a) aryl, wherein aryl is optionally substituted with one or more (e.g. 1, 2 or 3) Z11 ; b) aryl, heteroaryl and heterocycle, n aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and c) aryl, heteroaryl and heterocycle, n aryl, heteroaryl and heterocycle, are each independently tuted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups. r specific group of compounds of formula I are compounds wherein: R5 is selected fiom: a) aryl, wherein aryl is optionally substituted with one or more (e.g. 1, 2 or 3) Z11 35; b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl are heterocycle, are each ndently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; and c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are 3O each independently substituted with one or more (e.g. l, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; R3, is H.
Another c group of compounds of formula I are compounds wherein: R5 is selected from: a) aryl, wherein aryl is optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) aryl, heteroaryl and cycle, wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; and c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; R3, is H; R1 is H; and R2 is H or (C1-C6)alkyl.
Another specific group of nds of a I are compounds n: R5 is selected from: a) aryl, wherein aryl is optionally substituted with one or more (e.g. 1, 2 or 3) Z11 b) aryl, heteroaryl and heterocycle, n aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) 25 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; and c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently tuted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; R3, is H; R1 is H; R2 is H or (C1—C6)alky1; and R3 is -O(C1-C5)alkyl.
Another specific value for R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each ally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z1groups; and 3O c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; each 2“ is independently selected from 21°, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl, -C(=O)-N((C1-C4)alkyl)2, -C(=O)—aryl, -C(=O)-heterocycle and -C(=O)—heteroaryl; wherein each Z10 is independently selected from: W0 2012/145728 PCT/U82012/034593 i) halo, 0X0, thioxo, (C2-C6)alkenyl, (C1-C5)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -OH, -O(C1- C6)alkyl, -O(C1-C5)haloalkyl, -SH, -S(C1—C6)alky1, -SO(C1- C6)alkyl, -SOz(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl and -N((C1-C6)alkyl)2; ii) (C1-C6)alkyl substituted with -OH, —O—(C1-C6)haloalkyl, or -O-(C1- yl; and iii) aryl, heterocycle and aryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C1-C6)alkyl or COOH; and each Z11 is independently selected from Z10, -C(=O)—NH2, -C(=O)-NH(C1-C4)alkyl, -C(=O)—N((C1-C4)alkyl)2, -C(=O)-aryl, -C(=O)-heterocycle and -C(=O)-heteroaryl.
Another specific group of compounds of formula I are compounds wherein: R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and aryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) aryl, heteroaryl and cycle, wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and c) aryl, heteroaryl and cycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) 215 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; R3, is H; each Z10 is independently selected from: i) halo, 0x0, thioxo, (C2-C6)alkeny1, (C1-C6)haloalkyl, (C3- loalkyl, (C3-C7)cycloalkyl-(C1-C6)alky1-, -OH, -O(C1- C6)alkyl, -O(C1-C6)haloalkyl, -SH, -S(C1-C6)alkyl, -SO(C1- yl, -SOZ(C1-C6)alkyl, -NH2, -C6)alkyl and -C6)alky1)2; ii) (C1-C6)alkyl substituted with -OH, -O-(C1-C6)haloalkyl, or -O-(C1- 3O C6)alkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is ally substituted with halo, (C1-C6)alkyl or COOH; and each 2“ is independently selected from 21°, -C(=O)—NH2, -NH(C1-C4)alkyl, -C(=O)—N((C1-C4)alkyl)2, -C(=O)-ary1, -C(=O)—heterocycle and -C(=O)-heteroaryl.
Another specific group of compounds of formula I are compounds wherein: R5 is selected from: a) aryl, cycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; and c) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and cycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15 groups and optionally tuted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; R3" is H; R1 is H; R2 is H or (C1-C6)alkyl; each Z10 is independently selected from: i) halo, oxo, thioxo, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl—(C1-C6)alkyl-, -OH, -O(C1- C6)alkyl, -O(C1—C5)haloalkyl, -SH, -S(C1-C6)alkyl, -SO(C1- yl, -S02(C1—C5)alkyl, -NH2, -NH(C1-C6)alky1 and -N((C1-C6)alkyl)2; ii) (C1-C6)alkyl substituted with -OH, -O-(C1-C6)haloalkyl, or -O—(C1- yl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C1-C6)alky1 or COOH; and each Z11 is independently selected from Z10, -C(=O)-NH2, —C(=O)—NH(C1-C4)alkyl, -C(=O)—N((C1-C4)alkyl)2, -C(=O)—aryl, -C(=O)-heterocycle and -C(=O)-heteroaryl.
Another c group of compounds of formula I are compounds n: R5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z11 groups; b) aryl, heteroaryl and cycle, wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Zlgroups; and c) aryl, heteroaryl and heterocycle, n aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z15"groups and ally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1groups; R33 is H; R1 is H; R2 is H or (C1-C6)alkyl; R3 is -O(C1-C6)a1kyl; each Z10 is independently selected from: i) halo, oxo, thioxo, (C2—C6)alkenyl, (C1-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C5)alkyl-, -OH, -O(C1— C6)alkyl, -O(C1-C6)haloalkyl, -SH, -S(C1—C6)alkyl, -SO(C1- C6)alky1, -SOz(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl and -N((C1-C6)alky1)2; ii) )alkyl substituted with -OH, -O-(C1—C6)haloalkyl, or -O-(C1- C6)alkyl; and iii) aryl, cycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally tuted with halo, (C1-C6)alkyl or COOH; and each 2“ is independently selected from 21°, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl, -C(=O)-N((C1-C4)alkyl)2, -C(=O)—aryl, —C(=O)-heterocycle and -heteroaryl.
Another specific value for R5 is: 2012/034593 PORf; Gd $§ XNCNQ/O % ,E Q}; OE 0% F0 ' ‘h' Q5; ' 8}; 12 "° Go ,Q: .
C50 Q0 Q0 9 @i , CH HQ}; In one embodiment ofthe invention the compound of formula I is selected from a nd of formulas Ia100-Ia145 (e.g. compounds Ia100, IalOl, Ia102, Ia103, Ia104, Ia105, Ia106,1a107,Ia108,Ia109,Ia110,Ia111,Ia112,Ia113,Ia114,Ia115,Ia116,Ia117,Ia118,Ia119, Ia120, Ia121, Ia122, Ia123, Ia124, Ia125, Ia126, Ia127, Ia128, Ia129, Ia130, Ial31, Ia132, Ia133, Ia134, Ia135, Ia136, Ia137, Ia138, Ia139, Ia140, Ia141', Ia142, Ia143, Ia144, Ia145): Ia106 121107 Ia108 WO 45728 O \ / R4R3 Rs' R“R3 R4 R3 R3 °” R3'O 0 3 \ N R20 . 03m Ia109 13110 13111 Ia116 Ia117 /—\ N— _N N \ / R4 R3 R3 R4 R3 R3 3 OH S OH \ O N RZo N . R2 Ia118 Ia119 WO 45728 R4 R3 R3‘ R4 R3 R3‘ s 0H s OH R4 R3 R3' < >—<\ < > <\ s OH N R20 N R20 0 \ 1 R1 N 20 13123 Ia124 —0 Ia125 Go CI R“ R3 R3‘ S OH R4 R3 0 R3' 0 R4 R3 R3' \ S OH 3 OH N R2 \ O \ N , 20 13126 Ia127 Ia128 N R2 — N R R R1 R1 R1 13129 Ia130 Ia131 R4 R3 s OH R3" 046% s 0H N_ N R2 Q \ N 1 R20 R , Ia132 Ia133 \ R4 R3 R3' ‘ O S O” °” \ \ N R20 0 \ / F R4 R3 R3 R4 R3 R3'O —O s OH \ | N R20 , S Ial37 Ia138 \ / R4 R3 R3 R4 R3 R3' s OH O R20 R2 ' Ia139 Ia140 G R R S OH <~ H \ 0 R1 if???” ' Ia14l 121142 \ / R4 R3 R3 R4 R3 R3'O R4 R3 R30 N R20 and Ial43 Ia144 Ia145 and salts thereof.
In one embodiment, the nds of formula I are selected from the compounds of formulas Ia100-Ia145 wherein: R1 is H; R2 is methyl, R3, is H; R3 is —OtBu; and R4 is: and salts thereof.
In r embodiment, the compounds of formula I are selected from the compounds of formulas Ia100-Ia145 wherein: R1 is H; R2 is methyl, R3, is H; R3 is —OtBu; and R4 is: and salts thereof.
In r ment, the compounds of formula I are selected from the compounds of formulas IalOO—Ia145 wherein: R1 is H; R2 is methyl, R3, is H; R3 is —OtBu; and R4 is: and salts thereof.
In another embodiment of the ion, the compounds of formula I are selected from the compounds of formulas Ial OO-Ia145 wherein: R1 is H; R2 is methyl, R3, is H; R3 is —OtBu; and R4 is: and salts thereof.
In one embodiment of the invention the compounds of formula I are selected from the compounds of formulas IalOO-Ia145 wherein R3 is H; R3 is -O(C1-C5)alky1 and the stereochemistry of the carbon g the R3 (-O(C1-C6)alkyl) group is (S).
In another embodiment of the invention the nds of formula I are selected from the compounds of formulas Ial OO-Ia145 wherein R3’ is H; R3 is -O(C1-C6)alkyl and the stereochemistry of the carbon bearing the R3 (-O(C1-C6)alkyl) group is (R).
In one embodiment ofthe invention, the compounds of formula I are selected from: and salts thereof.
Prodrugs In one embodiment, the invention provides for a prodrug of a compound of the invention. The term “prodrug” as used herein refers to any compound that when administered to a biological system generates a compound of the invention that inhibits the replication of HIV (“the active tory compound”). The nd may be formed from the prodrug as a result of: (i) spontaneous chemical on(s), (ii) enzyme catalyzed chemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemical on(s).
“Prodrug moiety” refers to a labile functional group which separates from the active tory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process aard, Hans, n and Application ofProdrugs” in A 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 tion mechanism with the prodrug compounds of the invention include, but are not limited to, amidases, esterases, ial enzymes, olipases, cholinesterases, and ases.
Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A prodrug moiety may include an active metabolite or drug itself.
Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters —CH20C(=O)R99 and acyloxymethyl carbonates —CH20C(=O)OR99 where R99 is C1—C6 alkyl, C1—C6 substituted alkyl, C6—C20 aryl or C5-C20 substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et a1. (1983) J Pharm. Sci. 72: 24; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH20C(=O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH20C(=O)OC(CH3)3.
Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral ilability (De Lombaert et al. (1994) J Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to a ate have also been described (Khamnei and Torrence, (1996) J Med. Chem. 39:4109-4115). Benzyl esters are reported to generate parent onic acids.
In some cases, tuents at the ortho- - position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g. , esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C—O bond to generate phosphoric acid and a quinone methide intermediate.
Examples ofthis class ofprodrugs are described by Mitchell et al. (1992) J Chem. Soc. Perkin Trans. 11 2345; Glazier W0 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene er W0 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonatc drugs. These ers contain an hio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide.
Deesterification or reduction ofthe disulfide generates the free thio intermediate which uently breaks down to the phosphoric acid and episulfide (Puech et a1. (1993) Antiviral Res., 22: 155-174; ia et al. (1996) J Med. Chem. 39: 4958).
Combination Therapy In one embodiment, the invention provides for a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV ion.
In one ment, the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically able salt thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier. For example, the eutic agent used in combination with the nd of the present ion can be any IV agent.
In one embodiment, the invention provides ceutical compositions comprising a compound ofthe present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent selected from the group consisting of HIV se inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV side tors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV ase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drug for treating HIV, and combinations thereof, and a pharmaceutically acceptable carrier.
In another ment, the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent selected from the group ting of: (1) HIV protease inhibiting compounds selected from the group ting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC—126, TMC-114, mozenavir (DMP—450), JE-2147 (AG1776), L—756423, ROO334649, KNI-272, 1, DPC-684, GW640385X, DG17, PPL- 100, DG35, and AG 1859; (2) HIV non-nucleoside inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV—150, and TMC-120, rilpivirene, BILR 355 BS, VRX 840773, UK-453061, and RDEA806; (3) HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, larnivudine, abacavir, vir, elvucitabine, alovudine, MIV—210, i—FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine 4), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), ; (4) HIV nucleotide tors of reverse transcriptase selected from the group consisting oftenofovir, tenofovir disoproxil fumarate, GS-7340 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix) (5) HIV ase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoquuinic acid, derivatives of 3,5-dicafi‘eoquuinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, c acid phenethyl ester, tives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, 8-1360, AR-177, L-870812, and L-870810, raltegravir, EMS-538158, GSK364735C, EMS-707035, MK-2048, BA 011 and dolutegravir; (6) gp41 inhibitors ed from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144; (7) the CXCR4 inhibitor 0; (8) the entry inhibitor SPOIA; (9) the gp120 inhibitor EMS-488043; (10) the G6PD and NADH-oxidase inhibitor immunitin; (11) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004; (12) other drugs for treating HIV selected from the group consisting of BAS-lOO, SPI- 452, REP 9, , TNX-355, DES6, ODN-93, ODN-112, VGV-l, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDXOlO (ipilimumab), PBS 119, ALG 889, and PA-105004O (PA-040).
In another embodiment, the invention provides pharmaceutical itions comprising a compound of the present invention, or a pharrnaceutically able salt thereof, in combination with two, three, four or more onal therapeutic . For example, a compound of the present invention, or a pharmaceutically acceptable salt, thereof, is combined with two, three, four or more onal eutic agents selected from the classes of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse riptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gplZO inhibitors, CCR5 inhibitors, capsid rization inhibitors and other drug for treating HIV. The two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different s of therapeutic agents.
In one embodiment, the invention es for a combination pharmaceutical agent comprising: a) a nd ofthe invention (e.g. a compound of Formula I), or a pharmaceutically acceptable salt, thereof; and b) at least one additional active agent which is suitable for ng an HIV infection.
In another embodiment, the invention provides a combination pharmaceutical agent comprising: a) a compound of the invention (e.g. a compound of Formula I), or a pharmaceutically acceptable salt thereof; and b) at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase tors, gp4l inhibitors, CXCR4 tors, gplZO inhibitors, CCR5 inhibitors, capsid polymerization inhibitors and other drug for treating HIV.
It is also possible to combine any compound of the invention with one or more other active eutic 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.
It is also possible to co-administer a compound of the invention with one or more other active therapeutic agents. Co-administration of a compound ofthe invention with one or more other active therapeutic agents generally refers to aneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective s of the compound of the ion and one or more other active eutic agents are both present in the body of the patient. inistration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages 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 eutic agents. For example, a unit dose of a nd of the invention can be administered 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 ion within seconds or s. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, ed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. 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 administration of a unit dose of a compound of the invention.
The combination y may provide "synergy" and "synergistic effect", 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: (l) co-formulated and administered or delivered simultaneously in a ed formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) PCT/U82012/034593 by some other regimen. When delivered in alternation y, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different ions in separate es. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i. e. serially, whereas in combination therapy, effective dosages oftwo or more active ingredients are administered together.
In yet another embodiment, the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination With a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV se inhibiting compounds, HIV non- nucleoside inhibitors of reverse transcriptase, HIV side inhibitors of reverse transcriptase, HIV nucleotide inhibitors of e transcriptase, HIV integrase inhibitors, gp4l inhibitors, CXCR4 inhibitors, gp120 tors, CCRS inhibitors, capsid polymerization inhibitors, and other drug for treating HIV.
In yet another embodiment, the present application es a method for treating an HIV infection comprising stering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically able salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of: (1) HIV protease inhibiting nds selected from the group consisting of amprenavir, avir, fosamprenavir, indinavir, lopinavir, ritonavir, vir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2l47 6), L-756423, ROO334649, KNI-272, DPC—68l, DPC-684, GW640385X, DGl7, PPL— 100, DG35, and AG 1859; (2) HIV non-nucleoside tors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, pine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-96l, DPC-963, MIV-150, and 0, rilpivirene, BILR 355 BS, VRX 840773, UK—453061, and RDEA806; (3) HIV side inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, i—FTC, D—d4FC, emtricitabine, phosphazide, fozivudine l, apricitibine (AVX754), amdoxovir, KP-l461, and fosalvudine tidoxil (formerly HDP 99.0003), ; (4) HIV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, GS-734O (Gilead Sciences), adefovir, adefovir dipivoxil, CMX—OOl (Chimerix) or CMX-157 (Chimerix) (5) HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoquuinic acid, derivatives of 3,5—dicaffeoquuinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, tin, derivatives of tin, S-1360, AR-177, L-870812, and L-870810, raltegravir, 8158, GSK364735C, EMS—707035, MK-2048, BA 011 and dolutegravir; (6) gp41 inhibitors selected from the group ting of enfuvirtide, sifilvirtide, FBOO6M, and TRI-1144; (7) the CXCR4 inhibitor AMD—O70; (8) the entry inhibitor SPOIA; (9) the gp120 inhibitor EMS—488043; (10) the G6PD and NADH-oxidase inhibitor immunitin; (11) CCR5 inhibitors selected from the group consisting of roc, vicriviroc, roc, PRO-140, INCB15050, PF-232798 (Pfizer), and b004; (12) other drugs for treating HIV selected from the group consisting of BAS-lOO, SPI- 452, REP 9, SP-OlA, TNX-355, DES6, ODN—93, ODN—112, VGV—l, PA-457 (bevirimat), HRG214, 0, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO—OZS, BAY 50—4798, MDXOlO (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040).
Pharmaceutical Formulations The compounds ofthis invention are ated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will n excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally n excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, ing agents such as EDTA, carbohydrates such as dextrin, yalkylcellulose, hydroxyalkylmethylcellulose, 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 administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and ally other therapeutic ients. The carrier(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 routes. The formulations may conveniently be ted in unit dosage form and may be ed by any of the methods well known in the art of pharmacy. Techniques and ations 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 prepared by uniformly and intimately bringing into association the active ingredient with liquid rs or finely divided solid carriers or both, and then, if ary, shaping the product.
Formulations of the present invention suitable for oral administration 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 es; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in—oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded s may be made by g in a suitable machine a mixture of the ed active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are ated so as to provide slow or controlled release of the active ingredient therefrom.
For administration to 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 example, 0.075 to 20% w/w (including active ingredient(s) in a range n 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an nt, the active ingredients may be employed with either a paraffinic or a 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 hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including 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 ed areas. es of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to e both an oil and a fat. Together, the emulsifier(s) with or without izer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the led emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, yl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the d cosmetic properties. 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 dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol r of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, lhexyl palmitate or a blend of branched chain esters known as Crodarnol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties ed. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other l oils are used.
