NZ624596B2 - QUINOLINE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE - Google Patents

QUINOLINE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE Download PDF

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NZ624596B2
NZ624596B2 NZ624596A NZ62459612A NZ624596B2 NZ 624596 B2 NZ624596 B2 NZ 624596B2 NZ 624596 A NZ624596 A NZ 624596A NZ 62459612 A NZ62459612 A NZ 62459612A NZ 624596 B2 NZ624596 B2 NZ 624596B2
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New Zealand
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methyl
alkyl
found
fluorophenyl
calc
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NZ624596A
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NZ624596A (en
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Christopher James Bungard
Antonella Converso
Leon Pablo De
Barbara Hanney
Timothy John Hartingh
Jesse Josef Manikowski
Peter J Manley
Robert Meissner
Zhaoyang Meng
James J Perkins
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Merck Sharp & Dohme Corp
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Priority claimed from PCT/US2012/062027 external-priority patent/WO2013066736A1/en
Publication of NZ624596A publication Critical patent/NZ624596A/en
Publication of NZ624596B2 publication Critical patent/NZ624596B2/en

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    • 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
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

Disclosed are quinoline carboxamide and quinoline carbonitrile compounds of formula (I) wherein ring A, RQ, -L-, R1, n, R2, and R3 are as defined in the specification. The compounds are useful as non-competitive metabotropic glutamate receptor 2 (mGluR2) antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders. Examples of a compound of formula (I) are: 4-(4-fluorophenyl)-7-((3-methyl-2,5-dioxoimidazolidin-1-yl)methyl)quinoline-2-carboxamide 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-methoxyphenyl)quinoline-2-carboxamide Ethyl-1-{[2-carbamoyl-4-(4-fluorophenyl)quinolin-7-yl]methyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate 7-[(4,4-dimethyl-2,6-dioxopiperidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile dulators (NAMs), and in methods of treating diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders. Examples of a compound of formula (I) are: 4-(4-fluorophenyl)-7-((3-methyl-2,5-dioxoimidazolidin-1-yl)methyl)quinoline-2-carboxamide 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-methoxyphenyl)quinoline-2-carboxamide Ethyl-1-{[2-carbamoyl-4-(4-fluorophenyl)quinolin-7-yl]methyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate 7-[(4,4-dimethyl-2,6-dioxopiperidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile

Description

- 1 – TITLE OF THE INVENTION INE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC TORS, COMPOSITIONS, AND THEIR USE FIELD OF THE INVENTION The invention is directed to certain quinoline carboxamide and quinoline itrile derivatives, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body. The quinoline amide derivatives of the invention tropic glutamate receptor 2 (mGluR2 ) modulators, and hence are useful in the treatment of Alzheimer’s Disease and other diseases mediated by the mGluR2 receptor.
BACKGROUND OF THE INVENTION Alzheimer’s Disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. tion of metabotropic glutamate receptor 2, which is prevalent in the cortex and hippocampus and regulates the release of the brain's major excitatory neurotransmitter glutamate at key neural synapses has been demonstrated to have a major role in ive sing. r, modulation of mGluR2 improves cognitive performance in preclinical species (Higgins,G.A. et al. (2004) Pharmacological manipulation of mGlu2 receptors influences cognitive mance in the rodent. Neuropharmacology 46, 907-917).
The metabotropic glutamate receptors are known to contain one or more allosteric sites, which may alter the affinity with which glutamate and other mGluR ligands bind to the primary binding or teric sites. As the orthosteric binding site is highly conserved between all of the known metabotropic glutamate receptors, functional ivity may best be achieved through allosteric interaction with the receptor.
Certain substituted quinoline carboxamides and quinoline carbonitriles are known in the art. See, for example, US Patent Application No. 2008/0188521, WO2007/038865, WO 1996/13500, each disclosing compounds as leukotriene inhibitors, and Canadian Patent Application No. 1, disclosing compounds as leukotriene and SRS-A inhibitors. There remains a need in the art for novel compounds that are effective as non-competitive mGluR2 tors, and/or mGluR2 negative allosteric modulators (NAMs). - 2 – SUMMARY OF THE INVENTION The present invention provides certain novel substituted quinoline carboxamide and quinoline carbonitrile derivatives, which are collectively or individually ed to herein as "compound(s) of the invention," as described herein. The compounds of the invention are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating a patient (preferably a human) for diseases or ers in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain ers and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions which include an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically able carrier, and the use of the compounds and pharmaceutical compositions of the invention for the manufacture of ments for the treatment of such diseases.
DETAILED PTION OF THE INVENTION In a first aspect, the invention provides a compound selected from the group consisting of: - 3 – , , , , and , or a pharmaceutically acceptable salt of said compound.
In a further aspect, the invention provides a pharmaceutical composition comprising a compound or ceutically acceptable salt of the first aspect of the ion, and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides the use of a compound or pharmaceutically acceptable salt of the first aspect of the invention, for the manufacture of a medicament for the ent of a disease or disorder mediated by the mGluR2 receptor, wherein said disease or disorder is Alzheimer’s disease, cognitive ment, schizophrenia, mood er, pain, or sleep disorder.
The invention is as defined in the claims. The description which follows also refers to additional compounds, compositions and methods outside the scope of the present . This description is retained for technical information.
Accordingly, also described herein are compounds which have the structural Formula (I): - 4 – L N RQ R2 n or a isomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein: ring A is a moiety selected from the group consisting of: phenyl, 6) lkyl, -(C5-C6) cycloalkenyl, -pyridinyl, pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and -oxazolyl; RQ is selected from the group consisting of -CN and –C(O)NH2; -L- is a bond or a divalent moiety selected from the group consisting of: -(C(R1L)2)p-, , -C(O)-,. -S(O)-, and -S(O)2-; p is 1, 2, or 3; each R1L is independently selected from the group consisting of H, -CH3, -CF3, -OH, -C(O)-, halogen, -cyclopropyl, -O-CH3, and -O-CF3; R1 is selected from the group consisting of: (1) heterocycloalkyl and heterocycloalkenyl, wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclic or yclic ring systems comprising from 3 to 10 ring atoms in which 1, 2, or 3 of the atoms of each said ring system is a ring atom independently selected from the group consisting of N, S, S(O), S(O)2, and O, and wherein each said heterocycloalkyl group and each said cycloalkenyl group is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C1-C6) l, -(C1-C6) haloalkyl, hydroxy-substiuted -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -(C3-C8) cycloalkyl, - 5 – -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkylmonocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -(C3-C8) spiroheterocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R1A)C(O)-(C1-C6) alkyl, )2, -C(O)N(R1A)2, -S(O)2H, -S(O)-phenyl, -S(O)-(C1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O)2-(C1-C6) alkyl-phenyl, -S(O)2OH, and -S(O)2-(C1-C6) alkyl, wherein each R1A group is independently selected from the group consisting of H and -(C1-C6 alkyl); (2) heteroaryl, wherein said heteroaryl is a monocyclic or multicyclic ring system comprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms of said ring system is a ring nitrogen atom, and wherein said heteroaryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C1-C6) alkynyl, -(C1-C6) haloalkyl, hydroxy-substituted -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -(C3-C8) cycloalkyl, -cycloalkyl, -CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R1B)C(O)-(C1-C6) alkyl, )2, -C(O)N(R1B)2, -S(O)2H, -S(O)-phenyl, (C1-C6) alkyl-phenyl, -phenyl, -S(O)2-(C1-C6) alkyl-phenyl, -S(O)2OH, and -S(O)2-(C1-C6) alkyl, wherein each R1B group is ndently selected from the group consisting of H and 6 alkyl), with the proviso that R1 is not unsubstituted or substituted triazolyl, and with the further proviso that when R1 is substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl, then –L- is selected from the group consisting of -(C(R1L)2)p-, and ; (3) phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, -(C1-C6) alkynyl, -(C1-C6) kyl, -C6) alkyl, -(C3-C8) cycloalkyl, -alkyl-cycloalkyl, )cycloalkyl, clic heteroaryl, -alkyl- monocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -C(O)H, - 6 – H, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R 1C )C(O)-(C 1C ) 1-C6) alkyl, -N(R 2, -C(O)N( R1C )2, -S(O)2H, -S(O)-phenyl, -S(O)-(C 1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O) 2-(C 1-C6) alkyl-phenyl, -S(O) 2OH, and -S(O) 2-(C 1-C6) alkyl, wherein each R1C group is independently selected from the group consisting of H and -(C 1-C6 alkyl); (4) H and -(C1-C6) alkyl; (5) –CH2N(R 1D )R 1E , n: R1D is selected from the group consisting of H, -(C1-C6) alkyl, and -C(O)OR1F ; R1E is selected from the group consisting of –O-(C1-C6) alkyl, heteroalkyl,-alkyl-C(O)N(R 1F ), and –C(O)OR1F , wherein each R1F is independently ed from the group consisting of H and -(C 1-C6) alkyl; and (6) –CH2N(R 1F )OR 1G , wherein: R1F is selected from the group consisting of H, -(C1-C6) alkyl, and -C(O)OR1F ; R1G is selected from the group consisting of H and -(C1-C6) alkyl; n is 0, 1, 2, or 3; each R2 (when present) is independently selected from the group consisting of halogen, -CN, -OH, 6) alkyl,-O-(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NH 2, -NH(C1-C6)alkyl, -N(C1-C6alkyl) 2, (C 1-C6) alkyl, and phenyl; and R3 is selected from the group consisting of hydrogen and ne.