Pharmaceutical formulations according to the present ion comprise one or more compounds ofthe invention together with one or more phannaceutically acceptable carriers or ents and optionally other therapeutic . 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.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one or more agents including ning agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically able excipient which are le for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and ating agents, such as magnesium stearate, stearic acid or talc.
Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay egration and tion in the gastrointestinal tract and y provide a sustained action over a longer period. For example, 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 gelatin capsules where the active ient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft n capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions ofthe invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e. g. , lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. , polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. ecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. sorbitan monooleate). , polyoxyethylene The aqueous suspension may also contain one or more vatives such as ethyl or n-propyl p- hydroxy—benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions may be formulated by ding the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a l oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard n or cetyl alcohol. Sweetening agents, such as those set forth above, and ng agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an idant such as ascorbic acid.
Dispersible powders and granules ofthe invention suitable for preparation of an aqueous sion by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. le dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional ents, for example sweetening, flavoring and ng 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 s oil, a mineral oil, such as liquid n, or a e of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan eate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. 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 ent, a vative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile inj ectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and ding agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable t or solvent, such as a solution in 1,3-butane-diol or prepared 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 addition, sterile fixed oils may conventionally be employed as a solvent or suspending . For this purpose any bland fixed oil may be employed including 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 ation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightzweight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For e, an s on intended for intravenous infusion may contain from about 3 to 500 pg 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. ations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable r, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a tration of 0.5 to 20%, advantageously 0.5 to 10% 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 sing for example cocoa butter or a late.
Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including le sizes in a range n 0.1 and 500 s in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal e or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily ons of the active ingredient. ations suitable for aerosol or dry powder administration may be prepared according to tional methods and may be delivered with other therapeutic agents.
Formulations suitable for vaginal administration may be presented as pessaries, 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, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending 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 addition of the sterile liquid r, for example water for injection, ately prior to use. Extemporaneous injection solutions and suspensions are ed from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate on thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents tional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are ible with the active ingredient. These veterinary compositions may be administered orally, erally or by any other desired route.
Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharrnacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provides compositions sing one or more compounds of the ion formulated for ned or controlled release. ive dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower closes), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
Routes of Administration One or more compounds of the invention (herein referred to as the active ingredients) are stered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, l (including buccal and sublingual), vaginal and eral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It 2O will be appreciated that the preferred route may vary with for example the ion of the recipient. An advantage of the compounds of this ion is that they are orally bioavailable and can be dosed orally.
The antiviral properties of a compound ofthe invention may be determined using Test A described below.
Test A: Antiviral Assays in MT4 Cells For the antiviral assay utilizing MT—4 cells, 0.4 uL of 189X test concentration of 3-fold serially diluted nd in DMSO was added to 40 uL of cell growth medium (RPMI 1640, 10%FBS, 1% penicilline/Streptomycine, 1% L-Glutamine, 1% HEPES) in each well of 384-well assay plates (10 concentrations) in quadruplicate. 1 mL aliquots of 2x10e6 MT-4 cells are pre—infected for l and 3 hrs respectively, @ 37°C with 25 uL (MT4) or of either cell grth medium (mock-infected) or a fresh 1:250 dilution of an HIV-IIIb concentrated ABI stock m.o.i. for MT4 cells). Infected and PCT/U82012/034593 uninfected cells are diluted in cell growth medium and 35 uL of 2000 (for MT4) cells is added to each well of the assay .
Assay plates were then incubated in a 37°C incubator . After 5 days of incubation, 25 ul of 2X concentrated CellTiter—GloTM Reagent (catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added to each well ofthe assay plate. Cell lysis was carried out by ting at room temperature for 2-3 min and then chemiluminescence was read using the Envision reader (PerkinElmer).
Compounds of the present invention demonstrate antiviral activity in this assay (Test A) as depicted in the table below. Accordingly, the compounds ofthe ion may be useful for treating the proliferation of the HIV virus, treating AIDS or delaying the onset ofAIDS or ARC symptoms WO 45728 14b 480 Nr—A 149 NN 170 u: 127 L» O\ 6211 o 722 H 923 N 103 .5; DJ 5090 AA 1&7 45 670 AO\ 163 AA OO\] 26500 A\O 13300 LII O 523 VI '—‘ 5250 U! 534 LIIUI Aw 37500 U‘I U1 53000 U1 ON 62A LII 147 £11 00 3520 WO 45728 U1 \0 149 34510 O’\ H 987 ON 4880 0’\ L») 351 ON 53000 \1O 808 \) p... 984 \l 298 \I\l 43w 522 \1 O'\ 26 \l 00 726 \l\O 45900 0000 Mr— 27400 00 L») 932 0000 (Jr-B 14900 61.7 00 \l 1570 00 00 133 \ON 353 \O\O\O DJ 1420 £11 655 \1 1240 2510 In certain embodiments, the compounds demonstrate an EC50 of < 50 uM. In certain embodiments, the compounds demonstrate an ECSO of< 30 uM. In certain embodiments, the compounds demonstrate an ECSO of< 10 14M. In certain embodiments, the compounds demonstrate an EC50 of < 1 uM.
The specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are t pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or ences in the results are contemplated in accordance with practice of the present invention.
The invention has been bed with reference to various specific and preferred embodiments and techniques. However, it should be tood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
The invention will now be illustrated by the following non-limiting Examples.
Example 1: ation of tert-butoxy-[7-chloro—5-(4-chloro—pheny1)methyl-quinolin—6-yl]- acetic acid (5L): S O\ <\ <8\ 5K 5L (S)tert—butoxy(7—(4-chlorophenyl)—5-methylbenzo[d]thiazol—6-yl)acetic acid (5L): A stock solution ofperiodic acid/chromium trioxide was prepared according to W0 99/52850 by ving periodic acid (11.4g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H20) to a volume of 114 mL. This stock solution (0.090 mL) was added to a solution of tert-butoxy(7-(4-chlorophenyl)methylbenzo[d]thiazolyl)ethanol (5K) (5 mg, 0.013 mmol) in wet acetonitrile (1.0 mL, 0.75% H20) at 0°C. Reaction mixture was stirred for 0.5 hour at 0 °C. Then more stock solution (0.2 ml) was added and the reaction e was stirred for 1h at 0 °C . The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 10 to 95% ACN/H2O + 0.1% TFA). Product lyophilized to give a white powder. 1H-NMR: 300 MHz, ) 8: 9.06 (s, 1H), 7.78 (s, 1H), 7.57—7.42 (m, 4H), 5.16 (s, 1H), 2.52 (s, 3H), 0.86 (s, 9H). LCMS-ESI+: calc’d for C20H20C1N03S: 390.0 (M+H+); Found: 390.1 (M+H+).
Preparation of (S)tert-butoxy(7-(4—chlorophenyl)methylbenzo[d]thiazol-6— yl)ethanol (5K): SELL- Preparation of 6-methoxymethylbenzo[d]thiazolamine (5A): To a on of 4- ymethylbenzenamine (1 .05g, 7.66 mmol) in acetic acid (30 m1) at 0 °C as added KSCN with heavy stirring. The reaction mixture was then stirred at room temperature for 45 min. The on was cooled to 0 °C and bromine was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected, washed by acetic acid, dichloromethane, minimal water and dried under high vacuum to give the product as brown yellow solid. LCMS-ESI+: calc’d for CngoNzOS: 195.0 (M+H+); Found: 195.1 (M+H+).
Preparation of 6-methoxymethylbenzo[d]thiazole (5B): To a solution of 6-methoxy methylbenzo[d]thiazol—2-amine (5A) (1.24g, 6.42 mmol) in H3PO4 (5 mL) at 0 °C, was added NaNOz (2.2 g, 32 mmol) in minimal amount of water. The reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was then transferred to ice-cold hypophosphorous acid (50 %, ml) and slowly warmed to room temperature and stirred at room temperature until evolution ceases. Solid Na2CO3 was added to neutralize the reaction and the mixture was ted by ethyl acetate. The c phase was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ESI+: calc’d for CgHgNOS: 180.0 (M+H+); Found: 180.1 (M+H+). $212; Preparation of 5-methylbenzo[d]thiazol—6-ol (5C): To a suspension of oxy—5- methylbenzo[d]thiazole (5B) (160 mg, 0.89 mmol) in dichloromethane (5 mL) was added boron mide (1 M in dichlorrnethane, 1.8 ml) at 0 °C. The on mixture was stirred at 0 °C for 2 h. The reaction was quenched by adding a saturated NaHCO3 solution, extracted with PCT/U82012/034593 dichlormethane and trace MeOH. The organic layer was dried over MgSO4, d, concentrated and purified by silica gel column (0-100% Ethyl acetate/hexanes). LCMS—ESI+: calc’d for C8H7NOS: 166.0 (M+H+); Found: 166.2 (M+H+).
Preparation of 7-bromo—5-methylbenzo[d]thiazol-6—ol (5D): To a suspension of 5- methylbenzo[d]thiazolol (5C) (140 mg, 0.84 mmol) in acetic acid (5 ml), was added bromine (40 uL) slowly. The reaction mixture was stirred at room temperature for 1 h. The precipitate was collected, washed with acetic acid, water and dried under high vacuum. LCMS—ESI+: calc’d for CgHgBrNOS: 244.0 (M+H+); Found: 244.1 (M+H+).
SEQ.- Preparation of 7-(4-chlorophenyl)methylbenzo[d]thiazolol (5E): The reaction mixture of 7-bromomethylbenzo[d]thiazolol (5D) (90 mg, 0.37 mmol), 4-chlorophenyl boronic acid (86 mg, 0.55 mmol), Pd(PPh3)4 (40 mg, 0.037mmol), K2C03 (153 mg, 1.11 mmol) in 1,2-dimethoxyethane (1 ml)/HzO(0.5 ml) was heated at 110 °C in the microwave for 10 min.
Then the reaction mixture was diluted with water, extracted with ethyl e. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ESI+: calc’d for CMHIOCINOS: 276.0 (M+H+); Found: 276.2 (M+H+).
Preparation of 7-(4-chloropheny1)methylviny1benzo[d]thiazole (5G): To a solution of hlorophenyl)methylbenzo[d]thiazolol (SE) (107 mg, 0.39 mmol) in romethane (3 mL)/pyridine (1 mL) at 0 °C, was added romethanesulfonyl acid ide (130 uL, 0.80 mmol). The reaction mixture was stirred at 0 °C for l h. Then the reaction was quenched by adding saturated NaHCO3 solution, extracted by ethyl ecetate. The organic layer was dried over MgSO4, filtered, concentrated to give 7-(4-chloropheny1) methylbenzo[d]thiazolyl trifluoromethanesulfonate (5F) which was used in next step without purification. 7—(4-chlorophenyl)-5—methylbenzo[d]thiazoly1 trifluoromethanesulfonate (5F) from above reaction was dissolved in DMF (3 ml). ylvinyltin (130 11L), PdC12(PPh3)2 (27 mg, 0.039 mmol) and LiCl (49 mg, 1.17 mmol) were added. The reaction mixture was stirred at 120 °C in microwave for 30 min. The reaction mixture was diluted by ethyl acetate, washed with saturated NaHC03 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, d, concentrated and purified by silica gel column (0-50% ethyl e/hexanes).
LCMs—Esr‘: calc’d for C16H20C1NS: 286.0 (M+H+); Found: 286.1 (M+H+).
Step7.
Preparation of (S)—1-(7-(4-chlorophenyl)—5-methylbenzo[d]thiazolyl)ethane-1,2—diol (51-1): A biphasic mixture ofAD mix-0L (1.5 g) in utanol (5 mL)/HzO (5 mL) was cooled to 0°C and 7-(4-chlorophenyl)methyl-6—vinylbenzo[d]thiazole (5G) (0.050 g, 0.175 mmol) was added. Reaction mixture was d overnight at 0 °C. Sodium sulfite (1.5 g) was added at 0 °C, then warmed to room ature and stirred for 30 min to give a white mixture. e was diluted with ethyl ecetate and H20. Extracted with ethyl ecetate (3x) and combined organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the product.
SF: calc’d for C16H14C1N02S: 320.0 (M+H+); Found: 320.1 (M+H+). m Preparation of (S)(7-(4-chlorophenyl)—5—methylbenzo[d]thiazoly1)hydroxyethyl pivalate (51): To a solution of (S)(7-(4-chlorophenyl)—5-methylbenzo[d]thiazolyl)ethane- 1,2-diol (5H) (0.018 g, 0.056 mmol) in pyridine (0.5 mL)/dichoromethane (1 mL) was added trimethylacetyl chloride (0.010 mL, 0.081 mmol). Reaction mixture was stirred for 1 h at room ature and additional trimethylacetyl chloride (0.020ml 0.081 mmol) was added and left it overnight at room temperature. More trimethylacetyl chloride (0.030 ml, 0.242 mmol) was added to the mixture and stirred at room temperature for 30 min. Reaction mixture was diluted with ethyl acetate. Organic layer was washed with saturated sodium bicarbonate solution, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes)._LCMS-ESI+: calc’d for C21H22C1NO3S: 404.1 (M+H+); Found: 404.1 (M+H+).
Preparation of (S)tert—butoxy(7-(4-chlorophenyl)methylbenzo[d]thiazol yl)ethyl pivalate (SJ): A solution of (7-(4-chlorophenyl)methy1benzo[d]thiazolyl) hydroxyethyl pivalate (51) (0.016 g, 0.040 mmol) and perchloric acid, 70% (6 141, 0.1 mmol) in tert-butyl acetate (1 mL) was stirred at room temperature for 2 h. Reaction mixture was quenched with solid sodium bicarbonate (0.05 g) for 1h. Saturated sodium bicarbonate solution was added and extracted with ethyl e (3x). The combined c layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes)._LCMS-ESI+: calc’d for C25H30C1NO3S: 460.2 (M+H+); Found: 460.2 (M+H+).
M ation of (S)—2-tert-butoxy(7-(4-chlorophenyl)methylbenzo[d]thiazol anol (5K): To a solution of (S)-2—tert-butoxy(7-(4-chlorophenyl) methylbenzo[d]thiazolyl)ethyl pivalate (5.)) (8 mg, 0.0174 mmol) in MeOH (0.5 mL) and THF (1 mL) was added sodium hydroxide (2 M, 0.1 mL, 0.2 mmol) and the reaction mixture was stirred at room temperature overnight. Reaction mixture d with ethyl acetate and washed with saturated sodium bicarbonate solution. Aqueous layer back-extracted with ethyl acetate and combined organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes). LCMS—ESI+: calc’d for C20H22C1Nozs: 376.1 (M+H+); Found: 376.1 (M+H+).
Example 2: Preparation of 2-cyclopropylmethoxy—5-methylbenzo[d]thiazole (6B). mil 2 mi?N8 O\ S 0 5A 6A a W031S O\ Step 1.
To a solution of 2-bromomethoxymethylbenzo[d]thiazole (6A) (720 mg, 2.8 mmol) in dioxane (10 ml), was added cyclopropyl boronic acid (722 mg, 8.4 mmol), ium ate (2.3 g, 10.9 mmol), PdClzdppf (294 mg, 0.40 mmol). The mixture was reacted at 100 °C overnight. The on mixture was cooled to room temperature, washed with water, extracted with EtOAc. The organic phase was combined, dried over MgSO4, filtered, trated and d by silica gel , eluting by 0-50% EtOAc in hexanes. LCMS- ESI+: calc’d for C12H13NOS: 220.1 (M+H+); Found: 220.2 (M+H+). 51.6% Preparation of (2-bromomethoxy—5-methylbenzo[d]thiazole (6A): To a solution of t-butylnitrite (5.17 ml, 43.5 mmol) in acetonitrile (50 ml) was added coppeer (II) bromide (7.2 g, 32.2 mmol) slowly. The reaction mixture was stirred at room temperature for half hour. Then the reaction mixture was put to a 60 °C oil bath and 6-methoxy methylbenzo[d]thiazol-2—amine (5A) (4.2g, 21.76 mmol) was added slowly. The reaction mixture was d at 60 °C for l h. The reaction was cooled to room temperature; washed with water and extracted with EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. LCMS- ESI+z calc’d for CgHgBrNOS: 257.9 (M+H+); Found: 258.0 (M+H+).
Example 3: Preparation of (S)tert-butoxy(7—(4-chlorophenyl)-2,5-dimethylbenzo[d]thiazol— 6-yl)acetic acid (7). nd 7 was synthesized from compound 6A according to the procedure used to prepare compound 6B (except that trimethylboxine was used instead of cyclopropyl boronic acid ) followed by the procedures to t compound SE to compound 5L as outlined in e 1. 1H-NMR: 400 MHz, (CD3OD) 8: 7.69 (s, 1H), 7.65-7.51 (m, 4H), 5.22 (s, 1H), 2.76 (s, 3H), 2.57 (s, 3H), 0.94 (s, 9H). LCMS—ESI+: calc’d for C21H18C1N03: 404.1 (M+H+); Found: 404.1 (M+H+).
Example 4: Preparation of (S)—2—tert-butoxy(7-(4-chlorophenyl)isobutyl methylbenzo[d]thiazolyl)acetic acid (8J) and (S)tert-butoxy—2-(2-isobutylmethyl-7— phenylbenzo[d]thjazolyl)acetic acid (8K).
The mixture of 7-(4-chlorophenyl)methy1—2-(2-methylpropenyl)benzo[d]thiazol 01 (8E) (56 mg, 0.13 mmol), Pd/C (200 mg) in EtOH (5ml) and EtOAc( 5 ml) was stirred at room ature under an atmosphere ofH2 for 30 min, which gave a mixture of 7-(4- chlorophenyl)—2-isobutylmethylbenzo[d]thiazol01 (8F) and 2-isobutylmethyl phenylbenzo[d]thiazolol (8G). The reaction mixture was filtered over celite, concentrated and taken on to next step without purification.
The mixture was converted to a e of compound 8J and compound 8K by the same steps used to convert compound SE to compound 5L as outlined in e 1. The mixture of compounds SJ and 8K were separated by reverse phase HPLC to provide the pure compounds.
Compound 8J: : 400 MHz, (CD30D) 8: 7.72 (s, 1H), .50 (m, 4H), 5.22 (s, 1H), 2.92 (d, J = 3.6 Hz, 2H), 2.58 (s, 3H), 2.17-2.13 (m, 1H), 1.01-0.99 (m, 6H), 0.95 (s, 9H).
LCMs-ESF: calc’d for C21H18C1N03: 446.1 (M+H+); Found: 446.2 .
Compound NMR: 400 MHz, (CD30D) 6: 7.70 (s, 1H), 7.64-7.50 (m, 5H), 5.29 (s, 1H), 2.92 (d, J = 3.6 Hz, 2H), 2.57 (d, J = 0.4Hz, 3H), 2.17-2.13 (m, 1H), 1.01—0.99 (m, 6H), 0.92 (s, 9H). LCMs-Esfz calc’d for C21H18C1NO3: 412.1 (M+H+); Found: 412.2 (M+H+).
Preparation of 7-(4-chlorophenyl)—5-methy1(2-methylpropeny1)benzo [d]thiazol 01 (8E): Preparation of_7-bromomethoxy—5-methylbenzo[d]thiazol—2-amine (8A). To a on of 6-methoxymethylbenzo[d]thiazolamine (5A) (1.0 g, 5.15 mmol) in H2S04 at 0 °C, was added NBS (550 mg, 3.07 mmol). The reaction mixture was stirred at 0 °C for 211. Then the reaction mixture was poured to ice-water, neutralized by 50% KOH solution to pH about 3.
The precipitation was collected, washed by water and dried over high vacuum. LCMS-ESI+: calc’d for cngBeros: 273.0 (M+H+); Found: 273.0 (M+H+). $10—2- Preparation of 7-(4-chlorophenyl)methoxy—5-methylbenzo[d]thiazolamine (8B).
The e of 7-bromomethoxymethylbenzo[d]thiazolamine (8A) (1.72 g, 6.32 mmol), 4-chlorophenyl boronic acid (1.2 g, 7.67 mmol), K2C03 (2.63 g, 18.9 mmol), Pd(PPh3)4 (364 mg, 0.315 mmol) in DME (8 ml) and H20 ( 4m1) was reacted in microwave at 110 °C for 1h. Then 4—chlorophenyl boronic acid (100 mg, 0.64 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol) were added and reacted in microwave at 110 °C for 0.5 h and 120 °C for 20 min. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated down and purified by silica gel column, g by 0-100% EtOAc in hexanes. LCMS-ESI+: calc’d for C15H13C1N20S: 305.0 (M+H+); Found: 305.1 (M+}F).
Sip—3.
Preparation of 2-bromo-7—(4-chlorophenyl)methoxymethylbenzo[d]thiazole (8C).
Compound 8C was synthesized from SR according to the procedure used to prepare compound 6A of Example 2. SP: calc’d for C15H11BrClNOS: 367.9 (M+H+); Found: 368.0 Preparation of 7-(4-chlorophenyl)methoxymethyl(2-methylprop enyl)benzo[d]thiazole (8D). The mixture of 2-bromo(4-chlorophenyl)methoxy benzo[d]thiazole (8C) (0.153 g, 0.417 mmol), 4,4,5,5-tetramethyl—2-(2-methylprop 1,3,2—dioxaborolane (0.256 ml, 1.24 mmol), K3PO4 ( 0.35 g, 1.66 mmol), PdC12(dppt) (45 mg, 0.062 mmol) in DME (1 ml) and H20 ( 0.5ml) was reacted in microwave at 120 °C for 0.5h.
The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in s. LCMS-ESI+: calc’d for C19H18C1NOS: 344.1 (M+H+); Found: 344.1 (M+H+).
M Preparation of 7-(4-chlorophenyl)methyl(2-methylpropenyl)benzo[d]thiazol 01 (8E). Compound SE was synthesized from compound 8D according to the procedure used to prepare compound 5C of Example 1.
LCMs—ESI"; calc’d for C19H16C1NOS: 330.0 (M+H+); Found: 330.2 (M+H+).
Example 5: Preparation of compound (9).
Compound 9 was synthesized from 8C by the method to used convert compound SC to compound 8J as outlined in Example 4, except that tributylvinyltin was used in first the cross coupling reaction according to the procedure used to prepare nd 5G of Example 1. 1H— NMR: 400 MHz, (CD3OD) 8: 7.71 (s, 1H), 7.65—7.51 (m, 4H), 5.22 (s, 1H), 3.11-3.07 (m, 2H), 2.58 (s, 3H), 1.40 (t, J = 7.6 Hz, 3H), 0.94 (s, 9H). SP: calc’d for C21H13C1NO3: 418.1 (M+H+); Found: 418.1 (M+H+).
Example 6: Preparation of compound (10).
Compound 10 was synthesized from compound 8C by the method used to convert compound SC to compound 8J as outlined in Example 4, except that cyclopropylboronic acid, / 5 was used in first the cross coupling reaction. : 400 MHz, (CD30D) 5: 7.63 (s, 1H), 7.61-7.49 (m, 4H), 5.20 (s, 1H), 2.55 (s, 3H), 2.41—2.36 (m, 1H), 1.26-1.22 (m, 2H), 1.14-1.10 (m, 2H), 0.94 (s, 9H).
LCMs—Esr‘: calc’d for C21H18C1NO3: 430.1 (M+H+); Found: 430.1 (M+H+).
Example 7: Preparation of compound 12.
Compound 12 was synthesized from compound 11 according to the ure used to prepare compound 8J from compound 8D as outlined in e 4. 1H-NMR: 400 MHz, (CD3OD) 8: 7.62-7.49 (m, 4H), 7.34 (s, 1H), 5.15 (s, 1H), 3.27 (s, 6H), 2.53 (s, 3H), 0.94 (s, 9H). LCMs-ESI“: calc’d for C21H13C1NO3: 433.1 (M+H+); Found: 433.1 (M+H+).
WO 45728 2012/034593 Preparation of 6-methoxy-N,N,5-trimethylbenzo[d]thiazolamine (11). To a solution of 2—bromo(4-chlorophenyl)methoxy-5—methylbenzo[d]thiazole (8C) (135 mg, 0.37 mmol) in DMF (2 ml), was added dimethylamine in THF (2M, 0.46 ml, 0.92 mmol). The reaction mixture was stirred at 80 °C. After the reaction finished, the reaction was cooled and concentrated. The e was purified by silica gel column, eluting by 0—100% EtOAc in hexanes. LCMS-ESI+: calc’d for C17H17C1N20S: 333.1 (M+H+); Found: 333.1 (M+H+).
Example 8: Preparation ofcompound 14. nd 14 was synthesized from compound 13 according to the procedure used to prepare compound 8J from compound 8D as outlined in Example 4. 1H-NMR: 400 MHz, (CD30D) 8: 7.74 (s, 1H), 7.62-7.50 (m, 4H), 5.22 (s, 1H), 2.58 (s, 3H), 1.61-1.59 (m, 1H), 1.03- 1.01 (m, 2H), 0.94 (s, 1H), 0.91-0.88 (m, 2H). LCMS-ESI+: calc’d for C21H18C1N03: 454.1 (M+H+); Found: 454.1 (M+H+). 14b Compound 14b was obtained as a side-product of Compound 14. 1H-NMR: 400 MHz, (CD30D) 5: 7.99 (s, 1H), 7.64—7.55 (m, 5H), 5.26 (s, 1H), 2.91 (t, J = 3 Hz, 2H), 2.70 (m, 2H), 2.62 (s, 3H), 0.95 (s, 9H).
LCMS-ESF: calc’d for C25H24C1NO4S: 470.1 mm”); Found: 470.1 (M+H+). ation of 2-(2-cyclopropylethynyl)methoxymethy1benzo[d]thiazole (13). To a solution of 2-bromo—7-(4-chlorophenyl)methoxymethylbenzo[d]thiazole (8C) (188 mg, 0.512 mmol) in THF (3ml), was added ethynylcyclopropane (0.09 ml, 1.2 mmol), CuI (10 mg, 0.052 mmol), Et3N (0.36 ml, 2.58 mmol) and PdC12(dppf) (19 mg, 0.026 mmol). The reaction mixture was stirred at 60 °C for 2hs. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes.
LCMS-ESI+: calc’d for C20H16C1NOS: 354.0 (M+H+); Found: 354.1 .
Example 9: ation of (S)tert-butoxy((S)cyclopropyl—7-(2,3-dihydropyrano[4,3,2- de]quinolin—7-yl)—5—methy1benzo[d]thiazol-6—yl)acetic acid (21) and (S)tert-butoxy((R) cyclopropyl(2,3-dihydropyrano[4,3,2-de]quinolinyl)—5-methylbenzo[d]thiazolyl)acetic acid (22).
Br Br Br Mil —»HS OH S OTf S \ N N N 16 O Compounds 21 and 22 were prepared from nds 19 and 20 by the method to used convert compound SJ to compound 5L as outlined in Example 1.
Compound 21: 1H-NMR: 400 MHz, (CD30D) 5: 8.77 (d, J = 3H2, 1H), 7.87-7.80 (m, 3H), 7.40 (d, J = 4.2 Hz, 1H), 5.21 (s, 1H), 4.72-4.68 (m, 2H), 3.64 (t, J = 6Hz, 2H), 2.73 (s, 3H), 2.35-2.33 (m, 1H), 1.23-1.20 (m, 2H), 1.10-1.07 (m, 2H), 0.90 (s, 9H). LCMS-ESI+: calc’d for C21H13C1N03: 489.1 (M+H+); Found: 489.1 (M+H+). nd 22: 1H-NMR: 400 MHz, ) 5: 8.66 (d, J = 2.6 Hz, 1H), 8.13 (d, J = 4 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 4H2, 1H), 2.52 (s, 1H), 4.66 (t, J = 6 Hz, 2H), 3.57 (t, J = 5.8 Hz, 2H), 2.68 (s, 3H), 2.37-2.31 (m, 1H), 1.22-1.19 (m, 2H), 1.08-1.06 (m, 2H), 0.89 (s, 9H).
LCMS-ESI+: calc’d for C21H18C1N03: 489.1 (M+H+); Found: 489.1 (M+H+).
Preparation of compound 19 and compound 20.
S_tep_1_- Preparation of 7«bromocyclopropylmethylbenzo[d]thiazolol (15). Compound 15 was prepared from compound 6B by the method used to prepare compound 5D from compound 5B as outlined in Example 1. LCMS-ESI+: calc’d for 0BI‘NOSZ 284.0 (M+H1); Found: 284.2 (M+H+).
Preparation of 7-bromocyclopropylmethylbenzo[d]thiazolyl trifluoromethanesulfonate (16). To a solution of 7-bromo—2—cyclopropyl methylbenzo[d]thiazolol (15) (500 mg, 1.766 mmol) in DCM (8 m1) and 2,6-1utine (2 ml) at - 78 °C was slowly added trifluoromethanesulfonic anhydride (0.59 ml, 3.51 mmol). The ature was allowed to slowly warm to 0 °C over 2h. The reaction mixture was washed by saturated NaHCO3 solution, extracted with DCM. The organic phase was combined, dry over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. LCMs-EsF: calc’d for C12H9BrF3NO3S2: 415.9 (M+H+); Found: 415.9 (M+H+).
Sig-i ation of 7-bromocyclopropylmethy1vinylbenzo[d]thiazole (17). To a solution of 7-bromocyclopropylmethylbenzo[d]thiazol—6—yl trifluoromethanesulfonate (16) (410 mg, 0.988 mmol) in DMF (4ml), was added tributylvinyltin (0.43 ml, 1.47 mmol), LiCl (125 mg, 2.94 mmol) and PdC12(PPh3)2 ( 70 mg, 0.096 mmol). The on mixture was reacted at 80 °C overnight. The reaction was cooled down, washed by saturated NaHCO3 solution, extracted by EtOAc. The organic phase was ed, dry over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in s.
LCMs-ESF: calc’d for C13H12BrNS: 294.0 (M+H+); Found: 294.1 .
M Preparation of (S)(7-bromocyclopropyl-5—methylbenzo[d]thiazolyl)tert- butoxyethyl pivalate (18). Compound 18 was prepared from compound 17 by the method used to convert compound 5G to compound 5J as outlined in Example 1. LCMS-ESI+: calc’d for C22H3oBI‘N203SE 468.1 (M+H+); Found: 468.2 . 3O M Preparation ofthe (S)-2—tert—butoxy(2-cyclopropyl(2,3-dihydropyrano[4,3,2- dc]quinolinyl)methylbenzo[d]thiazolyl)ethyl pivalate isomers (l9 and 20) . To a solution of (S)(7—bromocyclopropylmethylbenzo[d]thiazolyl)—2-tert—butoxyethyl pivalate (18) (23 mg, 0.047 mmol) in DMA (2m1), was added 2,3-dihydropyrano[4,3,2- nolinylboronic acid ( 25 mg, 0.099 mmol), 2N K2CO3 solution (0.11 ml, 0.22 mmol) PCT/U82012/034593 and Pd(PPh3)4 (6 mg, 0.005 mmol). The reaction mixture was reacted at 85 °C for 2hs. The reaction was cooled down, washed by saturated NaHC03 solution, extracted by EtOAc. The c phase was combined, dry over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. Two s were separated and went through the chemistry sequence as above. LCMS-ESI+: calc’d for C33H38N204S: 559.2 (M+H+); Found: 559.1 .
Example 10. Preparation of (S)((S)(azetidin-l-y1)(2,3-dihydropyrano[4,3,2-de]quinolin- 7-y1)—5-methylbenzo[d]thiazolyl)tert-butoxyacetic acid (35) and (S)—2-((R)—2-(azetidin—1- yl)—7-(2,3-dihydropyrano[4,3,2-de]quinolin—7-yl)methylbenzo[d]thiazol-6—yl)—2-tert- butoxyacetic acid (36).
To a solution of 34 (23 mg, 0.043 mmol) in THF (1 mL) and MeOH (1 mL) was added a solution of NaOH (2 M, ~4OO uL). The reaction mixture was heated at 70 0C for 4 h. The reaction was brought to ~pH 5 with TFA and was then purified by reverse phase HPLC HZO containing 0.1% TFA) to give 6 mg of compound 35 and 10 mg of compound 36.
Compound 35: 1H-NMR: 400 MHz, (CDgOD) 5: 8.75 (d, J = 2.6 Hz, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.72 (d, J = 2.6 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J = 4.0 Hz, 1H), 5.13 (s, 1H), 4.67- 4.65 (m, 2H), 4.17 (t, J = 7.6 Hz, 4H), 3.59-3.58 (m, 2H), 2.66 (s, 3H), 2.52-2.50 (m, 2H), 0.88 (s, 9H). LCMS-ESF; calc’d for N3O4S: 504.2 (M+H+); Found: 504.0 .
Compound 36: lH—NMR: 400 MHz, (CD3OD) 5: 8.67 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.40 (s, 1H), 7.27 (d, J = 4.2 Hz, 1H), 5.18 (s, 1H), 4.60- 4.57 (m, 2H), 4.27 (t, J = 7.8 Hz, 4H), 3.48-3.45 (m, 2H), 2.61 (s, 3H), 2.58-2.54 (m, 2H), 0.80 (s, 9H). LCMS—ESF: calc’d for C23H29N3O4S: 504.2 (M+H+); Found: 504.1 (M+H+).
Preparation of (2S)-ethyl 2-(2-(azetidin—1-yl)(2,3-dihydropyrano[4,3,2-de]quinolin yl)—5-methylbenzo[d]thiazol-6—yl)—2-tert-butoxyacetate (34). $19—1- Preparation of 2-bromomethylcyclohexane-l ,3-dione (24). To a solution of 5-methyl- 1,3-cyclohexanedione (23) (45.4 g, 360 mmol) in acetic acid (540 mL) was added bromine (19.4 mL, 378 mmol) over 5 min. After 30 min of ng (with mechanical stirrer), the reaction mixture was filtered. The solid was left under high vacuum overnight and used in the subsequent step without further purification.
Preparation of 2-aminomethyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one (25). To a solution of 24 in acetic acid (540 mL) was added sodium acetate (44.3 g, 540 mmol) and thiourea (28.8 g, 378 mmol). The reaction mixture was stirred with a mechanical stirrer at 100 °C for 3 h. The reaction mixture was partially concentrated in vacuo. EtOAc was added (500 mL). The mixture was made basic with 1 M NaOH, and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic layers were dried, filtered, and concentrated in vacuo to give 49.3 g of 25, which was taken on without further purification.
LCMs—Esr: calc’d for C3H11N20S: 183.1 (M+H+); Found: 183.1 (M+H+).
SEE; Preparation of 2—bromo—5-methyl—5,6-dihydrobenzo[d]thiazol-7(4H)—one (26). To a solution of 25 (53.9 g, 296 mmol) in MeCN (600 mL) at 0 °C, while mechanically stirred), was added copper (II) bromide (79.2 g, 355 mmol) then t-butyl e (46.8 mL, 355 mmol). The on e was stirred from 0 °C to room temperature over 2 h and was then partially concentrated. EtOAc (400 mL) and a 0.5 M HCl on were added. The layers were separated, and the organic layer was washed with a brine solution. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude product was adsorbed on ~150 g of silica then run through a plug of silica with 40% hexanes to give 58.3 g of 26. 1H—NMR: W0 2012/145728 400 MHz, (CDC13) 8: 3.16 (dd, 1H. J = 18, 4 Hz), 2.66 (m, 2H), 2.47 (m, 1H), 2.34 (dd, 1H, J = 16, 12 Hz), 1.19 (d, 3H, J= 7 Hz). LCMS-ESI+: calc’d for CgHgBrNOS: 245.9 (M+H+); Found: 246.1 (M+H+). $1.11.- ation of 2-bromo—5-methylbenzo[d]thiazol-7—ol (27). To a solution of 26 (7.38 g, .0 mmol) in CC14 (90 mL) was added NBS (5.61 g, 31.5 mmol) and dibenzoyl peroxide (727 mg, 3.0 mmol). The reaction was heated at 90 °C in a sealed reaction vessel for about 4 h. Then DBU (6.73 mL, 45.0 mmol) in CH2C12 (15 mL) was added. The mixture was heated a reflux for min, then a 1 M HCl solution was added. The layers were separated, and the aqueous layer was extracted with CHzClz. The ed organic layers were washed with a brine solution.