In one embodiment, the compounds described herein have the structural Formula (I): - 7 – (I.1) or a stereoisomer thereof, or a pharmaceutically able salt of said compound or said stereoisomer, wherein: ring A is a moiety selected from the group consisting of: phenyl, 6) cycloalkyl, -(C5-C6) lkyenl, -pyridinyl, pyrimidinyl, -pyrazolyl, and -thienyl; RQ is selected from the group consisting of -CN and H2; -L- is a bond or a divalent moiety selected from the group ting of: -(C(R1L)2)p-, , -S(O)-, and -S(O)2-; p is 1, 2, or 3; each R1L is independently selected from the group consisting of H, -CH3, -CF3, -OH, -C(O)-, halogen, -cyclopropyl, -O-CH3, and -O-CF3; R1 is selected from the group consisting of: (1) heterocycloalkyl, heterocycloalkenyl, wherein said heterocycloalkyl and said heterocycloalkenyl are clic or multicyclic ring systems comprising from 3 to 10 ring atoms in which 1, 2, or 3 of the atoms of each said ring system is a ring heteroatom independently selected from the group consisting of N, S, S(O), S(O)2, and O, and wherein each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, wherein said alkyl is tituted or substituted with hydroxyl, -(C1-C6) alkynyl, -(C1-C6) haloalkyl, hydroxy-substiuted -(C1-C6) haloalkyl, - 8 – -O-(C1-C6) alkyl, -(C3-C8) lkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R1A)C(O)-(C1-C6) alkyl, -N(R1A)2, -C(O)N(R1A)2, -S(O)2H, -S(O)-phenyl, -S(O)-(C1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O)2-(C1-C6) alkyl-phenyl, -S(O)2OH, and -S(O)2-(C1-C6) alkyl, n each R1A group is ndently selected from the group consisting of H and -(C1-C6 alkyl); (2) heteroaryl, wherein said heteroaryl is a monocyclic or multicyclic ring system comprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms of said ring system is a ring nitrogen atom, and wherein said heteroaryl is unsubstituted or substituted with 1 to 4 groups independently selected from the group ting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, wherein said alkyl is unsubstituted or substituted with yl, -(C1-C6) alkynyl, -(C1-C6) haloalkyl, hydroxy-substituted -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -(C3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -phenyl, monocyclic heteroaryl, -alkylmonocyclic aryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R1B)C(O)-(C1-C6) alkyl, )2, -C(O)N(R1B)2, -S(O)2H, -S(O)-phenyl, -S(O)-(C1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O)2-(C1-C6) phenyl, OH, and -S(O)2-(C1-C6) alkyl, wherein each R1B group is independently selected from the group consisting of H and -(C1-C6 alkyl), with the proviso that R1 is not unsubstituted or substituted triazolyl, and with the further proviso that when R1 is substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl, then –L- is selected from the group consisting of L)2)p-, and ; (4) phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 4 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, -(C1-C6) l, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -(C3-C8) cycloalkyl, -alkyl-cycloalkyl, )cycloalkyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -C(O)H, - 9 – -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R 1C )C(O)-(C 1C ) 1-C6) alkyl, -N(R 2, -C(O)N( R1C )2, -S(O)2H, -S(O)-phenyl, -S(O)-(C 1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O) 2-(C 1-C6) alkyl-phenyl, -S(O) 2OH, and -S(O) 2-(C 1-C6) alkyl, wherein each R1C group is independently selected from the group consisting of H and -(C 1-C6 alkyl); (4) H, 6) alkyl; and (5) –CH2N(R 1D )R 1E , wherein: R1D is selected from the group ting of H, -(C1-C6) alkyl, and -C(O)OR1F ; R1E is selected from the group consisting of –O-(C1-C6) alkyl, heteroalkyl,-alkyl-C(O)N(R 1F ), and –C(O)OR1F , wherein each R1F is independently selected from the group consisting of H and -(C 1-C6) alkyl; n is 0, 1, 2, or 3; each R2 (when present) is independently selected from the group consisting of halogen, -CN, -OH, -(C1-C6) alkyl,-O-(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) haloalkyl, -C(O)O(C 1-C6) alkyl, and phenyl; and R3 is selected from the group consisting of hydrogen and fluorine.
In one embodiment, in Formula (I), n is 0.
In one ment, in Formula (I), n is 1.
In one embodiment, in Formula (I), n is 2.
In one embodiment, in Formula (I), n is 3.
In one embodiment, in Formula (I), n is 0, 1, 2, or 3; and each R2 is independently selected from the group consisting of F, Cl, Br, methyl, ethyl, propyl, yl, yl, i-butyl, n-butyl, tert -butyl, -OCH3, -OCH 2CH 3, -CFH2, -CF2H, -CF3, -CH2CFH 2, -CH2CF 2H, -CH2CF 3, -NH2, -NH(C1-C6alkyl), -N(C 1-C6alkyl) 2, and phenyl.
In one embodiment, the nds described herein have the ural Formula (II): - 10 – (II) or a pharmaceutically acceptable salt thereof, wherein R1, RQ, -L-, n, R2, and R3 are as defined in Formula (I).
An alternative ment of Formula (II) comprises a compound of the Formula (II.1): (II.1) or a pharmaceutically acceptable salt thereof, wherein R1, RQ, -L-, n, R2, and R3 are as defined in Formula (I).
Another alternative ment of Formula (II) comprises a compound of the Formula (II.2): (II.2) or a pharmaceutically acceptable salt f, wherein R1, RQ, -L-, n, R2, and R3 are as defined in Formula (I). - 11 – In one ment, in each of Formulas (II), (II.1), and , n is 0.
In one embodiment, in each of Formulas (II), (II.1), and (II.2) n is 1, and each R2 is as defined in Formula (I).
In one embodiment, in each of Formulas (II), , and (II.2), n is 2, and each R2 independently is as defined in Formula (I).
In one embodiment, in each of Formulas (II), (II.1), and (II.2), n is 3, and each R2 is independently as defined in Formula (I).
In one embodiment, in each of Formulas (II), (II.1), and (II.2), n is 0, 1, 2, or 3; and each R2 is independently selected from the group consisting of halogen, CN, OH, -(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -O-(C1-C6) haloalkyl, , -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, and phenyl.
In one embodiment, the compounds described herein have the ural Formula (III): L N RQ (III) or a pharmaceutically able salt f, wherein m is 0, 1 or 2, the dotted line represents an optional double bond, and R1, RQ, -L-, n, R2, and R3 are as defined in Formula (I).
An alternative embodiment of Formula (III) comprises a compound of the Formula (III.1): L N RQ - 12 – (III.1) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2, the dotted line represents an optional double bond, and R1, RQ, -L-, n, R2, and R3 are as defined in Formula (I).
Another alternative embodiment of Formula (III) comprises a nd of the Formula (III.2): L N RQ (III.2) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2, the dotted line represents an optional double bond, and R1, RQ, -L-, n, R2, and R3 are as d in Formula (I).
In one ment, in each of as (III), (III.1) and (III.2), the moiety is selected from the group consisting of: R2 R2 , , n , n , , and , wherein n and each R2 is defined as in Formula (I).
In one embodiment, in each of Formulas (III), (III.1) and (III.2), each R2 is ndently selected from the group consisting of halogen, CN, OH, -(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -O-(C1-C6) haloalkyl, , -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, and phenyl.
In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is 0 and n is 0. - 13 – In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is 0, n is 1, and R2 is selected from the group consisting of halogen, CN, OH, -(C1-C6) alkyl, 6) haloalkyl, -O-(C1-C6) alkyl, -C6) haloalkyl, , -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, and phenyl.
In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is 0, n is 2, and R2 is independently selected from the group consisting of halogen, CN, OH, -(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -O-(C1-C6) kyl, , -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, and .
In one embodiment, in each of Formulas (III), (III.1) and (III.2), m is 0, n is 3, and R2 is independently selected from the group consisting of halogen, CN, OH, -(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -O-(C1-C6) haloalkyl, , -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, and phenyl.
In one embodiment, the compounds bed herein have the structural Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: ring A is a moiety selected from the group consisting of: -pyridinyl, dinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and -oxazolyl; and R1, RQ, -L-, n, R2 and R3 are as defined in a (I).
An alternative embodiment of Formula (IV) comprises a compound of the Formula (IV.1): - 14 – (IV.1) or a pharmaceutically acceptable salt thereof, wherein: ring A is a moiety selected from the group ting of: -pyridinyl, pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and -oxazolyl; and R1, RQ, -L-, n, R2 and R3 are as defined in Formula (I). r alternative embodiment of Formula (IV) comprises a nd of the Formula (IV.2): (IV.2) or a pharmaceutically acceptable salt thereof, wherein: ring A is a moiety selected from the group ting of: inyl, pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and -oxazolyl; and R1, RQ, -L-, n, R2 and R3 are as d in Formula (I).
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring A is pyrazolyl, which is unsubstituted or substituted with 1 to 2 R2 groups.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring A is thienyl, which is unsubstituted or substituted with 1 to 3 R2 groups.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring A is pyridinyl, which is unsubstituted or substituted with 1 to 3 R2 groups. - 15 – In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring A is pyrimidinyl, which is unsubstituted or tuted with 1 to 3 R2 groups.
In one embodiment, in each of as (IV), (IV.1), and (IV.2), Ring A is -thiazolyl, which is unsubstituted or substituted with 1 to 2 R2 .
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring A is –thiadiazolyl, which is unsubstituted or substituted with 1 R2 group.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), Ring A is –oxazolyl, which is unsubstituted or substituted with 1 to 2 R2 groups.
In one embodiment, in each of as (IV), (IV.1), and , n is 0.
In one ment, in each of Formulas (IV), (IV.1), and (IV.2), n is 0, 1, 2, or 3; and each R2 is independently selected from the group consisting of halogen, CN, -OH, -(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -O-(C1-C6) haloalkyl, and phenyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 0, 1, 2, or 3; and each R2 is independently selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, phenyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 1; and each R2 is independently selected from the group consisting of halogen, CN, -OH, -(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -O-(C1-C6) haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, and phenyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 1; and R2 is selected from the group consisting of halogen. In one such embodiment, R2 is fluoro.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), n is 2; and each R2 is independently ed from the group ting of halogen,–(C1-C6)alkyl, –(C1-C6)haloalkyl, and .
In one embodiment, in each of as (IV), (IV.1), and (IV.2), the Ring A is pyrazolyl R2 N N N R2 and the moiety is selected from the group consisting of: R2 , R2 , - 16 – N N N R2 R2 R2 , and R2 , wherein each R2 is independently as defined in Formula (I). In another such embodiment, R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, and phenyl.
In r such embodiment, n is 1 or 2 and each R2 is independently selected from the group consisting of halogen,–(C1-C6)alkyl, and .
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is pyrazolyl and the moiety is R2 , wherein each R2 is independently as d in Formula (I). In another such embodiment, R2 is selected from the group consisting of 6)alkyl, -(C1-C6)haloalkyl, phenyl. In another such embodiment, each R2 is independently selected from the group consisting of -(C1-C6)alkyl and phenyl.
In one embodiment, in each of as (IV), (IV.1), and (IV.2), the Ring A is lyl and the moiety is R2 , wherein R2 is as defined in Formula (I). In another such embodiment, R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, phenyl. In another such embodiment, R2 is selected from the group consisting of -(C1-C6)alkyl and phenyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is thienyl and the moiety is S , wherein R2 is as defined in Formula (I). In r such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl. - 17 – In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is pyridinyl R2 n and the moiety is , n R2 and n are each as defined in Formula (I). In r such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is N R2 n pyrimidinyl and the moiety is , wherein R2 and n are each as d in Formula (I). In another such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl.