The organic layer was then dried, filtered, and concentrated in vacuo. The crude product was adsorbed on ~30 g of silica then run through a plug of silica with 40% EtOAc/hexanes to give .2 g of 27. 1H-NMR: 400 MHz, (CD30H) 8: 7.25 (s, 1H), 6.69 (s, 1H), 2.40 (s, 3H). LCMS- ESI+z calc’d for C8H7BrNOS: 243.9 ; Found: 244.1 (M+H+). $1045.- Preparation of ethyl romohydroxymethylbenzo[d]thiazolyl) hydroxyacetate (28). To a solution of 27 (3.90 g, 16.0 mmol) in CH2C12 (80 mL) at 0 °C was added triethylamine (2.45 mL, 16.8 mmol) then a solution of titanium tetrachloride in CH2C12 (1.0 M, 16.8 mL, 16.8 mmol). After 15 min, ethyl glyoxalate (50% in toluene, 3.49 mL, 17.6 mmol) was added. The reaction mixture was d for 2 h while warming to room temperature.
Water (50 mL) and a saturated solution ofpotassium sodium tartrate (50 mL) were added. The mixture was stirred vigorously for 2 h. The layers were separated, and the aqueous layer was extracted with CH2C12. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was d by column chromatography to give 2.48 g of 28 and recovered ~500 mg of 27. 1H-NMR: 400 MHz, (CD3OH) 8: 7.33 (s, 1H), 5.69 (s, 1H), 4.17 (m, 2H), 2.50 (s, 3H), 1.18 (t, 3H, J = 7 Hz). LCMS—ESI+: calc’d for C12H13BrNO4S: 346.0 (M+H+); Found: 346.1 (M+H+).
SL622- Preparation of ethyl 2—(2-bromo-5—methyl (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)—2—hydroxyacetate (29). To a solution of 28 (2.42 g, 7.00 mmol) in CH2C12 (30 mL) at —78 °C was added triethylamine (1.02 mL, 7.70 mmol) followed by trifluoromethanesulfonic ide (1.24 mL, 7.35 mmol). After 15 min, saturated NH4C1 was added. The layers were ted. The organic layer was dried, filtered, and concentrated in vacuo. The crude al was purified by column chromatography to give 2.17 g of 29. 1H-NMR: 400 MHz, (CDC13) 8: 7.84 (s, 1H), 5.67 (s, 1H), 4.27 (m, 2H), 2.50 (s, 3H), 1.23 (t, 3H, J = 7 Hz). LCMS-ESI+: calc’d for C13H12BrF3N06S2: 477.9 (M+H+); Found: 478.2 (M+H+).
Preparation of ethyl 2-(2-bromomethyl (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)—2-oxoacetate (30). To a on of 29 (9.85 g, 20.6 mmol) in CH2C12 (100 mL) was added Dess-Martin periodinane (9.61 g, 22.6 mmol).
After 30 min, water (75 mL) and saturated Na2S204 solution (75 mL) was added. The mixture was stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with CH2C12. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to give 8.32 g of 30. 1H- NMR: 400 MHz, (CDCl3) 6: 7.91 (s, 1H), 4.40 (q, 2H, J= 7 Hz), 2.49 (s, 3H), 1.39 (t, 3H, J= 7 Hz).
LCMS-ESI+: calc’d for C13H10BrF3N06S2: 475.9 (M+H+); Found: 476.1 (M+H+).
Preparation of (S)-ethyl 2-(2-bromo—5-methyl (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)hydroxyacetate (31). To a solution of 30 (8.30 g, 17.4 mmol) in toluene (70 mL) was added ((R)—2-methyl-CBS-oxazaborolidine (725 mg, 2.61 mmol). The reaction mixture was then cooled to —35 °C and a on of olborane (freshly distilled) (1 M in toluene, 20.9 mL, 20.9 mmol) was added via addition funnel over 30 min. The reaction was stirred for 20 min while warming to -20 °C. A 2 M solution ofNa2C03 was added (50 mL). The layers were separated, and the c layer was washed with additional Na2C03 solution (3 x 25 mL). The organic layer was dried, filtered, and concentrated in vacuo to give 31, which had analytical data to match 29. The compound was taken on to the next step without further purification.
Preparation of hyl 2-(2-bromomethyl oromethylsulfonyloxy)benzo[d]thiazolyl)tert—butoxyacetate (32).
To a solution of 31 (~17 mmol) in t-butylacetate (70 mL) was added oric acid (1.23 mL, .4 mmol). After 3 h, water was added (50 mL). The layers were separated. The organic layer was washed with a saturated solution O3. The organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 7.22 g of 32 and 1.58 g of 31. 1H-NMR: 400 MHz, (CD3OH) 8: 7.82 (s, 1H), 5.59 (s, 1H), 4.08-4.25 (m, 2H), 2.55 (s, 3H), 1.20 (s, 9H), 1.16 (t, 3H, J= 7 Hz).
LCMs—ESF: calc’d for C17H20BrF3N0682: 534.0 ; Found: 534.1 (M+H+).
Preparation of (S)—ethy1 2-(2-(azetidiny1)methy1 (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)tert-butoxyacetate (33). To a solution of 32 (50 mg, 0.094 mmol) in THF (1 mL) was added azetidine (20 uL). The reaction mixture was heated at 70 °C for 30 min. A saturated solution of NH4C1 (3 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer were dried, filtered, and concentrated in vacuo. The crude material was d by column chromatography (EtOAc/hexanes) to give 38 mg of 33. LCMS-ESI+: calc’d for C20H25F3N20682: 511.1 (M+H+); Found: 511.0 (M+H+).
Preparation of (ZS)-ethy1 2-(2-(azetidinyl)(2,3—dihydropyrano[4,3,2-de]quinolin—7- yl)methylbenzo[d]thiazolyl)tert-butoxyacetate (34). To a solution of 33 (38 mg, 0.075 mmol) in freshly led DME (1 mL) was added 2,3-dihydropyrar10[4,3,2-de]quinolin ylboronic acid hydrochloride (24 mg, 0.097 mmol), chloro(2-dicyclohexylphosphino—2',6'-’ dimethoxy- 1 , 1 '-bipheny1) [2-(2-aminoethylphenyl)]pa11adium(II) methyl-t—butylether adduct, [SPhos Palladacycle] (5 mg, 0.0075 mmol), and cesium fluoride (46 mg, 0.3 mmol). The reaction mixture was heated in the microwave at 110 °C for 45 min. A ted on of NaHCO3 (3 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer were dried, d, and concentrated in vacuo. The crude material was purified by column tography (EtOAc/hexanes) to give 21 mg of34.
LCMS-ESI+: calc’d for C30H33N304S: 532.2 (M+H+); Found: 532.0 (M+H+).
Example 11. Preparation (S)—2-tert—butoxy—2—((S)carbamoyl(2,3—dihydropyrano[4,3,2- de]quinolinyl)—5-methylbenzo[d]thiazolyl)acetic acid (40). 398 40 Compound 40 was prepared from compound 39. To a solution of nd 39A (200 mg) in CH2C12 (5 mL) was added triethylamine (2 mL) and trifluoroacetic acid anhydride (100 uL). After 3 h, a ted solution ofNH4Cl was added. The layers were ted, and the aqueous layer was extracted with CH2C12. The combined organic layers were dried, filtered, and concentrated in vacuo. A solution of THF and MeOH was added (1:1, 5 mL) followed by NaOH solution (2 M, 200 uL). The reaction mixture was stirred at 45 °C for 6 h. The mixture was made acidic with 1 M HCl. The crude mixture was purified by reverse phase HPLC to give 10.8 mg of compound 40.
Compound 40. 1H-NMR: 400 MHz, (CD3OD) 5: 8.79 (d, J=5.2 Hz, 1H); 8.21 (s, 1H); 7.92 (d, J=8.0 Hz, 1H); 7.87(d, J=6.0 Hz, 1H); 7.46(d, J=8.0 Hz, 1H); 5.27 (s, 1H); .72 (m, 2H); 3.68 (t, J=6.0 Hz, 2H); 2.80 (s, 3H); 0.93 (s, 9H).
LCMS—ESI+: calc’d for C26H25N305S: 492.1 (M+H+); Found: 492.1 (M+H+).
WO 45728 Compound 41 was a by-product in the preparation of 40.
LCMS-ESI+: calc’d for NZOGS: 493.1 (M+H+); Found: 493.1 (M+H+).
Preparation of (S)-ethyl 2-tert-butoxy((S)—2-carbamoyl(2,3-dihydropyrano[4,3,2- de]quinolinyl)—5—methylbenzo[d]thiazolyl)acetate (39).
Preparation of (S)—ethyl 6-(1-tert—butoxy-2—ethoxyoxoethyl)-5—methyl (tn'fluoromethylsulfonyloxy)benzo[d]thiazolecarboxylate (37). To a a solution of (S)-ethyl 2— (2-bromomethyl(trifluoromethylsulfonyloxy)benzo[d]thiazolyl)tert-butoxyacetate (32) (1.07 g, 2.00 mmol) in DMF (10 mL) was added tributyl(l-ethoxyvinyl)stannane (867 mg, 2.40 mmol), copper iodide (38 mg, 0.20 ), and Pd(PPh3)4 (116 mg, 0.10 mmol). The reaction mixture was stirred at 45 °C for 2.5 h. A saturated solution ofNH4Cl was added and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined c layers were dried, d, and concentrated in vacuo. Methanol and CH2C12 (1 :1, 20 mL) added. The mixture was cooled to -78 °C and ozone (03) was bubbled through the solution for about 15 min until the reaction mixture was blue-green. Dimethysulfide (1 mL) was added and the reaction was d at rt for 20 min. The mixture was concentrated in vacuo and purified by column chromatography (EtOAc/hexanes) to give 811 mg of 37. : 400 MHz, ): 5 8.06 (s, 1H), 5.65 (s, 1H), 4.56 (q, J = 7 Hz, 2H), 4.14 (m, 2H), 2.59 (s, 3H), 1.49 (t, J = 7 Hz, 3H), 1.21 (s, 9H), 1.16 (t, J = 7 Hz, 3H). $13—2- Preparation of (S)-ethy1 6-((S)tert-butoxyethoxy—2-oxoethyl)(2,3- dihydropyrano[4,3,2-de]quinolinyl)—5-methylbenzo[d]thiazolecarboxylate (38). To a solution of 37 (807 mg, 1.53 mmol) and CsF (1.02 g, 6.73 rnrnol) in distilled dimethoxyethane (15 mL) was added 2,3-dihydropyrano[4,3,2-de]quinoliny1boronic acid (HCl salt, 770 mg, 3.06 mfirol) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2- aminoethylphenyl)]palladium(II) methyl-t-butylether adduct, [SPhos Palladacycle] (206 mg, 0.31 mmol). The reaction mixture was heated at 110 °C in a sealed tube for 2 h. The reaction was cooled to rt and saturated solution ofNaHCO3 was added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromagraphy (increasing EtOAc w/ 5% MeOH to hexanes) to give 224 mg of 38 and 348 mg of undesired atropisomer. : 400 MHz, ): 6 8.54 (d, J = 4 Hz, 1H), 8.04 (s, 1H), 7.55 (d, J = 8 Hz, 1H), 7.29 (d, J = 4 Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 5.18 (s, 1H), 4.55 (m, 2H), 4.41 (q, J = 7 Hz, 2H), 4.01 (m, 1H), 3.88 (m, 1H), 3.37 (m, 2H), 2.77 (s, 3H), 1.36 (t, J = 7 Hz, 3H), 1.00 (t, J = 7 Hz, 3H), 0.90 (s, 9H).
Preparation of (S)-ethyl 2-tert-butoxy((S)carbamoyl(2,3-dihydropyrano[4,3,2— de]quinolinyl)—5-methylbenzo[d]thiazol—6-yl)acetate (39). To a solution of 38 (224 mg) in MeOH (5 mL) was added NH40H (500 uL). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo to give 220 mg of 39.
LCMs—ESI+ (m/z): [M+H]+ calcd for C28H29N3OSSE 520.2 (M+H+); Found: 520.1, 493.07(M+H+).
Example 12. Preparation of (S)tert—butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin—7- yl)-2—(dimethylamino)—5-methylbenzo[d]thiazol-6—yl)acetic acid (42) and (S)tert-butoxy ((R)(2,3-dihydropyrano[4,3,2-de]quinolinyl)(dimethylamino)methylbenzo[d]thiazol- 6-yl)acetic acid (43).
Compounds 42 and 43 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that dimethylamine was used instead of azetidine) in Example 10.
Compound 42: 1H-NMR: 400 MHz, (CD3OD) 6: 8.76 (d, J=4.8 Hz, 1H); 7.82 (d, J=8.0 Hz, 1H); 7.73 (d, J=5.2 Hz, 1H); 7.50 (s, 1H); 7.35 (d, J=7.6 Hz, 1H); 5.14 (s, 1H); 4.67 (m, 2H); 3.61 (t, J=5.8 Hz, 2H); 3.13 (s, 6H); 2.66 (s, 3H); 0.89 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H30N3O4S: 492.20 (M+H+); Found: , 493.07(M+H+).
PCT/U82012/034593 Compound 43: 1H—NMR: 400 MHz, (CD3OD) 5 8.67 (d, J= 4.9 Hz, 1H), 8.04 (d, J= 8.1 Hz, 1H), 7.51 (d, J= 4.9 Hz, 1H), 7.45 (s, 1H), 7.30 (d, J: 8.1 Hz, 1H), 5.19 (s, 1H), 4.67 — 4.55 (m, 2H), 3.21 (s, 6H), 2.62 (s, 3H), 0.81 (s, 9H).
SI+ (m/z): [M+H]+ calcd for C27H29N3O4S: 492.20 (M+H+); Found: , 492.96(M+H+).
OTf OJ< / \N 0 Compound 42A: LCMS-ESI+ (m/z): [M+H]+ calcd for C19H25F3N20682: 499.1 (M+H+); Found: 499.0(M+H+).
Compound 4213: 1H—NMR: 400 MHz, (CDC13) 5: 8.75 (d, J = 1.8 Hz, 1H); 7.54 (d, J = 4.0 Hz, 1H), 7.48 (s, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.06 (d, J = 3.8 Hz, 1H), 4.94 (s, 1H), 4.54 (t, J = 5.6 Hz, 2H), 4.00-4.03 (m, 2H), 3.31—3.30 (m, 2H), 3.08 (s, 6H), 2.64 (s, 3H), 1.25-1.27 (m, 3H), 0.88 (s, 9H).
SI+ (m/z): [M+H]+ calcd for C29H33N3O4S: 520.2 (M+H+); Found: 520.0 (M+H+).
Example 13. Preparation of (S)—2-tert-butoxy((S)—7-(2,3-dihydropyrano[4,3,2-de]quinolin yl)—2-(ethyl(methyl)amino)methylbenzo[d]thjazolyl)acetic acid (44).
Compound 44 was prepared from compound 32 according to the procedure used to prepare compound 35 t that methylethylamine was used instead of azetidine) in Example Compound 44: 1H NMR (400 MHz, CD3OD) 5 8.77 (d, J= 5.4 Hz, 1H), 7.82 (d, J: 8.1 Hz, 1H), 7.72 (d, J= 5.3 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J= 8.1 Hz, 1H), 5.14 (s, 1H), 4.67 (t, J= .9 Hz, 2H), 3.59 (t, J= 5.9 Hz, 2H), 3.52 (dd, J= 14.3, 7.1 Hz, 2H), 3.12 (s, 3H), 2.66 (s, 3H), 1.20 (t, J: 7.1 Hz, 3H), 0.90 (s, 9H). SI+ (m/z): [M+H]+ calcd for N3O4S: 506.21 (M+H+); Found: 506.05, 507.00 (M+H+).
Example 14. Preparation of (S)tert-butoxy((S)(diethylamino)—7-(2,3- dihydropyrano[4,3,2-de]quinolin—7—yl)—5-methylbenzo[d]thiazolyl)acetic acid (45). nd 45 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that diethylamine was used instead of azetidine) in Example 10.
Compound 45: 1H NMR (400 MHz, CD3OD) 5 8.90 (s, 1H), 7.90 (d, J= 7.9 Hz, 2H), 7.61 (s, 1H), 7.44 (d, J= 7.9 Hz, 1H), 5.17 (s, 1H), 4.71 (m, 2H), 3.66 (s, 6H), 2.73 (s, 3H), 1.95 (s, 4H), 1.29 (d, J: 5.9 Hz, 6H), 0.90 (s, 8H).
LCMs-ESI+ (m/z): [M+H]+ calcd for C29H34N3O4S: 520.23(M+H+); Found: 520.05, 521.13 (M+H+).
Example 15. Preparation of (S)—2-tert—butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin yl)—2—(isopropyl(methyl)amino)-5—methylbenzo[d]thiazolyl)acetic acid (46) and (S)tert- butoxy((R)—7-(2,3-dihydropyrano[4,3,2-de]quinolinyl)-2—(isopropyl(methyl)amino) methylbenzo[d]thiazolyl)acetic acid (47).
Compounds 46 and 47 were prepared from compound 32 according to the procedure used to prepare nd 35 (except that N—methyl-N-isopropylamine was used instead of azetidine) in Example 10.
Compound 46: 1H-NMR: 400 MHz, (CD3OD) 5 8.76 (d, J= 5.4 Hz, 1H), 7.82 (d, J= 8.2 Hz, 1H), 7.73 (d, J: 5.2 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J: 8.1 Hz, 1H), 5.14 (s, 1H), 4.67 (t, J= .7 Hz, 2H), 4.23 — 4.06 (m, 1H), 3.59 (t, J= 5.8 Hz, 2H), 3.00 (s, 3H), 2.67 (s, 3H), 1.23 (t, J: 6.5 Hz, 6H), 0.89 (s, 9H). LCMs-Esr (m/z): [M+H]+ calcd for C29H34N3O4S: 520.23 (M+H*); Found: 519.95, 521.00 (M+H*).
Compound 47: : 400 MHz, (CD3OD) 5 8.67 (d, J= 4.9 Hz, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.48 (d, J: 4.6 Hz, 1H), 7.44 (s, 1H), 7.28 (d, J: 8.1 Hz, 1H), 5.19 (s, 1H), 4.67 — 4.52 (m, 2H), 4.11 ~ 4.00 (m, 1H), 3.50 — 3.43 (m, 1H), 3.08 (s, 5H), 2.62 (s, 4H), 1.26 (d, J= 6.1 Hz, 6H), 0.80 (s, 9H).
LCMs-ESI+ (m/z): [M+H]+ calcd for N3O4S: 520.23 (M+H+); Found: 520.05, 521 .08(M+H+).
Example 16a. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin yl)(isobuty1(methyl)amino)—5-methylbenzo[d]thiazolyl)acetic acid (48) and (S)tert- butoxy((R)—7—(2,3-dihydropyrano[4,3,2-de]quinolin-7—yl)—2-(isobutyl(methyl)amino)—5- methylbenzo[d]thiazolyl)acetic acid (49).
Compounds 48 and 49 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that N-methyl-N-isobuytlamine was used instead of azetidine) in Example 10.
Compound 48: lH-NMR: 400 MHz, (CD30D) 5 8.77 (d, J: 5.4 Hz, 1H), 7.83 (d, J= 8.3 Hz, 1H), 7.75 (d, J= 5.1 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J= 8.0 Hz, 1H), 5.13 (s, 1H), 4.68 (dd, J = 9.9, 6.0 Hz, 2H), 3.60 (t, J= 6.0 Hz, 2H), 3.27 (m, 2H), 3.13 (s, 4H), 2.66 (s, 3H), 2.08 , 0.89-0.87 (m, 15H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H36N304S: 534.24 (M+H*); Found: 533.9 (M+H+).
Compound 49: 1H-NMR: 400 MHz, (CDgOD) o 8.69 (d, J= 5.0 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.54 (d, J= 4.9 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J= 8.1 Hz, 1H), 5.19 (s, 1H), 4.62 (m, Hz, 2H), 3.50 (t, J= 5.8 Hz, 2H), 3.22 (s, 3H), 2.63 (s, 3H), 2.21 — 2.04 (m, 1H), 0.91 (d, J= 6.6 Hz, 6H), 0.83 (s, 9H). LCMs-ESI+ (m/Z): [M+H]+ calcd for N3O4S: 534.24 (M+H+); Found: 534.04, 535.05 (M+H+).
Example 16b. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin y1)methy1-2—(pyrrolidinyl)benzo[d]thiazoly1)acetic acid (50) and (S)tert-butoxy ((R)(2,3-dihydropyrano[4,3,2-de]quinolinyl)methyl(pyrrolidiny1)benzo[d]thiazol- 6-yl)acetic acid (51).
Compounds 50 and 51 were prepared from compound 32 ing to the procedure used to prepare compound 35 (except that pyrrolidine was used instead of azetidine) in Example 10. nd 50: lH-NMR: 400 MHz, (CD3OD) o 8.76 (d, J= 5.3 Hz, 1H), 7.80 (d, J= 8.1 Hz, 1H), 7.69 (d, J= 5.1 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J= 8.0 Hz, 1H), 5.15 (s, 1H), 9.03 — 0.64 (m, 79H), 4.70 — 4.60 (m, 2H), 3.56 (dd, J: 13.8, 7.7 Hz, 6H), 2.68 (s, 3H), 2.10 (t, J= 6.7 Hz, 4H), 0.89 (s, 10H). LCMs-ESI+ (m/z): [M+H]+ calcd for C29H32N3O4S: 518.21 ; Found: 517.99, 518.97(M+H+).
Compound 51: lH-NMR: 400 MHz, (CDgOD) 6 8.67 (d, J: 4.7 Hz, 1H), 8.01 (d, J= 8.1 Hz, 1H), 7.46 (d, J= 4.8 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J= 8.1 Hz, 1H), 5.20 (s, 1H), 4.68 — 4.50 (m, 2H), 3.57 (s, 3H), 3.45 (t, J= 5.8 Hz, 2H), 2.63 (s, 4H), 2.14 (t, J= 6.3 Hz, 4H), 0.79 (s, 9H). LCMs—ESI+ (m/z): [M+H]+calcd for C29H32N3O4S: 518.21 (M+H+); Found: 518.07, 519.07(M+H+).
Example 17. Preparation of (S)—2-tert—butoxy((S)(3,3-difluoroazetidiny1)—7—(2,3- dihydropyrano[4,3,2-de]quinolin—7-yl)methy1benzo[d]thiazoly1)acetic acid (52) and (S)—2- tert—butoxy—Z—((R)-2—(3 ,3 -difluoroazetidiny1)(2,3-dihydropyrano[4,3 ,2—de]quinolinyl)-5 - methylbenzo[d]thiazol-6—yl)acetic acid (53).
Compounds 52 and 53 were prepared from compound 32 according to the procedure used to prepare nd 35 (except that 2,2—difluoroazetidine was used instead of azetidine) in Example 10.
Compound 52: lH-NMR: 400 MHz, (CDgOD) 8 8.80 (d, J= 5.6 Hz, 1H), 7.87 (d, J= 8.2 Hz, 1H), 7.83 (d, J= 5.6 Hz, 1H), 7.61 (s, 1H), 7.41 (d, J= 8.2 Hz, 1H), 5.17 (s, 1H), 4.76 — 4.64 (m, 2H), 4.56 — 4.43 (m, 4H), 3.65 (t, J= 5.9 Hz, 2H), 2.69 (s, 3H), 0.91 (s, 9H). 191? NMR (377 MHz, CD3OD) a -77.88 (s). LCMs-ESI+ (m/z): [M+H]+calcd for C28H28F2N3O4S: 540.18 (M+H+); Found: 539.96, 540.96 (M+H+).
Compound 53: 1H-NMR: 400 MHz, (CD3OD) 8 8.71 (d, J = 5.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.69 (d, J= 5.4 Hz, 1H), 7.57 (s, 1H), 7.40 (d, J= 8.2 Hz, 1H), 5.21 (s, 1H), 4.72 — 4.60 (m, 2H), 4.56 — 4.42 (m, 4H), 3.58 (t, J= 6.0 Hz, 2H), 2.65 (s, 3H), 0.91 (s, 9H). LCMS— 1381+ (m/z): [M+H]+ calcd for C23H23F2N304S: 540.18 (M+H+); Found: 539.98, 541.02 .
Example 18. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin—7- y1)(3 -methoxyazetidin—1-yl)methylbenzo[d]thiazol-6—yl)acetic acid (54) and (S)—2-tert- butoxy((R)—7-(2,3—dihydropyrano[4,3 ,2-de]quinolin—7—yl)(3 -methoxyazetidin-1 — methylbenzo[d]thiazolyl)acetic acid (55).
Compounds 54 and 55 were ed from compound 32 according to the procedure used to prepare compound 35 (except that 2-methoxyazetidine was used instead of azetidine) in Example 10.
Compound 54: 1H-NMR: 400 MHz, (CD30D) 5: 8.78 (d, J= 5.5 Hz, 1H), 7.84 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 6.1 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J= 7.8 Hz, 1H), 5.16 (s, 1H), 4.73 — 4.64 (m, 2H), 4.41 (ddd, J= 9.9, 6.2, 3.4 Hz, 1H), 4.31 (td, J= 7.7, 1.0 Hz, 2H), 4.02 — 3.90 (m, 2H), 3.62 (t, J: 5.7 Hz, 2H), 2.68 (s, 4H), 0.91 (s, 11H). LCMs-ESI+ (m/z): [M+H]+ calcd for C29H32N3058: 534.21 (M+H+); Found: , 534.97(M+H*). nd 55: 1H-NMR; 400 MHz, (CD3OD) 8 8.67 (d, J= 5.1 Hz, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.52 (d, J= 4.7 Hz, 1H), 7.43 (s, 1H), 7.30 (d, J= 8.1 Hz, 1H), 5.19 (s, 1H), 4.66 — 4.56 (m, 2H), 4.42 (m, 1H), 4.38 — 4.32 (m, 2H), 4.08 — 4.01 (m, 2H), 3.49 (t, J= 6.0 Hz, 3H), 2.61 (s, 3H), 0.82 (s, 10H). LCMs-ESI+ (m/z): [M+H]+calcd for C29H32N3Oss: 534.21 (M+H+); Found: 534.03, 535.08 (M+H+).
Example 19. Preparation of (S)—2-tert-butoxy((S)-7—(2,3-dihydropyrano[4,3,2-de]quinolin—7— yl)(3-fluoroazetidinyl)methylbenzo[d]thiazolyl)acetic acid (56).
Compound 56 was prepared from compound 32 according to the procedure used to e compound 35 (except that 2-fluoroazetidine was used instead of azetidine) in Example PCT/U82012/034593 Compound 56: lH-NMR: 400 MHz, (CD30D) 5 8.79 (d, J= 5.5 Hz, 1H), 7.85 (d, J: 8.1 Hz, 1H), 7.79 (d, J= 5.1 Hz, 1H), 7.55 (s, 1H), 7.39 (d, J: 7.9 Hz, 1H), 5.58 — 5.38 (m, 1H), .16 (s, 1H), 4.70 (td, J= 5.9, 3.1 Hz, 2H), 4.49 — 4.35 (m, 2H), 4.28 — 4.12 (m, 2H), 3.63 (t, J= 6.0 Hz, 2H), 2.68 (s, 3H), 0.91 (s, 9H).
LCMs-ESI+ (m/z): [M+H]+ calcd for ngHzoFN304S: 522.19 (M+PF); Found: 521.97, 523.02 (M+H+).
Example 20a. Preparation of tert—butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin-7— methyl(3 -methylazetidinyl)benzo[d]thiazolyl)acetic acid (57).
Compound 57 was prepared from compound 32 ing to the procedure used to prepare compound 35 (except that 2-methylazetidine was used instead of azetidine) in Example Compound 57: lH—NMR: 400 MHz, (CD3OD) 5: 5 8.92 (s, 1H), 7.90 (d, J: 7.6 Hz, 2H), 7.56 (s, 1H), 7.44 (d, J= 7.3 Hz, 1H), 5.18 (s, 1H), 4.73 (s, 2H), 4.48 (s, 2H), 3.99 (s, 2H), 3.68 (s, 2H), 3.12 (m, 1H), 2.73 (s, 3H), 1.35 (d, J: 5.6 Hz, 3H), 0.91 (s, 9H). LCMs-ESI+ (m/z): [M+H]+ calcd for C29H32N3O4S: 518.21(M+H+); Found: 518.09, 519.12(M+H+).
Example 20b. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin y1)-5—methyl—2-(3 -(methylsulfonyl)azetidin-l-yl)benzo[d]thiazolyl)acetic acid (58).
Compound 58 was prepared from compound 32 ing to the procedure used to prepare compound 35 (except that ylsulfonylazetidine was used instead of azetidine) in Example 10.
PCT/U82012/034593 Compound 58: lH-NMR: 400 MHz, ) 8: 1H NMR (400 MHz, cd3od) 5 8.85 (d, J = 5.3 Hz, 1H), 7.89 (t, J= 6.7 Hz, 2H), 7.61 (s, 1H), 7.44 (d, J= 8.1 Hz, 1H), 5.18 (s, 1H), 4.72 (dd, J= 9.0, 6.2 Hz, 2H), 4.59 — 4.35 (m, 5H), 3.01 (s, 3H), 2.72 (s, 3H), 0.92 (s, 9H). LCMS- ESI+ (m/z): [M+H]+ calcd for C29H32N306S: 582.17 (M+H+); Found: 581.95, 583.02(M+H+).
Example 21. Preparation of (S)((S)—2-(((1 xolanyl)methyl)(methyl)amino)—7-(2,3- dihydropyrano[4,3,2-de]quinolinyl)methylbenzo[d]thiazoly1)tert—butoxyacetic acid (59) and (S)-2—((R)—2-(((1,3-dioxolan—2—yl)methyl)(methyl)amino)—7-(2,3-dihydropyrano[4,3,2- nolinyl)-5—methylbenzo[d]thiazol—6—yl)tert-butoxyacetic acid (60).
Compounds 59 and 60 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that 1-(1,3-dioxolanyl)-N—methylmethanamine was used instead of azetidine) in Example 10.
Compound 59: ‘H-NMR: 400 MHz, (CD3OD) 8: 8.81 (d, J = 6 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 7.81 (d, J = 6 Hz, 1H), 7.54 (s, 1H), 7.40 (d, J = 8 Hz, 1H), 5.15 (s, 1H), 5.07 (m, 1H), 4.69 (m, 2H), 3.91 (m, 2H), 3.82 (m, 2H), 3.63 (m, 2H), 3.30 (s, 3H), 2.68 (s, 3H), 0.89 (s, 9H).
LCMS—ESI+ (m/z): [M+H]+ calcd for C30H33N306S: 564.2 (M+H+); Found: 564.1 (M+H+).
Compound 60: : 400 MHz, (CD3OD) 5: 8.70 (d, J = 6 Hz, 1H), 8.09 (d, J = 8 Hz, 1H), 7.60 (d, J = 6 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J = 8 Hz, 1H), 5.19 (s, 1H), 5.07 (m, 1H), 4.65 (m, 2H), 3.92 (m, 2H), 3.83 (m, 2H), 3.53 (m, 2H), 3.23 (s, 3H), 2.63 (s, 3H), 0.85 (s, 9H).
LCMs-ESI+ (m/z): [M+H]+ calcd for C30H33N3068: 564.2 (M+H+); Found: 564.1 (M+H+).
Example 22. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin yl)—2-((2-(dimethylamino)ethyl)(methyl)amino)-5—methylbenzo[d]thiazol—6-yl)acetic acid (61) and (S)—2-tert-butoxy-2—((R)-7—(2,3 -dihydropyrano[4,3,2-de]quinolinyl)((2- (dimethylamino)ethyl)(rnethyl)amino)—5—methylbenzo[d]thiazolyl)acetic acid (62).
Compounds 61 and 62 were prepared from compound 32 according to the procedure used to prepare compound 35 (except that N1,Nl,NZ-trimethylethane-l,2-diamine was used instead of azetidine) in Example 10. \ 61 Compound 61: lH-NMR: 400 MHz, (CD30D) 5: 8.78 (d, J = 6 Hz, 1H), 7.80 (m, 2H), 7.57 (s, 1H), 7.38 (d, J = 8 Hz, 1H), 5.15 (s, 1H), 4.67 (m, 2H), 4.11 (m, 1H), 3.94 (s, 1H), 3.63 (t, J = 6 Hz, 2H), 3.47 (m, 2H), 3.02 (s, 6H), 2.66 (s, 3H), 0.89 (s, 9H). LCMs-ESI+ (m/z): [M+H]+ calcd for C30H36N4O4S: 549.3 (M+H+); Found: 549.0 .
Compound 62: lH-NMR: 400 MHz, (CD30D) a: 8.71 (d, J = 6 Hz, 1H), 8.13 (d, J = 8 Hz), 7.70 (d, J = 6 Hz, 2H), 7.54 (s, 1H), 7.41 (d, J = 8 Hz, 1H), 5.18 (s, 1H), 4.66 (m, 2H), 4.06 (m, 1H), 3.98 (s, 1H), 3.59 (t, J = 6 Hz, 2H), 3.47 (m, 2H), 3.02 (s, 3H), 3.00 (s, 3H), 2.63 (s, 3H), 0.89 (s, 9H).
LCMs—ESI+ (m/z): [M+H]+ calcd for C30H36N4O4S: 549.3 mm) Found: 549.0 (M+H+).
Example 23. Preparation of (2S)(2—(benzyl(methyl)amino)(2,3-dihydropyrano[4,3,2- nolinyl)—5-methylbenzo[d]thiazol—6-yl)tert-butoxyacetic acid (63).
Compound 63 was prepared as a mixture of atropisomers from compound 32 according to the procedure used to prepare compound 35 (except that N-methyl-N—benzylamine was used d of ine) in Example 10.
Compound 63: LCMs-ESI+ (m/z): [M+H]+ calcd for C33H33N3O4S: 568.2 (M+H+); Found: 568.1 (M+H*).
Examle 24. Preparation of tert-butoxy—2-((R)(2,3-dihydropyrano[4,3,2-de]quinolin yl)((2-(dimethylamino)oxoethyl)(methyl)amino)methy1benzo[d]thiazolyl)acetic acid (64). nd 64 was prepared from compound 32 according to the procedure used to prepare compound 35 (except that N,N-dimethyl(methylamino)acetamide was used instead of azetidine) in e 10.
Compound 64: lH-NMR: 400 MHz, (CDgOD) 5: 8.72 (d, J = 6 Hz, 1H), 8.14 (d, J = 8 Hz), 7.70 (d, J = 6 Hz, 2H), 7.48 (s, 1H), 7.41 (d, J = 8 Hz, 1H), 5.19 (s, 1H), 4.66 (m, 2H), 3.58 (t, J = 6 Hz, 2H), 3.42 (s, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.94 (s, 3H), 2.63 (s, 3H), 0.91 (s, 9H).
LCMS-ESF (m/z): [M+H]+ calcd for C30H34N4058: 563.2 (M+H+); Found: 563.1 (M+H+).
Example 25. Preparation of (S)—2-tert-butoxy((S)—7-(2,3-dihydropyrano[4,3,2-de]quinolin yl)methoxy-S-methylbenzo[d]thiazolyl)acetic acid (66).
PCT/U82012/034593 Compound 66: 1H-NMR: 400 MHz, (CD30D) 5: 8.63 (d, J=4.4 Hz, 1H); 7.68 (d, J=8.0 Hz, 1H); 7.54 (s, 1H); 7.38 (d, J=4.8 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 5.08 (s, 1H); 4.58-4.53 (m, 2H); 4.11 (s, 3H); 3.39 (t, J=6.0 Hz, 2H); 2.61 (s, 3H); 0.87 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H27N2058: 479.16 (M+H+); Found: 479.00, (M+H+). 11—»..2621’ —» 2.66—» “moo __1:0 fl“mom Step 1.
Preparation of 2-bromomethylnitrophenyl trifluoromethanesulfonate (65B). To a on of 2-bromo—6-methylm'trophenol (65A) (58.0 g, 250 mmol) in CH2C12 (500 mL) at - 70 0C was added triethylamine (45.3 mL, 325 mmol) then trifluoromethanesulfonic acid anhydride (46.3 mL, 275 mmol). After 20 min, a solution ofHCl was added (0.5 M, 500 mL).