In one ment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is thiazolyl and the moiety is , wherein R2 is each as defined in Formula (I). In another such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -C6alkyl), -N(C1-C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is thiazolyl and the moiety is N , wherein R2 is each as defined in Formula (I). In - 18 – another such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, propyl, -cyclobutyl, and -cyclopentyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is N S thiadiazolyl and the moiety is R2 , wherein R2 is each as defined in Formula (I). In another such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, 6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl.
In one embodiment, in each of as (IV), (IV.1), and (IV.2), the Ring A is thiadiazolyl and the moiety is , wherein R2 is each as defined in Formula (I). In another such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, 6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is yl and the moiety is , wherein R2 is each as defined in Formula (I). In another such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -C6)alkyl, -NH2, -NH(C1-C6alkyl), C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl. - 19 – In one embodiment, in each of Formulas (IV), , and (IV.2), the Ring A is oxazolyl and the moiety is R2 , wherein R2 is each as defined in a (I). In another such embodiment, R2 is selected from the group consisting of halo, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, propyl, -cyclobutyl, and -cyclopentyl.
In one embodiment, in each of Formulas (IV), (IV.1), and (IV.2), the Ring A is oxazolyl and the moiety is , wherein R2 is each as defined in Formula (I). In another such embodiment, R2 is selected from the group consisting of halo, 6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -cyclopropyl, -cyclobutyl, and -cyclopentyl.
In another embodiment, the compounds described herein have the structural Formula (V), shown below.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2): RQ is CN.
In one embodiment, in each of as (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), , (V), (V.1), and (V.2): RQ )NH2.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2): R3 is hydrogen.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2): R3 is fluorine. - 20 – In one embodiment, in each of as (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), , (IV.2), (V), (V.1), and (V.2): -L- represents a covalent bond.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2): -L- is –C(O)-.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2): -L- is -C(R1L)p-, wherein p is 0, 1, or 2, and each R1L is as defined in Formula (I).
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), ), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2): -L- is selected from the group ting of : -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CF3)-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH(OH)-, -CH2CH(OH)-, -CH(OH)CH2-, -CH(F)-, -CF2-, -C(CH3)(OH)-, –CH(OCH3)-, , , , , . -S(O)-, and -S(O)2-.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2): -L- is ed from the group consisting of: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CF3)-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH(OH)-, -CH2CH(OH)-, -CH(OH)CH2-, -CH(F)-, -CF2-, -C(CH3)(OH)-, H3)-, , , , , and -C(O)-. - 21 – In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is selected from the group ting of heterocycloalkyl and heterocycloalkenyl, wherein each of said heterocycloalkyl and said heterocycloalkenyl ns 1, 2, or 3 ring heteroatoms independently selected from the group consisting of N, S, S(O), S(O)2, and O, and wherein each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or substituted with 1 to5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C 1-C6) alkynyl, -(C 1-C6) haloalkyl, hydroxy-substituted -(C1-C6) haloalkyl, -O-(C 1-C6) alkyl, -(C 3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -phenyl, monocyclic heteroaryl, -alkylmonocyclic heteroaryl, 8) spirocycloalkyl, -C(O)H, H, -C(O)(C1-C6) alkyl, (C 1A )C(O)-(C 1A ) 1A ) 1-C6) alkyl, -N(R 1-C6) alkyl, -N(R 2, (R 2, H, -S(O)-phenyl, -S(O)-(C 1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O) 2-(C 1-C6) alkyl-phenyl, -S(O) 2OH, and -S(O) 2-(C 1-C6) alkyl, and wherein each R1A group is independently selected from the group consisting of H and -(C 1-C6 alkyl).
In one ment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is selected from the group consisting of heterocycloalkyl and heterocycloalkenyl, wherein each of said heterocycloalkyl and said heterocycloalkenyl contains 1, 2, or 3 ring heteroatoms independently selected from the group consisting of N, S, S(O), S(O)2, and O, and wherein each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, -CN, -OH, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -N(H)C(O)-(C1-C6) alkyl, -C(O)NH2, -C(O)N(H)(C 1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, phenyl, -(C3-C8) spirocycloalkyl, -(C 3-C8) cycloalkyl, -(C1-C6) haloalkyl, and phenyl. In alternatives of this embodiment, each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or tuted with 1 to 4 groups, or, alternatively, 1 to 3 , or, alternatively 1 to 2 groups, wherein each said group is independently ed from the group consisting of oxo, -CN, -OH, -(C 1-C6) alkyl, -O-(C1-C6) alkyl, -N(H)C(O)-(C1-C6) alkyl, -C(O)NH2, -C(O)N(H)(C1-C6 alkyl), - 22 – -C(O)N(C 1-C6 alkyl)2, phenyl, 8) ycloalkyl, -(C3-C8) cycloalkyl, -(C1-C6) kyl, and phenyl.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is selected from the group consisting of heterocycloalkyl and heterocycloalkenyl, wherein each of said cycloalkyl and said heterocycloalkenyl contains 1, 2, or 3 ring heteroatoms independently selected from the group consisting of N, S, S(O), S(O)2, and O, and wherein each of said heterocycloalkyl and said cycloalkenyl is unsubstituted or substituted with 1 to 5 groups, alternatively 1 to 4 groups, alternatively 1 to 3 groups, or, alternatively, 1 to 2 groups, independently selected from the group consisting of oxo, alkyl, -(C 3-C8) spirocycloalkyl, -(C3-C8) cycloalkyl, and -(C1-C6) haloalkyl.
In each of the above embodiments, non-limiting examples of the heterocycloalkyl portion of said optionally substituted heterocycloalkyl includes piperidinyl, oxetanyl, yl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides (including N-oxides) thereof.
In each of the above embodiments, non-limiting examples of the cycloalkenyl portion of said optionally tuted cycloalkenyl es 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, othiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluorodihydrofuranyl, icyclo[2.2.1]heptenyl, dihydrothiophenyl, and dihydrothiopyranyl.
In one embodiment, in each of in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), ), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is heteroaryl, wherein said heteroaryl is mono or bicyclic and comprises from 1 to 3 ring nitrogen atoms, and wherein said heteroaryl is unsubstituted or tuted with 1 to 5 groups, alternatively 1 to 4 groups, alternatively 1 to 3 groups, or, alternatively, 1 to 2 groups, independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C 1-C6) alkynyl, -(C 1-C6) haloalkyl, hydroxy-substituted -(C 1-C6) haloalkyl, -O-(C 1-C6) alkyl, -(C 3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, - 23 – phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkyl- clic heteroaryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R1B)C(O)-(C1-C6) alkyl, -N(R1B)2, -C(O)N(R1B)2, -S(O)2H, -S(O)-phenyl, S(O)-(C1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O)2-(C1-C6) alkyl-phenyl, -S(O)2OH, and -S(O)2-(C1-C6) alkyl, and wherein each R1B group is independently ed from the group consisting of H and -(C1-C6 alkyl), with the proviso that R1 is not tituted or substituted triazolyl, and with the further proviso that when R1 is substituted oxadiazolyl, tuted thiazolyl, or substituted thiadiazolyl, then –L- is selected from the group consisting of -(C(R1L)2)p-, and .
In one embodiment, in each of in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), ), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is heteroaryl, wherein said aryl is mono or bicyclic and ses from 1 to 3 ring nitrogen atoms, and wherein said heteroaryl is unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of oxo, CN, -OH, halogen, 6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C1-C6) alkynyl, -(C1-C6) haloalkyl, hydroxy-substituted -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -(C3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -phenyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R1B)C(O)-(C1-C6) alkyl, )2, -C(O)N(R1B)2, -S(O)2H, -S(O)-phenyl, S(O)-(C1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O)2-(C1-C6) alkyl-phenyl, -S(O)2OH, and -S(O)2-(C1-C6) alkyl, and wherein each R1B group is independently selected from the group consisting of H and -(C1-C6 alkyl), with the proviso that R1 is not unsubstituted or substituted triazolyl, substituted zolyl, substituted thiazolyl, or tuted thiadiazolyl.
In one embodiment, in each of in each of as (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is heteroaryl, - 24 – wherein said heteroaryl is mono or bicyclic and comprises from 1 to 3 ring nitrogen atoms, and n said aryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, -CN, -OH, -(C1-C6) alkyl, -O-(C 1-C6) alkyl, -N(H)C(O)-(C1-C6) alkyl, -C(O)NH2, -C(O)N(H)(C1-C6 alkyl), -C(O)N(C 1-C6 alkyl)2, phenyl, 8) spirocycloalkyl, -(C3-C8) cycloalkyl, -(C1-C6) haloalkyl, and phenyl, with the proviso that when R1 is not substituted unsubstituted or substituted triazolyl, substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl. In alternatives of this embodiment, each said heteroaryl group is unsubstituted or tuted with 1 to 4 groups, or, alternatively, 1 to 3 groups, or, atively 1 to 2 groups, wherein each said group is independently selected from the group consisting of oxo, -CN, -OH, -(C1-C6) alkyl, -O-(C 1-C6) alkyl, -N(H)C(O)-(C1-C6) alkyl, -C(O)NH2, -C(O)N(H)(C1-C6 alkyl), -C(O)N(C 1-C6 alkyl)2, phenyl, -(C3-C8) spirocycloalkyl, -(C3-C8) cycloalkyl, -(C1-C6) haloalkyl, and , , with the proviso that when R1 is not substituted unsubstituted or tuted lyl, substituted oxadiazolyl, substituted lyl, or substituted thiadiazolyl.
In one embodiment, in each of in each of Formulas (I), (I.1), (II), , (II.2), (III), ), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is selected from the group ting of heteroaryl, wherein said heteroaryl is mono or bicyclic and comprise from 1 to 3 ring nitrogen atoms, and wherein said heteroaryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, halogen, -(C1-C6) alkyl, hydroxysubstituted -(C1-C6) alkyl, -O-(C1-C6) alkyl, -N(R6)2, -C(O)N(R6)2, CN, -(C1-C6) haloalkyl, y-substituted -(C1-C6) kyl, -S(O)2H, -S(O)2-(C 1-C6) alkyl, and -(C1-C6) alkynyl, with the proviso that when R1 is not unsubstituted or substituted triazolyl, substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl. In alternatives of this embodiment, said heteroaryl is unsubstituted or substituted with 1 to 4 groups, alternatively 1 to 3 groups, alternatively 1 to 2 , wherein each said group is independently selected from the group consisting of oxo, halogen, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -O-(C1-C6) alkyl, -N(R 6) 6) 2, -C(O)N(R 2, CN, -(C1-C6) haloalkyl, hydroxy-substituted -(C1-C6) haloalkyl, -S(O)2H, - 25 – -S(O) 2-(C 1 is not unsubstituted or 1-C6) alkyl, and -(C1-C6) alkynyl, with the proviso that when R substituted triazolyl, substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), and (IV.2), the heteroaryl portion of said ally substituted heteroaryl of R1 is selected from the group consisting of pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl (including 1,2,4- thiadiazolyl), lyl, furazanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, o[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl, and oxides ding N-oxides) thereof, and benzo-fused versions thereof, wherein each said oxadiazolyl, thiazolyl, and thiadiazolyl, when t, is unsubstituted.
In one ment, in each of in each of Formulas (V), (V.1), and (V.2), the aryl portion of said optionally substituted heteroaryl of R1 is selected from the group consisting of pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as enyl), pyrimidinyl, ne (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl (including 1,2,4-thiadiazolyl), pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, lyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2- a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, olyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, pyridyl, quinazolinyl, pyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl, and oxides (including N-oxides) thereof, and benzo-fused versions thereof.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), , (V), (V.1), and (V.2), R1 is phenyl , wherein said phenyl is tituted or substituted with from 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, -(C1-C6) alkynyl, -(C 1-C6) kyl, -O-(C1-C6) alkyl, -(C 3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl- monocyclic aryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C 1C )C(O)-(C 1C ) 1C ) 1-C6) alkyl, -N(R 1-C6) alkyl, -N(R 2, -C(O)N(R 2, -S(O)2H, - 26 – phenyl, -S(O)-(C 1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O) 2-(C 1-C6) alkyl-phenyl, -S(O) 2OH, and -S(O) 2-(C 1-C6) alkyl, and wherein each R1C group is independently selected from the group consisting of H and -(C 1-C6 alkyl).
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 5 groups independently selected from the group consisting of halogen, -(C 1-C6) alkyl, phenyl, -O-(C1-C6) alkyl, CN, -S(O)-phenyl, -S(O)2-phenyl, -S(O)-(C 1-C6) alkyl-phenyl, and -S(O)2-(C 1-C6) alkyl-phenyl. In alternatives of this embodiment, said phenyl is unsubstituted or substituted with 1 to 4 groups, alternatively 1 to 3 groups, atively 1 to 2 groups, wherein said said group is independently ed from the group ting of halogen, -(C1-C6) alkyl, phenyl, -O-(C1-C6) alkyl, CN, -S(O)-phenyl, -S(O) 2-phenyl, -S(O)-(C1-C6) alkyl-phenyl, and -S(O)2-(C 1-C6) alkyl-phenyl.
In one embodiment, in each of as (I), (I.1), (II), (II.1), (II.2), (III), (III.1), ), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is phenyl, wherein said phenyl is unsubstituted or tuted with from 1 to 5 groups independently selected from the group consisting of halogen, -O-(C 1-C6) alkyl, CN, -S(O)-phenyl, -phenyl, -S(O)-(C1-C6) alkyl-phenyl, and -S(O) 2-(C 1-C6) alkyl-phenyl. In alternatives of this ment, said phenyl is unsubstituted or substituted with 1 to 4 groups, alternatively 1 to 3 , alternatively 1 to 2 groups, wherein said said group is independently selected from the group consisting of halogen, -C6) alkyl, CN, phenyl, -S(O)2-phenyl, -S(O)-(C1-C6) alkyl-phenyl, and -S(O)2-(C 1-C6) alkyl-phenyl.
In one embodiment, in each of Formulas (I), (I.1), (II), , (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1-L- is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, and optionally substituted – CH 2CH 2-phenyl, wherein said optional substituents are one to three substituents independently selected from the group ting of halogen, -O-(C 1-C6) alkyl, CN, -S(O)-phenyl, -S(O) 2-phenyl, -S(O)-(C1-C6) alkyl-phenyl, and -S(O)2-(C 1-C6) alkyl-phenyl.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is selected from the group consisting of H and -(C 1-C6) alkyl. - 27 – In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is -CH 1D 2N(R )R 1E , wherein: R1D is selected from the group ting of H, -(C1-C6) alkyl, and R1F ; R1E is selected from the group consisting of –O-(C1-C6) alkyl, heteroalkyl, -(C 1F ), and –C(O)OR1F , 1-C6) alkyl-C(O)N(R wherein each R1F is independently selected from the group consisting of H and -(C 1-C6) alkyl.
In one embodiment, in each of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and (V.2), R1 is –CH 1F )OR 1G 2N(R , n: R1F is selected from the group consisting of H, -(C1-C6) alkyl, and -C(O)OR1F ; R1G is selected from the group consisting of H and -(C1-C6) alkyl; n is 0, 1, 2, or 3.
In one embodiment, the compounds described herein comprise, collectively and individually, each of the example compounds shown in the tables below, and pharmaceutically acceptable salts thereof. Suitable pharmaceutically able salts of each of these nds include those discussed hereinbelow.
DEFINITIONS The terms used herein have their ordinary meaning and the meaning of such terms is independent at each ence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and al structures may be used interchangeably to describe that same structure. In the event where the chemical name and ure for a compound of the invention ee, the structure controls. These definitions apply regardless of whether a term is used by itself or in ation with other terms, unless otherwise indicated. Hence the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portion of “hydroxyalkyl”, lkyl”, arylalkyl-, alkylaryl-, “alkoxy,” etc.
It shall be understood that, in the various embodiments of the invention described herein, any variable not explicitly defined in the context of the embodiment is as defined in Formula (I).
All valences not explicitly filled are assumed to be filled by hydrogen. - 28 – In the various embodiments described herein, each variable is selected independently of the others unless ise indicated.
"Patient" includes both human and non-human animals. Non-human animals include research animals and ion animals such as mice, rats, primates, monkeys, great apes, chimpanzees, canine (e.g., dogs), and feline (e.g., house cats).
"Pharmaceutical composition" (or “pharmaceutically acceptable composition”) means a composition le for administration to a patient. Such compositions may contain the neat compound (or compounds) of the invention or es thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, or they may contain one or more pharmaceutically acceptable carriers or diluents. The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically ve excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active ". The bulk composition is al that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as s, pills and the like. Similarly, the herein-described method of ng a patient by stering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
The term "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the ation and not deleterious to the recipient thereof.
The terms "administration of" or "administering a" compound means providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual’s body in a therapeutically useful form and eutically useful amount, ing, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories. - 29 – The terms "effective " or "therapeutically effective amount" mean an amount of compound or a composition of the invention effective for inhibiting the herein-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
As used herein, the term "treatment" or "treating" means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the ogy or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
“Halogen” (or "halo") means fluorine, chlorine, bromine, or iodine. red are fluorine, chlorine and e.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. red alkyl groups n about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, yl, i-propyl, n-butyl ,i -butyl , t-butyl, pentyl, hexyl, heptyl, octanyl, etc., each of which may be straight or branched.
“Haloalkyl” means an alkyl as defined above wherein one or more en atoms on the alkyl is replaced by a halo group defined above. oalkyl" means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl l. Suitable such heteroatoms e O, S, S(O), S(O) 2, and -NH-, -N(alkyl)-. Non-limiting examples include ethers, thioethers, amines, and the like.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or - 30 – more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
"Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. “Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, lkyl, cyano, alkoxy and –S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, nyl, 3-methylbutenyl, npentenyl , octenyl and decenyl.
“Alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. More lly, the suffix “ene” on alkyl, aryl, ycloalkyl, etc. indicates a nt , e.g., -CH2CH2- is ethylene, and . is para-phenylene.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. ed means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
"Lower l" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of le alkynyl groups include ethynyl, propynyl, 2- butynyl and 3-methylbutynyl. “Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
“Alkenylene” means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include –CH=CH-, - C(CH3)=CH-, and –CH=CHCH2-.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, ably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system tuents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the - 31 – ring atoms is an element other than , for example nitrogen, oxygen or , alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be ally substituted by one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom tively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, lyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, l, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term oaryl” also refers to partially saturated aryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term “monocyclic heteroaryl” refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups sing from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, zinyl, pyridoneyl, thiazolyl, azolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, lyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non- limiting es of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Non-limiting es of suitable multicyclic - 32 – cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. Further miting examples of cycloalkyl include the following: "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contain at least one -carbon double bond. Preferred cycloalkenyl rings n about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. The term “monocyclic cycloalkenyl” refers to monocyclic versions of cycloalkenyl groups described herein and includes non-aromatic 3- to 7- membered monocyclic cycloalkyl groups which contains one or more carbon-carbon double bonds. Non-limiting examples include cyclopropenyl, cyclobutenyl, entenyl, cyclohexenyl, cyclohetpenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a le multicyclic cycloalkenyl is norbornylenyl.
“Heterocycloalkyl” (or "heterocyclyl") means a omatic ted monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any –NH in a heterocyclyl ring may exist ted such as, for e, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The cyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appears in a - 33 – definition of a variable in a general structure described herein, refers to the corresponding N- oxide, S-oxide, or S,S-dioxide. “Heterocyclyl” also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such =O groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone): . As used , the term “monocyclic heterocycloalkyl” refers clic versions of the heterocycloalkyl moities decribed herein and include a 4- to ered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently ed from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)2. The point of attachment to the parent moiety is to any ble ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, yl, piperazinyl, linyl, thiomorpholinyl, lidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma , delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Non-limiting examples of lower alkyl-substituted oxetanyl include the moiety: O .
“Heterocycloalkenyl” (or "heterocyclenyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for e nitrogen, oxygen or sulfur atom, alone or in combination, and which ns at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
The heterocyclenyl can be optionally substituted by one or more substituents, which may be the same or different, as bed herein. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2- dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6- - 34 – tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl” also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Example of such moiety is pyrrolidenone (or pyrrolone): . As used , the term “monocyclic heterocycloalkenyl” refers to monocyclic ns of the cycloalkenyl moities bed herein and include 4- to 7-membered monocyclic heterocycloalkenyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, e, S(O), and S(O)2.
The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
Non-limiting examples of monocyclic heterocyloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, olinyl, 3-pyrrolinyl, 2-imidazolinyl, zolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, and oxides thereof.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S 4 3 1 groups on carbon adjacent to another heteroatom. H , there is no -OH attached directly to carbons marked 2 and 5.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined.
Preferred hydroxyalkyls n lower alkyl. Non-limiting examples of suitable yalkyl groups e hydroxymethyl and 2-hydroxyethyl.
“Cyanoalkyl” means a NC-alkyl- group in which alkyl is as usly defined.
Preferred cyanoalkyls contain lower alkyl. Non-limiting examples of suitable cyanoalkyl groups include cyanomethyl and 2-cyanoethyl. - 35 – "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described.