The layers were separated. The organic layer was dried, filtered, and concentrated in vacuo. The crude oil was run through a plug of Si02 and celite with 10% EtOAc in hexanes to give 90 g of 65B. 1H-NMR: 400 MHz, (CDCl3) 5: 8.40 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 2.58 (s, 3H). 831% Preparation of 1-bromomethylnitrovinylbenzene (65C): The reaction mixture of 2-bromomethyl—4—nitrophenyl trifluoromethanesulfonate (65B) (10.1 g, 27.7 mmol), tributylvinyltin (8.18 ml, 27.7 mmol), LiCl (1.4g, 33.2 mmol), PdClzdppf (607 mg, 0.83 mmol) in DMF (50 ml) was reacted at 70 °C for 3h. Then 2N NaOH was added and d at 70 °C for min. The reaction e was cooled down, washed by sat. NaHCOg, extracted by EtOAc, dry over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0— 100% EtOAc in Hexanes to give 65C (1.9 g, 30%). 1H-NMR: 400 MHz, (CDC13) 5: 8.30 (d, J = 0.8 Hz, 1H), 8.03 (d, J = 1 Hz, 1H), .64 (dd, J = 18, 12 Hz, 1H), .74 (d, J = 12 Hz,1H), 5.51-5.46 (d, J = 18 Hz,1H), 2.48 (s, 3H). $2.12; Preparation of (S)(2-bromomethy1nitrophenyl)ethane—1,2-diol (65D): The reaction mixture of 1-bromomethylnitrovinylbenzene (65C) (12.3 g, 50.83 mmol), AD— mix a (71 g) , MeSOzNHz (4.8 g, 50.8 mmol) in t—butyl alcohol/H2O ( 1:1) (200 ml) was stirred at 0 °C for 3 days. Na2303 (~ 6 g) was added to quench the reaction, stirred at rt for 40 min. The reaction mixture was washed by water, extracted by EtOAc, dry over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 6.96 g of 65D and recovered 2.3 g of 65C. 1H-NMR: 400 MHz, (CDC13) 8: 8.25 (d, J = 2 Hz, 1H), 7.98 (d, J = 2 Hz, 1H), 5.55 (m, 1H), 3.93 (dd, J = 11, 9 Hz, 1H), 3.77 (dd, J = 11, 4 Hz), 2.66 (s, 3H).
§LCP_4- Preparation of (S)(2-bromomethyl—4-nitrophenyl)hydroxyethyl pivalate (65E): To a suspension of (S)(2-bromomethyl—4—nitrophenyl)ethane-1,2-diol (65D) (6.96 g, 25.22 mmol) in DCM (100 ml), was added pyridine (5 mL) at 0 °C. To the solution was added pivaloyl chloride (PivCl) slowly at 0 °C. The on mixture was stirred at 0 °C for 5 min, then raised to rt, stirred at rt for 5h. The reaction mixture was washed by sat. NaHCO3, extracted by DCM, dry over MgSO4, filtered, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 9.13 g of 65E. The product taken on without full characterization.
Preparation of (S)(2-bromo—6-methyl—4—nitrophenyl)tert-butoxyethyl pivalate (65F): To a solution of (2-bromomethylnitrophenyl)-2—hydroxyethy1 pivalate (65E) in t-butyl acetate at 0 °C, was added HClO4 loric acid) (5.45 ml) slowly, stirred at 0 °C for min, then the reaction mixture was warmed up to rt and stirred for 3hs. The mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, dry over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65F (9g, 85 %). 1H-NMR: 400 MHz, ) 5: 8.23 (d, J = 1 Hz, 1H), 7.96 (d, J =1.2 Hz, 1H), 5.58-5.54(m, 1H), .25 (m, l H), 4.16-4.12 (m, 1H), 2.71 (s, 3H), 1.154 (s, 9H), 1.151 (s, 9H).
Preparation of (2-aminobromo-5—methylbenzo[d]thiazolyl)—2-tertbutoxyethyl pivalate (65H): To a solution of S)—2—(2—bromomethylnitrophenyl)—2—tert- butoxyethyl pivalate (9 g, 21.63 mmol) in EtOH (50 ml) and EtOAc (50 ml) was added Pt/C ( 1.5g), attached with a balloon of H2. More Pt/ C (500 mg) was added after 3h. Then the reaction mixture was stirred at rt for another 2h. The reaction mixture was filtered over celite, concentrated down to give product (S)(4-aminobromomethylphenyl)tert-butoxyethyl pivalate (65G) and went to next step t purification. To a solution of (S)(4—amino bromomethylphenyl)tert-butoxyethyl te (65G) (21.63 mmol) in HOAc/ THF (80 ml , 1:1) was added KSCN at 0 °C. The reaction e was stirred at 0 °C for 0.5 h. Then Br; was added slowly, reacted at 0 °C. The reaction was quenched by adding sat. NaHSO3, extracted by EtOAc, dried over MgSO4, purified by silica gel column, eluting by 0-40% EtOAc in s to give 65H (2.3 g, 24% over 2 steps). 1H-NMR: 400 MHz, (CD3OD) 8: 7.15 (s, 1H), 5.51 (t, J = 7 Hz, 1H), 4.28 (m, 1H), 4.14 (m, 1H), 2.62 (s, 3H), 1.15 (s, 9H), 1.10 (s, 9H).
LCMS-ESI+: calc’d for C19H27BrN204S: 443.1 (M+H+); Found: 443.1 (M+H+).
Preparation of (S)(7-bromo-2—chloro-5—methylbenzo[d]thiazolyl)—2-tert- butoxyethyl pivalate (651): The reaction mixture of (2-aminobromo methylbenzo[d]thiazolyl)tert-butoxyethyl te (65H) (100 mg, 0.226 mmol), t-butyl nitrite (32 111, 0.271 mmol), CuClz (36 mg, 0.271 mmol) in acetonitrile (1.5ml) was reacted at rt.
The reaction mixture was diluted by EtOAc, washed by water, extracted by EtOAc dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 651 (90 mg, 86 %).
LCMS-ESI+: calc’d for C19H25C1BrNO3S: 462.0 (M+H+); Foundr 462.1 (M+H+).
Preparation of (S)(7-bromomethoxymethy1benzo[d]thiazolyl)tert— butoxyethyl pivalate : The reaction mixture of (S)—2-(7-bromochloro—5- methylbenzo[d]thiazol-6—yl)tert-butoxyethyl pivalate (651) (90 mg, 0.195 mmol), NaOMe in MeOH (25 % wt, 66 ul) in MeOH (3 ml) was heated at 50 °C for 20 min in sealed ave vial. The reaction e was washed by sat. NaHCO3, ted by EtOAc, dried over MgSO4, d, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65J (70 mg, 79 %).
LCMS—ESI+: calc’d for ConngrNO4S: 458.1 (M+H+); Found: 458.1 (M+H+).
Sieri Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolinyl) methoxymethylbenzo[d]thiazolyl)ethyl te (65K): The reaction mixture of (S)(7- bromomethoxymethylbenzo[d]thiazolyl)-2—tert-butoxyethyl pivalate (65K) (70 mg, 0.153 mmol), 2,3-dihydropyrano[4,3,2-de]quinolinylboronic acid hydrochloride (58 mg, 0.23 mmol), 2N K2CO3 ( 380ul), Pd(PPh3)4 (17 mg, 0.015 mmol) in DME (3 ml) was heated at 90 °C overnight. The reaction mixture was washed bysat. NaHC03, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and d by silica gel column, eluting by 0-100% EtOAc in s to give 65K.
LCMs-Esf: calc’d for C31H36N20532 549.2 (M+H+); Found: 549.0 (M+H+).
Preparation of (S)tert-butoxy((S)-7—(2,3 -dihydropyrano[4,3,2-de]quinolinyl) methoxy-S-methy1benzo[d]thiazolyl)etha.nol : The mixture of (S)tert-butoxy—2-((S)—7-(2,3- opyrano[4,3,2-de]quinoliny1)methoxymethylbenzo[d]thiazol—6-yl)ethyl pivalate (65K) (20 mg, 0.036 mmol), 2N NaOH (360 111) in THF/MeOH (1:1, 2 ml) was stirred at 40 °C overnight. The reaction mixture then was washed by sat. NaHC03, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give the product (11 mg).
LCMs-Esr': calc’d for C26H28N204S: 465.2 (M+H+); Found: 465.7 (M+H+).
SEN—1- Preparation of (S)tert-butoxy-2—((S)—7—(2,3-dihydropyrano[4,3,2-de]quinolin—7-yl) methoxy-5—methylbenzo[d]thiazolyl)acetic acid (66): To a solution of (S)tert-butoxy ((S)—7-(2,3 -dihydropyrano[4,3,2-de]quinolinyl)methoxy—5-methylbenzo[d]thiazol-6— yl)ethanol (11 mg, 0.024 mmol) in wet acetonitrile (0.75 % V H20), was added stock solution of H6105/Cr03 (0.439 mmol, 500 111) at 0 °C. After the reaction was finished, the reaction was quenched by adding 1.5 M KZHPO4, extracted by EtOAc, the organic phase was washed by NaH803/brine(1:1), dried over MgSO4, filtered, concentrated down and purified by silica gel column, g by 20-80% EtOAc in hexanes to give 66 (3.1 mg). 1H-NMR: 400 MHz, (CD3OD) 5: 8.63 (d, J=4.4 Hz, 1H); 7.68 (d, J=8.0 Hz, 1H); 7.54 (s, 1H); 7.38 (d, J=4.8 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 5.08 (s, 1H); .53 (m, 2H); 4.11 (s, 3H); 3.39 (t, J=6.0 Hz, 2H); 2.61 (s, 3H); 0.87 (s, 9H)ppm.
LCMS-ESI+ (m/z): [M+H]+ calcd for C26H27N205S: 479.16 (M+H+); Found: 479.00, 480.02(M+H+).
Example 26. Preparation of (S)—2-tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin -dimethy1oxo-2,3-dihydrobenzo[d]thiazolyl)acetic acid (68).
Compound 68: 1H-NMR: 400 MHz, (CDC13) 5: 8.66 (d, J=4.0 Hz, 1H); 7.69 (d, J=8.4 Hz, 1H); 7.29 (d, J=4.0 Hz, 1H); 7.16 (d, J=8.4 Hz, 1H); 6.97 (s, 1H); 4.94 (s, 1H); 4.59 (dd, 11: .2 Hz, J2=9.6 Hz, 2H); 3.44 (s, 3H); 3.39 (t, J=5.6 Hz, 2H); 2.64 (2, 3H); 0.90 (s, 9H). LCMS— ESI+ (m/z): [M+H]+ calcd for C26H27N205S: 479—.16 (M+H+); Found: 479.04, 480.06(M+H+).
Br O/l< Br 0 F : . OPiv S OPIV 3 Mf)? -+ 803.15.” J< J< Br 0 Br 0 Step 1.
Preparation of (S)(2-(benzyloxy)bromomethylbenzo[d]thiazolyl)—2—tert— ethyl pivalate (67A): NaH (415 mg, 10.38 mmol) was added to BnOH, stirred at rt for 0.5 h. The NaOBn solution was transferred to a flask charged with (S)(7-bromochloro-5— benzo[d]thiazoly1)—2-tert—butoxyethyl pivalate (651) (1.6g, 3.46 mmol). The reaction mixture was heated at 60 °C for 45 min. The reaction mixture was washed by sat NaHCOg, extracted by EtOAc, the organic phase was washed by brine, dry over MgSO4, filtered, concentrated down, distilled most NaOH off. The residue was purified by silica gel column, eluting by 0-50% EtOAc in hexanes. : 400 MHz, (CDC13) 6: 7.52-7.24 (m, 6H),5.58 (s, 2H), .45 (m, 1H), 4.35-4.27 (m, 1H), 4.18-4.12 (m, 1H), 2.68 (s, 3H), 1.07 (s, 18H). $13—2- Preparation of (S)—2-(7-bromo-2—hydroxymethy1benzo[d]thiazolyl)tert- butoxyethyl pivalate (67B): The e of (S)—2-(2-(benzyloxy)—7-bromo methylbenzo[d]thiazolyl)tert-butoxyethyl pivalate (67A), Pd/C (800 mg) in EtOAc/EtOH (10 m1, 1:1) was charged into a flask with a H2 balloon, and stirred at rt for 1h. The reaction mixture was filtered over celite, concentrated down, purified by silica gel , eluting by 0- 50% EtOAc in hexanes to give 67B (850 mg). 1H—NMR: 400 MHz, (CDC13) 8: 8.99 (s, 1H), 6.88 (s, 1H), 5.45 (t, J = 7 Hz, 4.26-4.22 (m, 1H), 4.14-4.09 (m, 1H), 2.62 (s, 3H), 1.13 (s, 18H). $13—3- Preparation of (S)(7-bromo-3,5-dimethy1—2—oxo-2,3-dihydrobenzo[d]thiazolyl) tert-butoxyethyl pivalate (67C): To a solution of (S)—2-(7—bromohydroxy benzo[d]thiaz01yl)—2—tert-butoxyethyl pivalate (67B) (40 mg, 0.090 mmol) in THF (lml) was added KOtBu (0.14 ml, 0.135 mmol, 1M in THF) slowly at -78 °C. After 15 min, Mel (8.5 ul, 0.135 mmol) was added at -78 °C and stirred at -78 °C for 15 min. Then the reaction was reacted at rt for 3hs. The reaction mixture was washed by sat. NaHC03, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0- 40% EtOAc in hexanes to give 67C (30 mg, 73%). : 400 MHz, (CDC13) 6: 6.79 (s, 1H), 5.49-5.45 (m, 1H), 4.27-4.23 (m, 1H), 4.14-4.10 (m, 1H), 3.40 (s, 3H), 2.66 (s, 3H), 1.46 (s, 18H). 519% Preparation of (S)tert-butoxy((S)—7—(2,3-dihydropyrano[4,3,2-de]quinolinyl)— 3,5—dimethyloxo-2,3-dihydrobenzo[d]thiazolyl)ethyl te (67D): The reaction mixture of (S)(7-bromo-3,5-dimethyloxo-2,3-dihydrobenzo[d]thiazolyl)tert-butoxyethyl pivalate (67C) (20 mg, 0.044 mmol), 2,3-dihydropyrano[4,3,2-de]quinolinylboronic acid hydrochloride (16.5 mg, 0.066 mmol), 2N K2CO3 (0.12 ml, 0.22 mmol), Pd(PPh3)4 (5.0 mg, 0.0044 mmol) in DME(1 ml) was heated at 120 °C in sealed microwave vial for 3hs. The reaction mixture was washed by sat. , extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-60% EtOAc in hexanes to give the product (15 mg, 62%).
LCMS-ESI+: calc’d for C31H36NZOSS: 549.2 ; Found: 549.0 (M+H+).
The der of the synthesis of compound 68 is analogous to the preparation of compound 66 from compound 65K in example 25.
Example 27. Preparation of compound (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2- de]quinolinyl)isopropoxymethylbenzo[d]thiazolyl)acetic acid (70).
Compound 70: 1H-NMR: 400 MHz, (CDC13) 6: 8.60 (d, J=4.8 Hz, 1H); 7.76 (d, J=7.6 Hz, 1H); 7.57 (s, 1H); 7.28-7.26 (m, 1H); 7.15 (d, J=8.0 Hz, 1H); 5.37-5.30 (m, 1H); 4.97 (s, 1H); 4.61-4.57 (m, 2H); 3.39 (t, J=6.2 Hz, 2H); 2.64 (s, 3H); 1.39 (dd, J1=6.4 Hz, If 14 Hz, 6H); 0.91 (s, 9H).
LCMs-ESI+ (m/z): [M+H]+ calcd for C28H31N2058: 507.19 (M+H+); Found: 507.01, 508.07(M+H+).
Br OJ< Br QJ< i ' s 0in s OPiv HO-<\N I —> o=<N | $13—1- Preparation of (S)—2-(7—bromomethyl—2-oxo((2-(trimethylsilyl)ethoxy)methyl)-2,3— dihydrobenzo[d]thiazol-6—yl)tert-butoxyethyl pivalate (69A): Prepared by the similar method to make (S)(7-bromo-3,5-dimethyl—2-oxo-2,3-dihydrobenzo[d]thiazolyl)—2-tert— butoxyethyl pivalate (67C) in example 26 from 67B using 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) instead of methyl iodide. 1H-NMR: 400 MHz, (CDCl3) 5: 7.05 (s, 1H); 5.53-5.49 (s, 1H), 5.34 (s, 2H), 4.32-4.27 (m, 1H), 4.18-4.14 (m, 1H), 3.66 (t, J = 8 Hz, 2H), 2.68 (s, 3H), 1.19 (s, 18H), 0.97—0.89 (m, 2H), 0.00 (s, 9H). ation of (S)-2—tert-butoxy((S)—7-(2,3-dihydropyrano[4,3,2-de]quinolinyl)—3,5- dimethyloxo-2,3-dihydrobenzo[d]thiazolyl)ethyl pivalate (69B): prepared by the similar method to make 67D from 67C in Example 26.
SP: calc’d for C36H43NZOGSSi: 665.3 (M+H+); Found: 664.9 .
Preparation of (S)tert-butoxy((S)(2,3—dihydropyrano[4,3,2-de]quinolin-7—yl) methyl-2—oxo-2,3-dihydrobenzo[d]thiazoly1)ethy1pivalate (69C): The reaction mixture of WO 45728 (S)—2—tert-butoxy-2—((S)(2,3-dihydropyrano[4,3,2-de]quinolin—7-yl)-3,5-dimethyloxo-2,3- dihydrobenzo[d]thiazolyl)ethyl pivalate (69B) (250 mg, 0.376 mmol), TBAF (1M in THF, 1.1 ml, 1.1 mmol) in DME was heated at 120 °C in sealed microwave vial for 3 h. The reaction mixture was cooled down, washed by sat. NaHC03, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and d by silica gel column, eluting by 0— 100% EtOAc in hexanes to give 69C (30 mg, 15 %).
LCMS-ESI+: calc’d for C30H34N2058: 535.2 (M+H+); Found: 535.0 (M+H+). figu- Preparation of (S)tert—butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolinyl)-2— isopropoxy—S—methylbenzo[d]thiazolyl)ethyl pivalate (69D): The reaction mixture of (S) tert-butoxy-2—((S)(2,3-dihydropyrano[4,3,2-de]quinolin—7-yl)—5—methy1—2-oxo—2,3- dihydrobenzo[d]thiazolyl)ethyl pivalate (69C) (30 mg, 0.056 mmol), Ag2C03 (50% wt on celite, 310 mg, 0.56 mmol), isopropy bromide (160 111, 1.68 mmol) in benzene/DME (1:1, 2 ml) was heated at 70 °C overnight. The reaction mixture was washed by water, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-60% EtOAc in s to give the product (15 mg, 46 %).
LCMS—ESI+: calc’d for C33H40NZOSS: 577.3 (M+H+); Found: 577.0 (M+H+).
The remainder of the synthesis of compound 70 is analogous to the preparation of compound 66 from compound 65K in example 25.