Non-limiting examples of suitable alkoxy groups e methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
“Spriocycloalkyl” means a cycloalkyl group attached to a parent moiety at a single carbon atom. Non-limiting examples of spirocycloalkyl wherein the parent moiety is a cycloalkyl e spiro [2.5] octane, spiro [2.4] heptane, etc. Non-limiting examples of spriocycloalkyl wherein the parent moiety is an The alkyl moiety linking fused ring systems (such as the alkyl moiety in heteroarylfused heteroarylalkyl-) may ally be substituted with spirocycloalkyl or other groups as bed herein. Non-limiting spirocycloalkyl groups include spirocyclopropyl, spriorcyclobutyl, spirocycloheptyl, and spirocyclohexyl.
The term “substituted” means that one or more ens on the designated atom is replaced with a selection from the ted group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a compound that is sufficiently robust to e isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term “optionally tuted” means al substitution with the specified groups, radicals or moieties.
When a variable appears more than once in a group, e.g., R6 in –N(R6)2, or a variable appears more than once in a structure presented herein, the variables can be the same or different.
The line ----,as a bond generally tes a mixture of, or either of, the le isomers, e.g., containing (R)- and (S)- stereochemistry. For example: OH OH OH means containing both and N N N H H H .
The wavy line , as used herein, indicates a point of attachment to the rest of the compound. Lines drawn into the ring systems, such as, for example: - 36 – indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.
“Oxo” is defined as a oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring bed herein, e.g., N .
In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring .
As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example: N N represents N N CH3 In another embodiment, the compounds of the invention, and/or itions comprising them, are present in isolated and/or ed form. The term "purified", "in purified form" or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or e of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, tallization and the like), in ient purity to be le for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It shall be understood that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a onal group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side ons at the protected site when the compound - 37 – is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, tive Groups in organic Synthesis (1991), Wiley, New York.
Also described herein are prodrugs and/or es of the compounds of the invention. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, h hydrolysis in blood. A discussion of the use of prodrugs is provided by T. i and W. , rugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of the invention or a pharmaceutically able salt thereof, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1– yl, (C2-C12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactonyl, di-N,N-(C1-C2)alkylamino(C 2-C3)alkyl (such as β- dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di )alkylcarbamoyl-(C1-C2)alkyl and dino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of the ion contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for e, (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl((C1- C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, (C 1-C4)alkanyl, arylacyl and -aminoacyl, or -aminoacyl- - 38 – -aminoacyl, where each -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl) 2 or glycosyl (the radical resulting from the l of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of the invention incorporates an amine functional group, a prodrug can be formed by the ement of a hydrogen atom in the amine group with a group such as, for example, onyl, RO-carbonyl, NRR’-carbonyl where R and R’ are each independently (C1- C10 )alkyl, (C3-C6) lkyl, benzyl, or R-carbonyl is a l -aminoacyl or natural - aminoacyl, —C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or , —C(OY2)Y 3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyl or mono-N—or di-N,N-(C 4)Y 5 wherein Y4 is H or methyl and Y5 is mono-N— or 1-C6)alkylaminoalkyl, —C(Y di-N,N-(C 1-C6)alkylamino morpholino, piperidinyl or pyrrolidinyl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both ed and unsolvated forms. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying s of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of ion, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable es e ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may ally be ted to a solvate.
Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci ., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures f) at a higher than t temperature, and cooling the solution at a rate sufficient to form ls which are then isolated by standard methods. Analytical techniques - 39 – such as, for example I. R. oscopy, show the presence of the solvent (or water) in the crystals as a e (or hydrate).
Another embodiment provides pharmaceutically acceptable salts of the compounds of the invention. Thus, reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise ted. The term "salt(s)", as employed herein, denotes acidic salts formed with nic and/or organic acids, as well as basic salts formed with inorganic and/or c bases. In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic , such as, but not d to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the nds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt itates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, es, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, ates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
Additionally, acids which are generally considered le for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of ceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, l of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl , and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups - 40 – may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl des, bromides and iodides), dialkyl sulfates (e.g. dimethyl, l, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Another embodiment es pharmaceutically acceptable esters of the compounds of the invention. Such esters e the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for e, ymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or sphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24 )acyl glycerol.
Another embodiment provides tautomers of the compounds of the invention, and salts, solvates, esters and prodrugs thereof. Also, for example, all nol and imine-enamine forms of the compounds are included in the invention.
The compounds of the invention may contain asymmetric or chiral centers, and, ore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In on, the present invention embraces all geometric and onal isomers. For example, if a nd of the invention incorporates a double bond or a fused ring, both the cis- and forms, as well as mixtures, are embraced within the scope of the invention. r embodiment provides for diastereomeric mixtures and individual enantiomers of the compounds of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical ences by methods well known to - 41 – those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
Enantiomers can be separated by ting the enantiomeric mixture into a reomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted s) and are ered as part of this invention. Enantiomers can also be ted by use of chiral HPLC column.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds of the invention (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including omeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and reomeric forms, are contemplated as embodiments within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of the invention orates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the ion. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.).
Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other s, or may be d, for e, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", “ester”, "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, isomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the ive compounds.
In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the - 42 – predominant hydrogen isotope found in nature. onal examples of isotopes that can be incorporated into compounds of the ion include (when present) isotopes of hydrogen, carbon, en, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
In an additional embodiment, the compounds of the invention are isotopically labeled for use as ch or stic agents. For example, compounds of the invention can be labeled for use in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14 C) isotopes are preferred for their ease of preparation and detectability. In another embodiment, the compounds of the invention can be labeled with heavier isotopes such as deuterium (i.e., 2H). Deuterium ment of the compounds of the invention may afford certain therapeutic ages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), or may provide a compound useful as a standard for characterization of biological samples, and hence may be preferred in some circumstances.
Isotopically labelled compounds of the invention can generally be prepared without undue experimentation by following procedures analogous to those disclosed in the s and/or in the Examples hereinbelow, by substituting an appropriate isotopically ed reagent for a nonisotopically labelled reagent. rphic forms of the nds of the invention, and of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention.
ITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions which comprise a therapeutically ive amount of a compound of the invention, or a steroisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, and a pharmaceutically acceptable carrier.
A preferred dosage is about 0.001 to 100 mg/kg of body weight/day of the nd of the invention. An especially preferred dosage is about 0.01 to 10 mg/kg of body weight/day of a compound of the invention, or a pharmaceutically acceptable salt of said compound.
The term aceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g. , two) pharmaceutically active agents such as, for example, a compound of the present invention and an - 43 – additional therapeutic agent selected from the lists of the additional agents described herein below, along with any pharmaceutically ve excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of ng a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, s, dispersible granules, es, cachets and suppositories.
The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
Suitable solid carriers are known in the art, e.g. , magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of cture for various itions may be found in A. Gennaro (ed.), Remington’s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
Liquid form preparations include solutions, suspensions and emulsions. es of materials useful for forming such liquid form preparations include water or water-propylene glycol solutions for parenteral injection, or sweeteners and iers for oral solutions, sions and emulsions. Liquid form preparations may also include ons or suspensions for intranasal administration.
Aerosol ations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a ceutically acceptable carrier, such as an inert compressed gas, e.g. , nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or eral stration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention can also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be - 44 – included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The nds of this invention may also be delivered subcutaneously.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g. , an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of ation may be varied or adjusted from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably from about 0.01 mg to about 10 mg per kg. The actual dosage employed may be varied depending upon the requirements of the t and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For ience, the total daily dosage may be divided and administered in portions during the day as required.
The compositions of the invention can further comprise one or more additional therapeutic agents, as discussed in further detail below. Accordingly, in one embodiment, the present invention es itions comprising: (i) a nd of the invention, or a stereoisomer f, or a pharmaceutically acceptable salt of said compound or said stereoisomer; (ii) one or more additional therapeutic agents, that are not compounds of the invention; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat one of the disease or conditions discussed herein.
USES OF THE COMPOUNDS OF THE ION Also described herein is a method of treating a patient (e.g., a human patient or a research animal) for diseases or disorders in which the mGluR2 receptor is involved. These methods comprise administering an effective amount of a nd of the invention or as described herein, or composition comprising a compound of the invention (or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said ismer), to a t in need thereof, to treat a disease or disorder in which the mGluR2 receptor is involved.
Also bed herein is the use of a compound of the invention or as described herein for treating a disease or disorder in which the mGluR2 receptor is involved, by administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. - 45 – In one ment, the nds useful in said methods or said uses comprise a compound according to any one of Formulas (I), (I.1), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), (IV.1), (IV.2), (V), (V.1), and/or (V.2), as described above, or according to any of the various embodiments described above. In another embodiment, the compounds useful in said methods and said uses comprise the compounds of the examples, e.g., as set forth in the Tables below.
Also bed herein is a method of using, in each of the methods and/or uses described herein, a compound according to Formula (I.2): (I.2) or a stereoisomer thereof, or a ceutically acceptable salt of said compound or said stereoisomer, n: R1 is heteroaryl, wherein said heteroaryl is a monocyclic or multicyclic ring system comprising from 5 to ring atoms in which from 1 to 4 of the atoms of said ring system is a ring nitrogen atom, and wherein said heteroaryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C1-C6) alkynyl, 6) haloalkyl, hydroxy-substituted -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -(C3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, clic heteroaryl, -alkyl- monocyclic aryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R1B)C(O)-(C1-C6) alkyl, -N(R1B)2, (R1B)2, -S(O)2H, -S(O)-phenyl, -S(O)-(C1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O)2-(C1-C6) alkyl-phenyl, -S(O)2OH, and -S(O)2-(C1-C6) alkyl, wherein each R1B group is independently selected from the group consisting of H and -(C1-C6 alkyl); - 46 – and –L-, R3,RQ, Ring A, R2, and n are each as described in Formula (I.1) above.
Another embodiment comprises a method of using, in each of the methods and/or uses described , a compound according to Formula (V): L N RQ R2 n (V) or a isomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein: ring A is a moiety selected from the group consisting of: phenyl, -(C5-C6) cycloalkyl, 6) cycloalkyenl, -pyridinyl, pyrimidinyl, -pyrazolyl, yl, -thiazolyl, -thiadiazolyl, and -oxazolyl; RQ is selected from the group consisting of -CN and –C(O)NH2; -L- is a bond or a divalent moiety selected from the group consisting of: -(C(R1L)2)p-, , -C(O)-,. -S(O)-, and -S(O)2-; p is 1, 2, or 3; each R1L is independently selected from the group consisting of H, -CH3, -CF3, -OH, , halogen, -cyclopropyl, -O-CH3, and ; R1 is selected from the group consisting of: (1) heterocycloalkyl, heterocycloalkenyl, wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclic or multicyclic ring systems comprising from 3 to 10 ring atoms in which 1, 2, or 3 of the atoms of each said ring system is a ring heteroatom independently selected from the group consisting of N, S, S(O), S(O)2, and O, - 47 – and wherein each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C1-C6) alkynyl, -(C 1-C6) haloalkyl, hydroxy-substiuted -(C1-C6) haloalkyl, -O-(C 1-C6) alkyl, -(C 3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkylmonocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -(C3-C8) spiroheterocycloalkyl, -C(O)H, -C(O)OH, -C(O)(C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R 1A )C(O)-(C 1A ) 1-C6) alkyl, -N(R 2, -C(O)N( R1A )2, -S(O)2H, phenyl, -S(O)-(C 1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O) 2-(C 1-C6) alkyl-phenyl, -S(O) 2OH, and -S(O) 2-(C 1-C6) alkyl, wherein each R1A group is ndently selected from the group consisting of H and -(C 1-C6 alkyl); (2) heteroaryl, wherein said heteroaryl is a monocyclic or multicyclic ring system comprising from 5 to ring atoms in which from 1 to 4 of the atoms of said ring system is a ring nitrogen atom, and wherein said heteroaryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, n, -(C1-C6) alkyl, hydroxy-substituted -(C1-C6) alkyl, -(C1-C6) alkynyl, -(C 1-C6) haloalkyl, hydroxy-substituted -(C 1-C6) haloalkyl, -O-(C 1-C6) alkyl, -(C 3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, -(C 3-C8) ycloalkyl, -C(O)H, -C(O)OH, C1-C6) alkyl, (C1-C6) alkyl, -N(R 1B )C(O)-(C 1B ) 1B ) 1-C6) alkyl, -N(R 2, -C(O)N(R 2, H, -S(O)-phenyl, -S(O)-(C 1-C6) alkyl-phenyl, -S(O)2-phenyl, -S(O) 2-(C 1-C6) alkyl-phenyl, -S(O) 2OH, and -S(O) 2-(C 1-C6) alkyl, wherein each R1B group is independently selected from the group consisting of H and -(C 1-C6 alkyl); (5) phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 5 groups independently selected from the group consisting of oxo, CN, -OH, halogen, -(C1-C6) alkyl, -(C1-C6) l, -(C 1-C6) haloalkyl, -C6) alkyl, -(C 3-C8) cycloalkyl, -alkyl-cycloalkyl, -CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, -(C3-C8) spirocycloalkyl, -C(O)H, -C(O)OH, C1-C6) alkyl, -C(O)O(C1-C6) alkyl, -N(R 1C )C(O)-(C 1C ) 1-C6) alkyl, -N(R 2, - 48 – -C(O)N(R1C)2, -S(O)2H, phenyl, -S(O)-(C1-C6) phenyl, -S(O)2-phenyl, -S(O)2-(C1-C6) alkyl-phenyl, -S(O)2OH, and -S(O)2-(C1-C6) alkyl, wherein each R1C group is independently selected from the group consisting of H and -(C1-C6 alkyl); (4) H, -(C1-C6) alkyl; (5) R1D)R1E, wherein: R1D is ed from the group consisting of H, -(C1-C6) alkyl, and -C(O)OR1F; R1E is selected from the group consisting of –O-(C1-C6) alkyl, alkyl,-alkyl-C(O)N(R1F), and –C(O)OR1F, wherein each R1F is independently selected from the group consisting of H and -(C1-C6) alkyl; and (6) –CH2N(R1F)OR1G, wherein: R1F is selected from the group consisting of H, -(C1-C6) alkyl, and -C(O)OR1F; and R1G is selected from the group consisting of H and -(C1-C6) alkyl; n is 0, 1, 2, or 3; each R2 (when present) is independently selected from the group consisting of halogen, -CN, -OH, -(C1-C6) alkyl,-O-(C1-C6) alkyl, -(C1-C6) haloalkyl, -O-(C1-C6) haloalkyl, cyclopropyl, utyl, cyclopentyl, cyclohexyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6alkyl)2, -C(O)O(C1-C6) alkyl, and phenyl; and R3 is selected from the group consisting of hydrogen and fluorine.
An alternative embodiment of the compounds of Formula (V) useful in said methods or said uses comprises a compound according to Formula (V.1): L N RQ R2 n - 49 – (V.1) or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein each of R1, -L-, Ring A, R2, n, R3, and RQ are as defined in Formula (V).
Another alternative embodiment of the compounds of Formula (V) useful in said methods or said uses comprises a compound according to Formula (V.2): L N RQ R2 n (V.2) or a stereoisomer f, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein each of R1, -L-, Ring A, R2, n, R3, and RQ are as defined in Formula (V).
In ative embodiments of Formulas (V), (V.1) and (V.2), when R1 is cycloalkyl, heterocycloalkenyl, heteroaryl, or , each said R1 group is unsubstituted or substituted with 1 to 4 , or, alternatively, 1 to 3 groups, or, alternatively 1 to 2 groups, wherein each said group is as defined in Formula (V).
Diseases or disorders in which the mGluR2 receptor may be involved include, but are not limited to, Alzheimer's Disease, cognitive impairment, schizophrenia, mood disorders, ing depression and anxiety, gastrointestinal disorders, pain disorders and sleep disorders.
Additional examples of pain disorders include acute pain, inflammatory pain and neuropathic pain. Neuropathic pain es, but is not limited to, postherpetic neuralgia, nerve injury, the "dynias", e.g., ynia, phantom limb pain, root ons, painful diabetic neuropathy, painful traumatic mononeuropathy, l polyneuropathy. Additional examples of pain disorders include central pain mes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated - 50 – with angina, and matory pain of varied s (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout), headache, migraine and r headache, headache, primary hyperalgesia, secondary hyperalgesia, y allodynia, secondary allodynia, or other pain caused by central sensitization. onal examples of cognitive ers include mild cognitive impairment. Other conditions that may be treated by the compounds and compositions of the invention include Parkinson’s Disease, ary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, Trisomy 21 (Down me), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral doses, diabetes, autism and atherosclerosis.
In preferred embodiments, the compounds of the invention are useful in treating Alzheimer’s Disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders. For example, the compounds may be useful for the prevention of ia of the Alzheimer’s type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the mer’s type.
Potential schizophrenia conditions or disorders for which the compounds of the invention may be useful e one or more of the following conditions or diseases: schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), phreniform er, schizoaffective disorder, delusional disorder, brief psychotic er, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketanine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosispsychotic disorder, psychosis associated with affective ers, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with sis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's - 51 – disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, ic disorders or age related cognitive decline.
Also described herein is a method for treating phrenia or psychosis comprising administering to a t in need f an effective amount of a compound (or composition providing a compound) of the invention, or a stereoisomer thereof.
Potential sleep conditions or disorders for which the compounds of the invention may be useful include enhancing sleep quality; improving sleep quality; augmenting sleep maintenance; increasing the value which is ated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling ; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; sing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing lta activity during sleep; increasing daytime alertness; reducing e ness; treating or reducing excessive daytime sleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleep apnea; wakefulness; nocturnal myoclonus; REM sleep interruptions; jet-lag; shift workers' sleep bances; dyssomnias; night terror; insomnias associated with depression, emotional/mood disorders, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules; conditions due to drugs which cause reductions in REM sleep as a side effect; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is ated with respiratory disturbances during sleep; and ions which result from a diminished quality of sleep.
Compounds of the invention may also be used to treat or prevent dyskinesias.
Furthermore, compounds of the invention may be used to decrease tolerance and/or dependence to opioid treatment of pain, and for treatment of withdrawal me of e.g., alcohol, opioids, and cocaine. - 52 – The subject or patient to whom the compounds of the present invention is administered is generally a human being, male or , in whom mGluR2 receptor inhibition is desired, but may also encompass other mammals such as those listed above, including dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which treatment the above noted disorders, or the study of mGluR2, is d.
Another embodiment provides a medicament or pharmaceutical composition for the inhibition of mGluR2 receptor, and/or for the treatment of any of the es or disorders listed above to a patient (preferably a human) in need of such treatment, which comprise a compound (or composition comprising a compound) of the invention, or a stereoisomer f, or a pharmaceutically acceptable salt of said compound or said stereoisomer, and a pharmaceutically able carrier.
Another embodiment provides a method for the manufacture of a medicament or a pharmaceutical composition for the inhibition of an mGluR2-NAM receptor, and/or for treating one or more diseases or conditions listed above, sing combining a compound (or composition comprising a compound) of the ion, or a stereoisomer thereof, or a pharmaceutically able salt of said nd or said stereoisomer, with a pharmaceutically able carrier.
ATION THERAPY The compounds and compositions of the invention or as described herein may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the invention have utility, where the combination of the drugs is desired, e.g., where the combination is safer or more effective than either drug alone. Additionally, the compounds of the invention or as described herein may be used in ation with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the invention or as described herein. Such other drugs may be administered, by a route and in an amount commonly used therefor, poraneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen. - 53 – Compounds described herein useful in said combinations comprise a compound according to any one of Formulas (I), (I.1), (I.2), (II), (II.1), (II.2), (III), (III.1), (III.2), (IV), , (IV.2), (V), (V.1), and/or (V.2) as described herein, or according to any of the various embodiments bed . In another embodiment, the compounds useful in said combinations comprise the compounds of the examples, e.g., as set forth as example compounds of the invention in the Tables herein.
In another embodiment, a compound or composition of the invention may be employed in combination with acetylcholinesterase inhibitors such as donepezil and rivastigmine, NMDA antagonist such as ine, inic receptor modulators, AMPA receptor modulators, mGluR3 receptor modulators, nicotinic alpha-7 and alpha4-beta 2 receptor modulators, 5-HT6 and 5-HT4 receptor modulators, modulators of phosphodiesterases (PDEs), alpha 2c receptor anagonists, histone deacetylases, and antioxidant therapies.
In another embodiment, a compound or composition of the ion may be employed in combination with therapies that may alter or modify the course of disease progression, including beta-amyloid modulating therapies such as BACE1 inhibitors, gamma-secretase modulators, tau and/or phosphor-tau modulators, and biologic therapies which modulate placques associated with neurological disorders including antibodies, RNAi, miRNA, and celltherapies.
In another ment, a compound or composition of the ion may be employed in combination with levodopa (with or without a ive erebral decarboxylase inhibitor such as opa or benserazide), anticholinergics such as den nally as its hydrochloride or lactate salt) and yphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide or pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
Additional examples of ations of the compounds include combinations with agents for the treatment of pain, for example non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, - 54 – ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 tors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such as AMG517, 705498, 782443, PAC20030, V114380 and A425619; bradykinin B l receptor antagonists, such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists, such as VX409 and ; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such as SD6010 and ; glycine site antagonists, including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such as AZD4282; potassium channel s; AMPA/kainate receptor antagonists; calcium channel blockers, such as ziconotide and NMED160; GABA-A receptor IO modulators (e.g., a GABA- A receptor agonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid sics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, one, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; olinergics; amantadine; ine oxidase Bl5 ("MAO-B") inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists, such as 2; alpha agonists, such as AGNXX/YY; neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists or antagonists, such as 2; NKI antagonists; selective serotonin reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reuptake inhibitors ("SSNRI"), such as duloxetine; tricyclic pressant drugs, nephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; iptan and sumatriptan.