Example 28. ation of (S)tert—butoxy((S)—7-(2,3—dihydropyrano[4,3,2-de]quinolin—7- yl)—5-methyl—2-oxo—3-(2-(trifluoromethyl)benzyl)—2,3-dihydrobenzo[d]thiazol—6-yl)acetic acid (71). nd 71 was prepared from nd 69C according to the procedure used to prepare compound 67C (except that 1-(bromomethyl)(trifluoromethyl)benzene was used instead of methyl iodide) in Example 26, and the remainder of the sis of compound 71 is analogous to the preparation of compound 66 from compound 65K in example 25.
\Interwoven\NRPortbl\DCC\RBR\14260881_1.doc-5/5/2017 Compound 71: 1H-NMR: 400 MHz, (CDCl3) δ: 8.72 (s, 1H); 7.76-7.73 (m, 2H); 7.50 (t, J=7.6 Hz, 1H); 7.42 (t, J=7.4 Hz, 1H); 7.33 (t, J=4.0 Hz, 1H); 7.2 (d, J=8.0 Hz, 1H); 7.13 (d, J=6.8 Hz, 1H); 6.72 (s, 1H); 5.34 (s, 1H); 4.95 (s, 1H); 4.65-4.60 (m, 2H); 3.42 (t, J=5.4 Hz, 2H); 2.52 (2, 3H); 0.88 (s, 9H). 19F NMR (377 MHz, CDCl 3) δ -60.73. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H30F3N2O4S: 623.18 (M+H+); Found: 623.09, 624.09(M+H+).
Example 29. Preparation of (S)((S)benzyl(2,3-dihydropyrano[4,3,2-de]quinolinyl)- -methyloxo-2,3-dihydrobenzo[d]thiazolyl)tert-butoxyacetic acid (72).
Compound 72 was prepared from compound 69C ing to the procedure used to prepare compound 67C (except that benzyl bromide was used instead of methyl iodide) in Example 26, and the remainder of the synthesis of compound 72 is ous to the preparation of compound 66 from compound 65K in example 25.
N O S OH N O Compound 72: 1H-NMR: 400 MHz, (CDCl3) δ: 8.67 (d, J=4.0 Hz, 1H); 7.70 (d, J=8.4 Hz, 1H); 7.37-7.36 (m, 4H); 7.34-7.29 (m, 2H); 7.16 (d, J=8.4 Hz, 1H); 6.92 (s, 1H); 5.21-5.01 (dd, 6 Hz, J2= 79.6 Hz, 2H); 4.92 (s, 1H); 4.63-41.56 (m, 2H); 3.39 (t, J=5.8 Hz, 2H); 2.55 (s, 3H); 0.88 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H31N2O5S: 555.19 (M+H+); Found: 555.08, 556.12 (M+H+).
Example 30. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)methyloxo(3-(trifluoromethyl)benzyl)-2,3-dihydrobenzo[d]thiazolyl)acetic acid (73). nd 73 was prepared from compound 69C ing to the procedure used to prepare compound 67C (except that 1-(bromomethyl)(trifluoromethyl)benzene was used instead of methyl iodide) in Example 26, and the der of the synthesis of compound 73 is analogous to the preparation of compound 66 from compound 65K in e 25.
N O S OH N O Compound 73: 1H-NMR: 400 MHz, (CDCl3) δ: 8.68 (s, 1H); 7.71 (d, J=7.6 Hz, 1H); 7.64 (s, 1H); 7.59 (d, J=6.4 Hz, 1H); 7.51-7.48 (m, 2H); 7.32 (d, J=3.2 Hz, 1H); 7.18 (d, J=7.6 Hz, 1H); 6.87 (s, 1H); 5.25-5.06 (dd, J1= 16Hz, J2= 63.2 Hz, 2H); 4.94 (s, 1H); 4.65-4.59 (m, 2H); 3.43 (t, J=5.2 Hz, 1H); 2.56 (s, 3H); 0.88 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H29N3O4S: 623.18 (M+H+); Found: 623.04, 624.09(M+H+).
Example 31. Preparation of tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)methyloxo(4-(trifluoromethyl)benzyl)-2,3-dihydrobenzo[d]thiazolyl)acetic acid (74).
Compound 74 was prepared from compound 69C according to the procedure used to prepare compound 67C (except that 1-(bromomethyl)(trifluoromethyl)benzene was used instead of methyl iodide) in Example 26, and the der of the synthesis of compound 74 is analogous to the preparation of compound 66 from compound 65K in example 25.
Compound 74: 1H-NMR: 400 MHz, ) 5: 8.67 (d, J=4.4 Hz, 1H); 7.70 (d, J=8.0 Hz, 1H); 7.63 (d, J=8.0 Hz, 1H); 7.46 (d, J=7.6 Hz, 1H); 7.31 (d, J=4.0 Hz, 1H); 6.86 (s, 1H); .25-5.07 (dd, J1=16, J2=56.8 Hz, 2H); 4.93 (s, 1H); 4.63-4.58 (m, 2H); 3.40 (t, J=5.8 Hz, 2H); 2.56 (s, 3H); 0.88 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H30F3N20582 623.18 (M+H+); Found: 623.06, 624.14(M+H+). e 32. Preparation of (S)((S)(azetidin—l-y1)(2,3-dihydropyran0[4,3,2-de]quinolin— 7-y1)fluoromethy1benzo[d]thiazoly1)-2—tert-butoxyacetic acid (76).
Compound 76: lH—NMR: 400 MHz, (CD3OD) 5: 8.65 (d, J=4.4 Hz, 1H); 7.70 (d, J=7.6 Hz, 1H); 7.39 (d, J=4.4 Hz, 1H); 7.16 (d, J=7.6 Hz, 1H); 5.04 (s, 1H); 4.57 (t, J=6.0 Hz, 2H); 4.15—4.10 (m, 4H); 3.41 (t, J=6.0 Hz, 2H); 2.50-2.46 (m, 6H); 0.90 (s, 9H). LCMs-ESI+ (m/z): [M+H]+ calcd for ngHngN3o4s: 522.19 (M+H+); Found: 521.99, 523.00(M+H+). «m? ? 3 OEt S CE —-> HI ”e N N Preparation of (S)-ethyl 2-(2-bromohydroxymethylbenzo[d]thiazolyl)—2-tert- butoxyacetate (75A): To a solution of (S)—ethyl romomethyl—7- (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)tert-butoxyacetate (32): (500 mg, 0.938 mmol) in THF (5ml) was added TBAF (1.0 M in THF, 4 ml) slowly. The reaction mixture was stirred at rt for 1h. The reaction mixture was washed by a mixture of H20 (20 m1) and HOAc(200 ul), extracted by EtOAc, the organic phase was washed by sat. NaHCO3, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75A (380 mg). LCMS—ESI+: calc’d for C16H20BrNO4S: 402.0 (M+H+); Found: 401.9 (M+H+).
Preparation of (S)-ethyl 2-(2-bromofluorohydroxymethylbenzo[d]thiazolyl)— -butoxyacetate (75B): The reaction mixture of (S)-ethyl 2-(2-bromohydroxy-5— methylbenzo[d]thiazoly1)tert-butoxyacetate (~75A) (380 mg, 0.948 mmol), Selectfluor (1.9 g, 4.74 mmol) in itrile (7 ml) was reacted at 0 °C for 5 days. The on mixture was washed by 1.5 M KH2P04, extracted by EtOAc, the organic phase was'dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0—40% EtOAc in hexanes to give 75B (137 mg, 35%). SI+: calc’d for C16H19FNO4S: 420.0 (M+H+); Found: 420.1 (M+H+).
Step 3.
WO 45728 2012/034593 Preparation of (S)—ethyl 2-(2-(azetidin—1-yl)fluorohydroxy- Smethylbenzo[d]thiazol—6-yl)tert-butoxyacetate (75C): Prepared by the similar method to make (S)—ethyl 2-(2-(azetidiny1)methyl-7—(trifluoromethylsulfonyloxy)benzo[d]thiazol yl)—2-tert-butoxyacetate (33) in Example 10. LCMS-ESP: calc’d for C19H25FN204S: 397.2 (M+H+); Found: 397.0 (M+H+).
Preparation of (S)-ethyl 2-(2—(azetidinyl)fluoro—5—methyl (trifluoromethylsulfonyloxy)benzo[d]thiazo1—6-yl)tert-butoxyacetate (75D): The reaction e of S)-ethyl 2—(2-(azetidin—1-yl)—4-fluorohydroxy-5methylbenzo[d]thiazolyl)—2- tert—butoxyacetate (75C) (50 mg, 0.126 mmol), N-phenyl triflimite (90 mg, 0.252 mmol), C52C03 ( 82 mg, 0.126 mmol) in THF (2 ml) was stirred at rt. After the reaction finished, the reaction was washed by sat NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, trated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75D (50 mg, 75%). LCMS-ESP: calc’d for C20H24F4N20682: 529.1 (M+H+); Found: 529.0 (M+H+).
The remainder of the synthesis of compound 76 is analogous to the preparation of compound 35 from compound 33 in example 10.
Example 33. Preparation of (S)tert-butoxy((S)—2-cyclopentenyl(2,3- dihydropyrano[4,3,2-de]quinolinyl)methylbenzo[d]thiazolyl)acetic acid (78) and (S) utoxy((R)cyclopentenyl(2,3-dihydropyrano[4,3,2-de]quinolin—7-yl)—5- methylbenzo[d]thiazol—6-yl)acetic acid (79).
Compound 78: 1H—NMR: 400 MHz, (CD3OD) 8:878 (d, J=5.6 Hz, 1H); 7.99 (s, 1H); 7.90 (d, J=8.0 Hz, 1H); 7.85 (d, J=5.6 Hz, 1H); 7.43 (d, J=7.6 Hz, 1H); 6.58 (s, 1H); 5.23 (s, 1H); 4.72-4.69 (m, 2H); 3.66 (t, J=5.8 Hz, 2H); 2.85-2.83 (m, 2H): 2.76 (s, 3H); 2.56 (m, 2H), 2.07—2.02 (m, 2H); 0.941 (s, 9H).
Compound 79: lH-NMR: 400 MHz, (CD30D) 8:8.71 (d, J=5.2 Hz, 1H); 8.22 (d, J=8.0 Hz, 1H); 7.97 (s, 1H); 7.77 (d, J=6.0 Hz, 1H); 7.47 (d, J=8.0 Hz, 1H); 6.56 (s, 1H); 5.27 (s, 1H); 4.70 (t, J=6.0 Hz, 2H); 3.63 (t, J=6.2 Hz, 2H); 2.84—2.83 (m, 2H); 2.72 (s, 3H); 2.55-2.54 (m, 2H); 2.07-2.03 (m, 2H); 0.94 (s, 9H).
OEt s OEt Br_<N\ l I o W o Preparation of (S)-ethyl 2-tert—butoxy(2-cyclopentenylmethyl (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)acetate (77). To a solution of 32 (100 mg, 0.19 mmol) in toluene (1 mL), l (0.5 mL), water (0.5 mL) was added potassium carbonate (77 mg, 0.56 mmol), cyclopentenylboronic acid (25 mg, 0.22 mmol), and 3)4 (11 mg, 0.0094 mmol). The on mixture was stirred at 90 °C for 2 h. The reaction was cooled to rt and diluted with water and EtOAc. The layers were separated, dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 96 mg of 77. lH-NMR: , (CDC13) 8: 7.82 (s, 1H), 6.72 (m, 1H), 5.60 (s, 1H), 4.17 (m, 1H), 4.11 (m, 1H), 2.92 (m, 2H), 2.63 (m, 2H), 2.53 (s, 3H), 2.10 (m, 2H), 1.17 (s, 9H), 1.13 (t, J = 7 Hz, 3H).
The remainder ofthe synthesis of 78 and 79 follows the same route as Example 10 from compound 33.
Example 34. Preparation of (S)tert—butoxy((S)cyclopentyl(2,3-dihydropyrano[4,3,2— de]quinolinyl)—5—methylbenzo[d]thiazol—6-yl)acetic acid (80) and (S)-2—tert-butoxy-2—((R) cyclopentyl—7-(2,3-dihydropyrano[4,3,2-de]quinolin—7-yl)methylbenzo[d]thiazol—6-yl)acetic acid (81).
Compound 80 was ed from compound 78 according to the procedure used to prepare compound 8F from 8E in Example 4. nd 80: : 400 MHz, ) δ: 8.77 (d, J=6.0 Hz, 1H); 7.96 (s, 1H); 7.88 (d, J=8.0 Hz, 1H); 7.83 (d, J=6.0 Hz, 1H); 7.42 (d, J=8.0 Hz, 1H); 5.23 (s, 1H); 4.73-4.69 (m, 2H); 3.67-3.64 (m, 2H); 3.53-3.44 (m, 1H); 2.75 (s, 1H); 2.17-2.14 (m, 2H); 1.81-1.71 (m, 6H); 0.90 (s, 9H).
Compound 81 was prepared from compound 79 according to the procedure used to prepare compound 8F from 8E in Example 4.
Compound 81: 1H-NMR: 400 MHz, (CD3OD) δ:8.67 (d, J=5.2 Hz, 1H); 8.15 (d, J=8.4 Hz, 1H); 7.90 (s, 1H); 7.68 (d, J=5.6 Hz, 1H); 7.41 (d, J=8.4 Hz, 1H); 5.27 (s, 1H); 4.69-4.65 (m, 2H); 4.67 (t, J=6.2 Hz, 2H); 3.59 (t, J=6.0 Hz, 2H); 3.50-3.42 (m, 1H); 2.71 (s, 3H); 2.16- 2.13 (m, 2H); 1.78-1.70 (m, 6H); 0.90 (s, 9H).
Example 35. Preparation of (S)tert-butoxy((S)cyclobutyl(2,3-dihydropyrano[4,3,2- de]quinolinyl)methylbenzo[d]thiazolyl)acetic acid (82).
Compound 82 was prepared from compound 32 according to the procedure used to prepare compound 77 in Example 33, except cyclobutyl zinc bromide was used instead of cyclopentenylboronic acid.
Compound 82: 1H-NMR: 400 MHz, (CD3OD) 5 8.79 (d, J= 5.6 Hz, 1H), 7.98 (s, 1H), 7.87 (dd, J= 13.1, 6.9 Hz, 2H), 7.44 (d, J= 8.4 Hz, 1H), 5.23 (s, 1H), 4.71 (dt, J= 11.5, 5.8 Hz, 2H), 3.91 (p, J= 8.3 Hz, 1H), 3.67 (t, J= 5.8 Hz, 3H), 2.76 (s, 3H), 2.50 — 2.40 (m, 2H), 2.39 — 2.27 (m, 2H), 2.19 — 2.05 (m, 1H), 0.91 (s, 9H). LCMs—ESI+ (m/z): [M+H]+ calcd for C29H31N204S: 503.20 (M+H+); Found: 503.07, 504.10(M+H+).
Example 36. Preparation of (S)teIt-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin yl)—2-isobutylmethylbenzo[d]thiazolyl)acetic acid (83) and (S)—2-tert-butoxy—2-((R)-7— (2,3-dihydropyrano[4,3,2-de]quinolinyl)—2-isobutylmethylbenzo[d]thiazolyl)acetic acid (84).
Compounds 83 and 84 were prepared from compound 32 according to the procedure used to prepare compound 77 in e 33, except tn'buty1(2-methylpropenyl)stannane was used d of cyclopentenylboronic acid. Also, hydrogenation was performed according to the ure used to prepare 8F from SE in Example 4.
Compound 83: 1H-NMR: 400 MHz, (CD3OD) 5: 8.74 (d, J= 5.4 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.74 (d, J= 5.7 Hz, 1H), 7.37 (d, J= 8.3 Hz, 1H), 5.22 (s, 1H), 4.69 (m, 2H), 3.61 (t, J: 5.9 Hz, 2H), 2.90 (d, J= 7.2 Hz, 2H), 2.75 (s, 3H), 0.97 (d, J= 6.5 Hz, 6H), 0.91 (s, 9H). LCMS—ESI+ (m/z): [M+H]+ calcd for C29H33N204S: 505.22 (M+H+); Found: 505.06, 506.06(M+H+).
Compound 84: 1H—NMR: 400 MHz, (CD30D) 5 8.65 (d, J= 5.2 Hz, 1H), 8.12 (d, J: 8.1 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J= 5.1 Hz, 1H), 7.37 (d, J: 8.2 Hz, 1H), 5.28 (s, 1H), 4.65 (t, J= 6.1 Hz, 2H), 3.55 (t, J= 5.9 Hz, 2H), 2.89 (d, J= 7.2 Hz, 2H), 2.70 (s, 4H), 0.97 (dd, J= 6.6, 3.2 Hz, 7H), 0.88 (s, 10H).
LCMS-ESF (m/z): [M+H]+ calcd for C29H33N204S: (M+H+); Found: 505.01, 506.07(M+H*).
Example 37. Preparation of (S)—2—tert—butoxy((S)cyclopropyl(2,3- dihydrobenzo[de]chromenyl)-S—methylbenzo[d]thiazolyl)acetic acid (85).
Compound 85 was ed from compound 18 according to the procedure used to prepare compounds 19 and 20 (except that 2,3-dihydrobenzo[de]chromenylboronic acid was used instead of 2,3-dihydropyrano[4,3,2-de]quinolinylboronic acid) in Example 9.
Compound 85: lH-NMR: 400 MHz, (CD30D) 5; 7.70 (s, 1H); 7.29—7.19 (m, 4H), 6.95 (d, J = 4 Hz, 1H), 5.07 (s, 1H), 4.48-4.45 (m, 2H), 3.29-3.27 (m, 2H), 2.64 (s, 3H), 2.32-2.28 (m, 1H), 1.20-1.18 (m, 2H), 1.056-1.03 (m, 2H), 0.96 (s, 9H).
SI+ (m/z): [M+H]+ calcd for C29H29NO4S: 488.2 ; Found: 488.1(M+H+).
Example 38. Preparation of (S)tert-butoxy-2—((S)(5-chloro-3,4—dihydro-2H- benzo[b][l,4]oxaziny1)cyclopropylmethy1benzo[d]thjazolyl)acetic acid (86) and (S)- 2-tert-butoxy((R)—7—(5 -chloro-3,4-dihydro—2H-benzo [b] [1 ,4]oxazin—6-yl)cyclopropyl methylbenzo[d]thiazol—6-yl)acetic acid (87).
Compounds 86 and 87 was prepared from compound 18 according to the procedure used to prepare compounds 19 and 20 (except that 5-chloro—3,4—dihydro-2H-benzo[b][1,4]oxazin—6- nic acid was used instead of 2,3-dihydropyrano[4,3,2-de]quinoliny1boronic acid) in Example 9.
Compound 86: 1H—NMR: 400 MHz, ) a: 7.63 (d, J = 0.4 Hz, 1H); 6.74 (d, J = 4.2 Hz, 1H), 6.44 (d, J = 4.2 Hz, 1H), 5.21 (s, 1H), 4.26 (t, J = 4.6 Hz, 2H), 3.51—3.49 (m, 2H), 2.65 (d, J = 0.4 Hz, 3H), 2.40—2.36 (m, 1H), 1.26-1.23 (m, 2H), 1.13-1.11 (m, 2H), 1.09 (s, 9H).
LCMs—Esr (m/z): [M+H]+ calcd for C25H27C1N204S: 487.1 (M+H+); Found: 487.1(M+H*). 87 Compound 87: lH—NMR: 400 MHz, (CD3OD) 5: 7.60 (s, 1H); 6.83—6.78 (m, 2H), 5.27 (s, 1H), 4.27-4.24 (m, 2H), 3.51-3.48 (m, 2H), 2.55 (s, 3H), 2.40-2.36 (m, 1H), .23 (m, 2H), 1.13—1.12 (m, 2H), 1.01 (s, 9H)..
LCMS-ESI+ (m/z): [M+H]+ calcd for C25H27C1N204S: 487.1 (M+H+); Found: M+H+).
Example 39. Preparation of (S)—2-tert-butoxy—2-((S)—7-(2,3-dihydropyrano[4,3,2-de]quinolin yl)isopropylmethylbenzo[d]thiazolyl)acetic acid (88).
Compound 88 was prepared from compound 32 according to the procedure used to prepare compound 77 in Example 33, except propeny1-(tri—n-butyl)tin was used instead of cyclopentenylboronic acid. Also, enation was med according to the procedure used to prepare 8F from SE in Example’4.
Compound 88: 1H NMR (400 MHz, CD3OD) 5 8.70 (d, J= 5.4 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J= 7.9 Hz, 1H), 7.66-7.60 (m, 1H), 7.31 (d, J: 8.0 Hz, 1H), 5.20 (s, 1H), 4.70-4.61 (m, 2H),3.59-3.51 (m, 2H), 3.15—3.09 (m, 1H), 2.72 (s, 3H), 1.36 (m, 6H), 0.90 (s, 9H). LCMS- ESI+: calc’d for C23H30N204S: 491.2 (M+H+); found: 491.4 (M+H+).
Example 40. Preparation of (S)((S)(azetidin—1-y1)(2,3-dihydropyrano —de]quinolin- -methylbenzo[d]thiazolyl)(tert-pentyloxy)acetic acid (89).
Compound 89: 1H NMR (400 MHz, CD30D) 5 8.75 (d, J: 5.1 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.71 (d, J= 5.6 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J= 8.1 Hz, 1H), 5.09 (d, J= 0.6 Hz, 1H), 4.69 — 4.62 (m, 2H), 4.17 (t, J= 7.7 Hz, 4H), 3.61 — 3.55 (m, 2H), 2.66 (s, 3H), 2.58 — 2.42 (m, 2H), 0.87 (d, J= 2.9 Hz, 6H), 0.59 (t, J= 7.0 Hz, 3H). ”P NMR (377 MHz, CD3OD) 5 - 77.77. LCMS: calc’d= 518.64, observed: 518.08 OTf OX/ OTf QH s OEt ' B —<SI::\WOE B'_<\N r \ o N 31 90 Preparation of 90: A slurry of 31 (740 mg, 1.55 mmol) in myl acetate (7.0 mL) was treated with 70% aq. HClO4 (5 uL) was added at 23 °C. Reaction became cloudy, but LCMS analysis ted minimal conversion. More 70% aq. HC104 (50 11L) was introduced. After 2 h, the reaction was added dropwise over 5 min to sat. aq. NaHC03 (20 mL). H20 (10 mL) was added, and the system was extracted with DCM (3 x 20 mL). Combined organic layers were dried (NaZSO4), filtered, concentrated, and treated with hexane (10 mL). The system was concentrated again to remove some residual t-amyl alcohol. The residue was treated with PhH and loaded onto a 12 gram “gold” ISCO silica gel column. Chromatography (eluent: Hexanes/ Ethyl Acetate) gave 90 (134 mg, 16% yield) along with some recovered 31. lH-NMR: 400 MHz, (CDC13) 5: 7.80 (s, 1H), 5.49 (s, 1H), 4.24-4.06 (m, 2H), 2.57 (s, 3H), 1.60-1.40 (m, 2H), 1.17 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H), 1.05 (s, 3H), 0.80 (t, J = 7.0 Hz, 3H). 19F-NMR: 376 MHz, (CDC13) 6: —73.8 The remainder of the synthesis of 89 follows the same route as e 10 from compound 32.
Example 41. Preparation of (S)tert-butoxy((S)(difluoromethyl)—7-(2,3- dihydropyrano[4,3,2—de]quinolin-7—yl)—5-methylbenzo[d]thiazolyl)acetic acid (92).
Compound 92: 1H NMR (400 MHz, CD30D) 5 8.67 (d, J= 5.6 Hz, 1H), 8.08 (d, J= 5.9 Hz, 1H), 7.78 — 7.75 (m, 1H), 7.29 — 7.22 (m, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 5.23 (s, 1H), 4.66 — 4.61 (m, 2H), 3.69 (s, 1H), 3.64 (s, 2H), 3.17 — 3.16 (m, 1H), 3.13 (dd, J: 4.1, 2.4 Hz, 2H), 2.75 (s, 3H), 0.90 (s, 9H).
OTf 9 OTf OX s OEt Br_<\N o //—<\NSmoa0 o/arid) "7 mm\ \ N 0 F N 913 91c ELCPL Preparation of (S)—ethyl -butoxy(5-methyl(trifluoromethylsulfonyloxy)—2- enzo[d]thiazol—6-yl)acetate (91A): A microwave vial was charged with CuI (9.4 mg, 49 umol), 3)4 (29 mg, 25 urnol), and 32 (250 mg, 0.494 mmol). The Vial was sealed and placed under a vacuum. The vessel was backfilled with argon and charged with DMF (1.0 mL) followed by vinyl-(tri—n-butyl)tin (173 11L, 0593 mmol). Reaction was stirred at 65 °C for 1 h, then cooled to 23 °C. Sat. aq. NH4C1 (40 mL) was added and the on was extracted with EtOAc (2 x 20 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated.
Hexane was added, and the slurry was concentrated again. The residue was treated with PhH and purified by silica gel column tography (eluent: Hexanes / Ethyl Acetate) giving 91A (173 mg, 77% yield). 1H—NMR: 400 MHz, (CDC13) 6: 7.80 (s, 1H), 7.00 (dd, J = 18.6, 10.9 Hz, 1H), 6.24 (d, J = 18.6 Hz, 1H), 5.82 (d, J = 10.9 Hz, 1H), 5.60 (s, 1H), 4.24-4.06 (m, 2H), 2.54 (s, 3H), 1.22 (s, 9H), 1.19 (t, J = 6.8 Hz, 3H). 19F-NMR: 376 MHz, (CDC13) 5: —73.8. 3429.2.- Preparation of (S)-ethy1 2-tert-butoxy(2-formylmethyl (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)acetate (91B): A solution of 91A (170 mg, 0.353 mmol), DCM (5.0 mL), and MeOH (5 .0 mL) was cooled to —78 °C and perfiised with oxygen gas for 3 min. Then using an ozonator, a stream of O3 in oxygen gas was bubbled through the solution for 5 min. After this, the reaction was stirred for 10 min, then sparged with oxygen gas for 2 min to drive out unreacted ozone in solution. While the on was still at —78 °C, dimethylsulfide (200 uL) was added and the on d to warm to 0 °C. After 30 min, % w/v aq Na2S203 (5 mL) was added and the reaction was warmed to 23 °C and stirred for 10 min. The reaction was diluted with H20 (20 mL) and extracted with DCM (3x 15 mL).
Combined organic layers were dried (Na2SO4), filtered, and concentrated. More DCM was added and the reaction was concentrated once more to remove residual methanol, giving 91B (165 mg, 97% . 1H—NMR: 400 MHz, (CDCl3) 6: 10.04 (s, 1H), 8.00 (s, 1H), 5.60 (s, 1H), 4.22-4.00 (m, 2H), 2.51 (s, 3H), 1.16 (s, 9H), 1.14 (t, J = 6.8 Hz, 3H). 19F-NMR: 376 MHz, (CDC13) 8: —73.6. _SLep_3_.
Preparation of (S)—ethyl 2-teIt-butoxy(2-(difluoromethyl)methyl ‘ (trifluoromethylsulfonyloxy)benzo[d]thiazolyl)acetate (91C): A on of Fluolead ® (318 mg, 1.27 mmol) in DCM (1.0 mL) was cooled to 0 °C and treated with a on of 91B (123 mg, 0.254 mmol) in DCM (1.5 mL). The reaction was allowed to warm to 23 °C. Absolute EtOH (5 uL) was added to initiate the reaction. After 1 h, additional Fluolead ® (318 mg, 1.27 mmol) was added. Once 4 h had passed, 0.5 M aq. NaOH (5 mL) was added, and the reaction reached a pH of ~2. DCM (10 mL) was introduced. 1.0 M aq NaOH (~5 mL) was added dropwise until the pH d 12. The system was ted with DCM (3x 10 mL). The combined organic layers were dried (Na2SO4), filtered, and carefully concentrated to a volume of ~3 mL. The system became a suspension, which was then filtered. The filtrate was directly PCT/U82012/034593 loaded onto a 12 gram “gold” ISCO silica gel column. ation by chromatography t: Hexanes / Ethyl e) gave 91C (67 mg, 52% yield). 1H-NMR: 400 MHz, (CDC13) 8: 7.97 (s, 1H), 6.92 (t, JHF = 44.5 Hz, 1H), 5.62 (s, 1H), 4.24— 4.08 (m, 2H), 2.59 (s, 3H), 1.27 (s, 9H), 1.19 (t, J = 6.8 Hz, 3H). 19F-NMR: 376 MHz, ) 8: —73.7 (3F), —110.6 (app. dd, JFF = 4.0 Hz, JHF = 44.5 Hz, 2F).
The remainder of the synthesis of 92 follows the same route as Example 10 from compound 33.
Example 42. Preparation of (S)((S)—2-acetamido(2,3-dihydropyrano[4,3,2-de]quinolin yl)—5-methylbenzo[d]thiazolyl)tert-butoxyacetic acid (93).
Compound 93: lH-NMR: 400 MHz, (CD30D) 5: 1H NMR (400 MHz, cdgod) 8 8.73 (d, J = 5.4 Hz, 1H), 7.85 (d, J= 8.2 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.72 (d, J= 5.6 Hz, 1H), 7.39 (t, J = 10.0 Hz, 1H), 5.20 (s, 1H), 4.68 (m, 4H), 3.64 — 3.57 (m, 2H), 2.71 (s, 3H), 2.17 (s, 3H), 0.91 (s, 9H). LCMs—ESF (m/z): [M+H]+ calcd for C27H28N30582 506.17 (M+H+); Found: 506.02, 507.03(M+H+).
Br OJ< Br O/|< s OPiV ? o s OPiv H2N—<\N l —’ HN—<\ l 65H 94 Preparation of compound (S)—2-(2-acetamidobromomethylbenzo[d]thiazolyl)—2— tertHbutoxyethyl te (94). To a solution of 65H in CH2C12 was added pyridine, acetic anyhydride, and trace DMAP. Upon consumption of starting material by LC-MS, the mixture was concentrated in vacuo and purified by column chromatography to give 94.
LCMs-Esr (m/z): [M+H]+ calcd for C21H29BrN204S: 487.1 (M+H+); Found: 486.9 (M+H+).
The remainder of the synthesis of compound 93 is analogous to the preparation of compound 66 from compound 65J in example 25 Example 43. Preparation of (S)tert-butoxy—2-((S)(2,3-dihydropyrano[4,3,2-de]quinolin-7— yl)methylbenzo[d]thiazolyl)acetic acid (95).
Compound 95 was a by-product in the preparation of 40.
Compound 95: 1H-NMR: 400 MHz, (CD3OD) 5940 (s, 1H); 8.82 (d, J=6.0 Hz, 1H); 8.17 (s, 1H); 7.93 (d, J=8.0 Hz, 1H); 7.89 (d, J=6.0 Hz, 1H); 7.46 (d, J=8.0 Hz, 1H); 5.27 (s, 1H); 4.76-4.71 (m, 2H); 3.69 (t, J=6.0 Hz, 2H); 2.81 (s, 3H); 0.92 (s, 9H). LCMs-Esr+ (m/z): [M+H]+ calcd for C25H24N204S: 449.2 (M+H+); Found: 449.1 (M+H+).
Example 44. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2—de]quinolin yl)methyl(methylcarbamoyl)benzo[d]thiazolyl)acetic acid (97).
Compound 97: 1H-NMR: 400 MHz, (CD3OD) 5: 8.77 (d, J=6.0 Hz, 1H); 8.18-8.15 (m, 1H); 7.91 (m, 1H); 7.84 (d, J=5.2 Hz, 1H); 7.45 (d, J=8.4 Hz, 1H); 5.26 (s, 1H); 4.75-4.71 (m, 2H); 3.67 (t, J=6.0 Hz, 2H); 2.93 (s, 3H); 2.79 (s, 3H); 0.92 (s, 9H). LCMS—ESI+ (m/z): [M+H]+ calcd for C27H27N305S: 506.2 (M+H+); Found: 506.0 (M+H+).
SELL Preparation of ((S)tert-butoxy-2—ethoxyoxoethyl)(2,3- dihydropyrano[4,3,2-de]quinolin—7-yl)methylbenzo[d]thiazolecarboxylic acid (96A): To a solution of compound 38 (40 mg) in THF/MeOH (1 :1, 2 mL) was added a NaOH on (2 M, 100 11L). The reaction mixture was stirred at rt for 1 h. A ted solution ofNH4Cl was added, and the aqueous was extracted with EtOAc. The c layer was dried, d, and concentrated in vacuo to give 95A. 1H-NMR: 400 MHz, (CD3OD) 5: 8.63 (d, J = 6 Hz, 1H), 8.05 (br s, 1H), 7.63 (d, J = 8 Hz, 1H), 7.46 (d, J = 6 Hz), 7.21 (d, J = 8 Hz, 1H), 5.20 (s, 1H), WO 45728 4.58 (m, 2H), 4.04 (m, 1H), 3.91 (m, 1H), 3.46 (m, 2H), 2.76 (s, 3H), 1.03 (t, J = 7 Hz, 3H), 0.89 (s, 9H).
Step 2.
To a solution of 96A (15 mg) in CH2C12 (1 mL) was added carbonyldiimidazole (10 mg) and then methylamine (solution in MeOH, 100 uL). Once sion is complete by LC-MS, the solution was concentrated to give crude 96B. Then THF/MeOH added (1:1, 1 mL) followed by NaOH solution (2 M, 100 pL). The on mixture was stirred at 55-60 °C for 4 h. Purified by reverse phase HPLC to give 3.8 mg of 97.
Example 45. Preparation of (S)tert-butoxy((S)(2,3-dihydropyrano[4,3,2-de]quinolin—7- yl)methyl(phenethylcarbamoyl)benzo[d]thiazolyl)acetic acid (98).
Compound 98 was prepared from compound 96A according to the procedure used to prepare compound 97 (except that 2-phenylethanamine was used instead of methylamine) in Example 44.
Compound 98: lH-NMR: 400 MHz, (CDgOD) 5: 8.76 (d, J=6.0 Hz, 1H); 8.17 (s, 1H); 7.90 (d, J = 8 Hz, 1H); 7.82 (d, J = 6 Hz, 1H); 7.43 (d, J = 8 Hz, 1H); 7.20 (m, 5H), 5.26 (s, 1H); WO 45728 PCT/U82012/034593 4.71 (m, 2H); 3.64 (t, J=6 Hz, 2H); 2.91 (t, J = 7 Hz, 2H), 2.77 (m, 2H), 2.72 (s, 3H), 0.92 (s, 9H). LCMs-ESI+ (m/z): [M+H]+ calcd for C34H33N3OSS: 596.2 (M+H+); Found: 596.1 (M+H+).
Example 46. Preparation of (S)—2-tert-butoxy—2-((S)(2,3—dihydropyrano[4,3,2-de]quinolin yl)(4-methoxybenzylcarbamoyl)—5-methy1benzo[d]thiazoly1)acetic acid (99).
Compound 99 was prepared from compound 96A according to the procedure used to prepare compound 97 (except that oxybenzylamine was used instead of methylamine) in Example 44.
Compound 99: LCMs—ESI+ (m/z): [M+H]+ calcd for C34H33N306S: 612.2 (M+H+); Found: 612.1 (M+H+).
Example 47.
The following rate representative pharmaceutical dosage forms, ning a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans. (i) Tablet 1 ngtablet nd X: 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3 300.0 (ii) Tablet 2 mgltablet Compound X= 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate fl 500.0 WO 45728 (iii) Capsule mglcapsule Compound X: 10.0 Colloidal silicon dioxide 1.5 e 465.5 Pregelatinized starch 120.0 Magnesium stearate fl 600.0 (iv) Injection 1 (1 mglml) m m1 Compound X= (free acid form) 1.0 Dibasic sodium phosphate 12.0 sic sodium phosphate 0.7 Sodium de 4.5 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s.
Water for injection q.s. ad 1 mL (v) Injection 2 110 ngml) m ml Compound X= (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s.
Water for injection q.s. ad 1 mL (vi) Aerosol m can Compound X: 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,0000 Dichlorotetrafluoroethane 5,000.0 The above formulations may be obtained by conventional ures well known in the pharmaceutical art.
All publications, patents, and patent documents are incorporated by nce herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be 40 understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
The reference in this ication to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or ion or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. - 170A -

Claims (4)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A compound, or a pharmaceutically able salt thereof, selected from: , , , Cl Cl O O S OH S OH N O N O CN , F , , Cl O O S OH N O , and .
2. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable r.
3. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the cture of a medicament for treating an HIV infection in a patient.
4. Use of claim 3, wherein the medicament is formulated for treating an HIV infection in a patient in ation with one or more additional therapeutic agents selected from the H:\rbr\Interwoven\NRPortbl\DCC\RBR\14260881_1.doc-5/
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