In another embodiment, the compounds and compositions of the invention may be administered in combination with compounds useful for the treatment of schizophrenia or enhancing sleep quality and preventing and treating sleep disorders and sleep bances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and /2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic , other orexin antagonists, orexin agonists, eticin ts and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the - 55 – like, or the compound of the present ion may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
When administering a combination therapy to a t in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, rently, together, simultaneously and the like.
In one embodiment, the compound of the invention is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
In another embodiment, the compound of the ion and the additional eutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder.
In r embodiment, the compound of the invention and the additional therapeutic agent(s) are administered in doses lower than the doses commonly ed when such agents are used as monotherapy for treating the er.
In one ment, the compound of the invention and the additional therapeutic s) are present in the same composition, which is suitable for oral administration.
In some embodiments, the compound of the ion and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower s of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
The doses and dosage regimen of the additional therapeutic agent(s) used in the combination therapies of the present ion for the treatment or prevention of a disease or disorder can be determined by the ing clinician, taking into consideration the approved doses and dosage regimen in the package ; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
Another embodiment provides a kit comprising a therapeutically effective amount of the compound (or a composition comprising a compound) of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, optionally together with at least one additional therapeutic agent listed above, and a pharmaceutically acceptable carrier, vehicle or diluent. - 56 – When stering a combination therapy to a patient in need of such administration, the eutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
In one embodiment, the compound of the invention is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
In another embodiment, the compound of the invention and the additional therapeutic agent(s) are administered in doses commonly ed when such agents are used as monotherapy for treating the disorder.
In r embodiment, the compound of the invention and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder.
In one embodiment, the compound of the invention and the additional therapeutic agent(s) are t in the same composition, which is suitable for oral stration.
PREPARATIVE EXAMPLES In general, the compounds of the invention or as described herein may be produced by a variety of processes known to those d in the art and by known, ses analogous thereto. The ion disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. The practitioner is not limited to these methods.
One skilled in the art will recognize that one route will be optimized depending on the choice of appendage substituents. Additionally, one skilled in the art will ize that in some cases the order of steps has to be controlled to avoid functional group incompatability.
The prepared nds may be ed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy and IR spectra.
One skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective lents. Hence, when a specific solvent or reagent is mentioned, it is meant to be an illustrative example of the conditions desirable for that particular reaction scheme or for the preparation bed below.
Where NMR data are presented, 1H spectra were obtained on either a Varian VXR-400 (400 MHz, 1H), Varian Gemini-300 (300 MHz), Varian Mercury VX-400 (400 MHz), Bruker-Biospin AV-500 - 57 – (500 MHz) or Bruker Avance DRX-500 (500 MHz), and chemical shifts are reported as ppm with number of protons and multiplicities indicated parenthetically. Where LC/MS data are ted, analyses was performed using a 1200 series Agilent 6140 Quadrupole LCMS with a 1.8 µM Zorbax SB-C18 column (10-95% of MeCN-H2O with 0.1% TFA over 2.7 min, 1 mL/min) or with an Applied Biosystems API- 150 mass spectrometer and Gemini C18 column (50 x 4.6 mm, 10-95% CH3CN-H2O with 0.05% TFA over 5 min, 1 mL/min).
Preparative chiral HPLC separations were generally carried out using supercritical fluid tography by eluting a chiral column such as OJ-H, (4.6 x 250mm, Chiral Technologies, Inc., West Chester, Pennsylvania) with a mobile phase of isopropanol and supercritical CO2.
The starting materials and reagents used in preparing nds described below are either available from cial suppliers such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA) or were prepared by literature methods known to those skilled in the art.
In the Schemes below, R1 corresponds to the moiety shown in the various embodiments of the compounds of the invention, including in Formula (I). Compounds of the invention may be ed as outlined in Schemes A-G. Preparation of key intermediate A-9 is described in Scheme A below. 7-Methylquinoline A-1 can be converted to 7-methylquinolinecarbonitrile A-2 by oxidation followed by nucleophilic attack of cyanide on the activated N-oxide. r ion of A-2 followed by treatment with POCl3 yields 4-chloromethylquinolinecarbonitrile A-3. Metal catalyzed coupling introduces group R1 to give A-5, which can then be brominated at the benzylic position giving A-6. Bromide A-6 can be dislplaced by nucleophile A-7 in the presence of base in a polar solvent to yield A-8. The nitrile in A-8 can subsequently be yzed to primary amide A-9 using basic peroxide or under acidic conditions.
Compounds A-3 to A-9 of Scheme A can be further modified by manipulation of the substitutent groups by general s known in the art, including (but not d to) cross coupling, oxidation, reduction, dealkylation, alkylation, ion, and the like, and this modification may occur prior to or after deprotection. - 58 – Scheme A An alternative route to compounds like A-9 is shown in Scheme B. Starting from A-3, bromination followed by nucleophilic displacement yields B-2, which undergoes metal catalyzed cross coupling to give cyanoquinoline A-8. ysis of the nitrile in A-8 to primary amide A-9 can be achieved using conditions similar to those in Scheme A. Additionally, the order of the nucleophilic cement and ysis steps to give A-9 can be reversed as needed. Compound B-2 of Scheme B can be further ed by manipulation of the substitutent groups by general s known in the art, including (but not limited to) cross coupling, oxidation, reduction, dealkylation, alkylation, acylation, and the like, and this modification may occur prior to or after deprotection.
Scheme B The metal catalyzed cross coupling step can also be carried out in the presence of the primary carboxamide in C-1 as in Scheme C for the synthesis of compounds of general formula A-9. - 59 – Scheme C Compounds of general formula D-4 can be synthesized according to synthetic Scheme D below.
Cyanoquinoline A-5 can be bis-brominated with NBS to yield gem-dibromide D-1 which can be converted to the corresponding aldehyde D-2 with silver nitrate. ion to carboxylic acid D-3 followed by amide coupling with amine A-7 yields amide D-4. Compounds D-2 to D-4 of Scheme D can be r modified by manipulation of the substitutent groups by general s known in the art, including (but not limited to) cross ng, oxidation, reduction, dealkylation, alkylation, acylation, and the like, and this modification may occur prior to or after deprotection.
Scheme D nds of general formula E-1 can be synthesized according to synthetic Scheme E below.
Addition of organometallic reagents to aldehyde D-2 yields alcohol E-1. Compound E-1 of Scheme E can be further modified by manipulation of the substitutent groups by general methods known in the art, including (but not limited to) cross coupling, ion, reduction, dealkylation, alkylation, acylation, and the like, and this modification may occur prior to or after deprotection.
Scheme E - 60 – Keto-carboxamides F-4 can be prepared according to tic Scheme F. Displacement of bromide A-6 with aldehyde-containing nucleophile F-5 yields cyanoquinoline F-1. Hydrolysis of the nitrile to the corresponding carboxamide F-2 and subsequent reaction of the aldehyde with organometallic reagents yields alcohol F-3 which can be oxidized to F-4 with an oxidant such as Dess-Martin periodinane. Compounds F-1 to F-4 of Scheme F can be further modified by manipulation of the substitutent groups by general methods known in the art, including (but not limited to) cross coupling, oxidation, ion, dealkylation, alkylation, acylation, and the like, and this cation may occur prior to or after deprotection.
Scheme F Preparation of key compounds such as G-9 is described in Scheme G below. -substituted aniline G-1 can be converted to the corresponding butanedioates G-2 by condensation with dimethyl 2- oxobutanedioate in the presence of TsOH. Microwave irradiation of G-2 followed by treatment with POCl3 yields fluorochloromethylquinolinecarboxylate G-4. Metal catalyzed coupling introduces group R1 to give G-5, which can then be brominated at the benzylic position giving G-6. e G-6 can be dislplaced by succinimide in the presence of base in a polar solvent to yield G-7. Hydrolysis of the ester and subsequent coupling with ammonium ide yields primary amide G-9. Compounds G-4 to G-9 of Scheme G can be further modified by manipulation of the substitutent groups by general methods known in the art, ing (but not limited to) cross coupling, oxidation, reduction, dealkylation, alkylation, ion, and the like, and this modification may occur prior to or after deprotection. - 61 – Scheme G Metal catalyzed cross couplings can be carried out with bromide A-6 and arylbornic acids as in Scheme H for the synthesis of compounds of general formula H-2. Compound H-1 and H-2 of Scheme H can be r modified by manipulation of the substitutent groups by general methods known in the art, including (but not limited to) cross coupling, oxidation, ion, dealkylation, alkylation, acylation, and the like, and this modification may occur prior to or after deprotection. - 62 – Scheme H N CN Ar-B(OH)2 N CN Br Ar 2(Na2CO3—1.5H2O2) Suzuki CH3CN/H2O, 50 oC R1 R1 A-6 H-1 Ar NH2 H-2 R1 Compounds of general formula I-6 can be synthesized according to Scheme I. Metal catalyzed cross coupling of ride I-1 affords I-3 after ysis of the nitrile to the methyl ester. Chloride I-3 can be cross coupled with vinyl trifluoroborate salts to yield styrenly compounds I-4. Hydroboration of the vinyl substituent and subsequent cross coupling with aryl or heteroaryl halides yields compound I-5. ysis of the ester affords I-6. Compounds I-2 to I-6 of Scheme I can be further modified by manipulation of the substitutent groups by general methods known in the art, including (but not limited to) cross coupling, oxidation, reduction, dealkylation, alkylation, acylation, and the like, and this modification may occur prior to or after deprotection.
Scheme I EXAMPLES - 63 – Scheme 1.1 O- ON mCPBA TMSCN N CN N+ mCPBA N+ CN DCM, 34 C Me2NCOCl, rt DCM, 34 C 1-1 1-2 1-3 1-4 N CN N CN (HO)2B F POCl3 CHCl3, 70 C 3)4, Na2CO3 Dioxane:H2O, 100 C 1-5 F O 1-6 O3 1.5H2O2) acetone:H2O, 50 C Example 1.1: Synthesis of 4-(4-fluorophenyl)methylquinolinecarboxamide (1-7) 7-Methylquinoline N-oxide (1-2) 7-Methylquinoline (1-1, 240 g, 1.7 mol, 1.0 equiv) was dissolved in methylene chloride (5 L, 0.34 M). 3-Chloroperoxybenzoic acid (488 g, 2.2 mol, 1.3 equiv) was added nwise with cooling so that the reaction temperature did not rise above 34 oC. After stirring for 1h, the reaction mixture was quenched with 2L of 1N aqueous NaOH and the product was extracted with methylene chloride. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and filtered. Heptane was added and the organic layer was evaporated to dryness, giving 246 g of 7- methylquinoline N-oxide (1-2) as a pink solid that was carried on without further purification. LRMS m/z (M+H)+ 160.1 found, 160.2 required. 7-Methylquinolinecarbonitrile (1-3) To a solution of 7-methylquinoline N-oxide (1-2, 246 g, 1.54 mol, 1.0 equiv) in methylene chloride (5 L, 0.31 M) was added TMS-CN (414 ml, 3.1 mol., 2 equiv.) followed by dimethylcarbamoyl chloride (284 ml, 3.1 mol. 2 equiv), and the resulting e was stirred at room temperature overnight.
The solution was quenched with saturated sodium bicarbonate, diluted with water, and extracted with dichloromethane. The combined organic layers were dried over MgSO4, ed and the solvent d to give 260 g of crude material which was recrystallized from ol to give 186g of 7- methylquinolinecarbonitrile (1-3) in two crops. LRMS m/z (M+H)+ 169.1 found, 169.2 required. - 64 – 7-Methylquinolinecarbonitrile N-oxide (1-4) 7-Methylquinolinecarbonitrile (181g, 1.1 mol, 1.0 equiv.) was dissolved in dichloromethane (3.3 L, 0.3 M). m-Chloroperbenzoic acid (500 g, 2.9 mol, 2.6 equiv) was added and the reaction mixture was heated to 40 °C. After 3 hr mCPBA (7 g, 40 mmol, 0.04 equiv.) was added and the mixture was allowed to stir overnight at room temperature. The mixture was extracted with 3 L of 1N NaOH aq., washed twice with 20ml of dichloromethane and the combined organic phases were washed with DI water then dried over MgSO4. The organics were filtered and the solvent was d to give 192 g of 7-methylquinolinecarbonitrile N-oxide (1-4). LRMS m/z (M+H)+ 185.2 found, 185.2 required. 4-Chloromethylquinolinecarbonitrile (1-5) 7-Methylquinolinecarbonitrile N-oxide (1-4, 5.3 g, 28.8 mmol, 1.0 ) was ved in CHCl 3 (80 ml, 0.36 M), and POCl3 was added (16.09 ml, 173 mmol, 6.0 equiv.). The mixture was heated to 70°C overnight, quenched onto crushed ice and extracted three times with dichloromethane. The combined organic layers were washed with water followed by saturated aqueous sodium bicarbonate, dried over MgSO4, filtered and the solvent was removed to yield crude yellow solid. Recrystallization from heptane/EtOAc gave 95 g of 4-chloromethylquinolinecarbonitrile (1-5). LRMS m/z (M+H)+ 203.2 found, 203.6 required. 4-(4-Fluorophenyl)methylquinolinecarbonitrile (1-6) 4-Chloromethylquinolinecarbonitrile (1-5, 2.47 g, 12.2 mmol, 1.0 equiv.), 4- fluorophenylboronic acid (2.05 g, 14.63 mmol, 1.2 ), Pd(PPh3)4 (0.7 g, 0.61 mmol, 0.05 equiv), and 1M aqueous Na2CO 3 (12.2 ml, 2.39 mmol) was added into 1,4-dioxane (40 mL). The mixture was degassed and stirred at 100 °C for 16 hours, until disappearance of the starting material. The mixture was , saturated aqueous sodium hydrogen carbonate (2 mL) was added and the e was extracted with ethyl acetate (2x 50 mL). The combined organic fractions were washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced re. The e was treated with 50 ml of MeOH, stirred vigorously at rt for 1 h, the mixture was filtered and washed with MeOH. The solid was collected and dried under vacuum. The filtrate was concentrated and retrated with MeOH to get a second crop of white solid that was combined to the first to give 2.75 g of 4-(4-fluorophenyl)methylquinoline- 2-carbonitrile (1-6). LRMS m/z (M+H)+ 263.3 found, 263.3 ed. luorophenyl)methylquinolinecarboxamide (1-7) 4-(4-Fluorophenyl)methylquinolinecarbonitrile (1-6, 25 mg, 0.095 mmol, 1.0 equiv.) was dissolved in acetone (2.3 ter (1.5 mL) and sodium percarbonate (79.0 mg, 0.477 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50°C for 1 hour. The mixture was cooled and concentrated. The crude residue was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA er). Fractions containing product were pooled and treated with Na2CO 3. The resulting - 65 – mixture was extracted with CHCl3. The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 4-(4-fluorophenyl)methylquinolinecarboxamide (1-7). LRMS m/z (M+H)+ 280.9 found, 281.3 required.
Scheme 1.2 Example 1.2: Synthesis of 4-(2,6-dichlorofluorophenyl)quinolinecarboxamide (1-9) 4-(2,6-Dichlorofluorophenyl)quinolinecarboxamide (1-9) 4-Bromoquinolinecarboxamide (1-8, 50.0 mg, 0.199 mmol, 1.0 equiv.), (2,6-dichloro phenyl)boronic acid (77.0 mg, 0.398 mmol, 2.0 equiv.), cesium carbonate (130.0 mg, 0.398 mmol, 2.0 equiv), Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.05 equiv.), DPPF (11.0 mg, 0.020 mmol, 0.1 ) and copper(I) e (19.7 mg, 0.199 mmol, 1.0 equiv.) were added into DMF (1.0 mL). The mixture was stirred at 100 °C overnight. After cooling, s sodium hydrogen carbonate (saturate, 2.0 mL) was added and the mixture was extracted with dichloromethane (2x 5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford 4-(2,6-dichloro fluorophenyl)quinolinecarboxamide (1-9, 6.20 mg, 9.8%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.281 (s, 1 H); 8.226 (m, 1 H); 8.175 (br s, 1 H); 7.801-7.843 (m, 1 H); 7.601-7.637 (m, 2 H); 7.137-7.183 (m, 2 H); 6.140 (br s, 1 H). LRMS m/z (M+H)+ 319.0 found, 319.0 required.
The ing compounds have been prepared according to ures similar to those in Scheme 1.1 and 1.2 selecting the appropriate quinoline derivative and boronic acid derivative and provide examples of compounds in the invention. - 66 – Table 1 Exact Mass Example Structure IUPAC Name [M+H]+ 4-[4- (difluoromethoxy)phe F O nyl]quinoline Calc'd 315.1, 1-10 F carboxamide Found 315.1 4-cyclopenten Calc'd ylquinoline , carboxamide (TFA Found 1-11 salt) 466.07 4-(1-methyl-1H- pyrazol yl)quinoline Calc'd 253.1, 1-12 carboxamide Found 253.1 4-(4-methylthiophen- Calc'd 269.1, 3-yl)quinoline Found 1-13 S carboxamide 267.07 4-(5-methylphenyl- 1H-pyrazol noline Calc'd 329.1, 1-14 carboxamide Found 329.1 - 67 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(4- bromophenyl)quinolin Calc'd 327.0, 1-15 Br ecarboxamide Found 327.0 4-(2- Br bromophenyl)quinolin Calc'd 327.0, 1-16 ecarboxamide Found 327.0 4-(4-chloro Calc'd 297.1, methylphenyl)quinoli Found 1-17 Cl necarboxamide 297.08 F 4-(4-chloro Calc'd 301.1, phenyl)quinolin Found 1-18 Cl ecarboxamide 301.05 Cl 4-(2-chloro Calc'd 301.1, fluorophenyl)quinolin Found 1-19 F ecarboxamide 301.05 - 68 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(2-fluoro methoxyphenyl)quino Calc'd 297.1, 1-20 O linecarboxamide Found 297.1 F 4-(2-fluoro methylphenyl)quinoli Calc'd 281.1, 1-21 necarboxamide Found 281.1 4-(1-phenyl-1H- N N pyrazol yl)quinoline Calc'd 315.1, 1-22 carboxamide Found 315.1 N 4-(2-cyano methylphenyl)quinoli Calc'd 288.1, 1-23 arboxamide Found 288.1 4-(4- fluorophenyl)quinolin Calc'd 267.1, 1-24 F ecarboxamide Found 267.1 - 69 – Exact Mass Example Structure IUPAC Name [M+H]+ 7-methyl(4- methylphenyl)quinoli Calc'd 277.1, 1-25 necarboxamide Found 277.0 4-(4-methoxyphenyl)- O 7-methylquinoline Calc'd 293.1, 1-26 carboxamide Found 293.0 4-(2-chlorophenyl) methylquinoline Calc'd 297.1, 1-27 carboxamide Found 297.0 luorophenyl) methylquinoline Calc'd 281.1, 1-28 carboxamide Found 281.0 4-(4-cyanophenyl) methylquinoline Calc'd 288.1, 1-29 N carboxamide Found 287.9 - 70 – Exact Mass Example Structure IUPAC Name [M+H]+ Scheme 2.1 Example 2.1: Synthesis of 4-(4-fluorophenyl)((3-methyl-2,5-dioxoimidazolidin yl)methyl)quinolinecarboxamide (2-3) 7-(Bromomethyl)(4-fluorophenyl)quinolinecarbonitrile (2-1) 4-(4-Fluorophenyl)methylquinolinecarbonitrile (1-6, 450 mg, 1.7 mmol, 1.0 equiv) was dissolved in carbon tetrachloride (8.5 mL). NBS (310 mg, 1.7 mmol, 1.0 equiv) and AIBN (8 mg, 0.05 mmol, 0.03 equiv) were added and the mixture was refluxed overnight. The mixture was then cooled to room temperature and the white precipitate was filtered off to give momethyl)(4- fluorophenyl)quinolinecarbonitrile (2-1). LRMS m/z (M+H)+ 342.7 found, 342.0 required. 4-(4-Fluorophenyl)[(3-methyl-2,5-dioxoimidazolidinyl)methyl]quinolinecarbonitrile (2-2) 7-(Bromomethyl)(4-fluorophenyl)quinolinecarbonitrile (2-1, 50.0 mg, 0.147 mmol, 1.0 ), 1-methylimidazolidine-2,4-dione (18.4 mg, 0.161 mmol, 1.1 equiv.) and cesium carbonate (95.0 mg, 0.293 mmol, 2.0 equiv.) were combined into 1.0 ml of DMF. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was filtered and the te was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA er) to afford 4-(4-fluorophenyl)[(3-methyl-2,5- - 71 – dioxoimidazolidinyl)methyl]quinolinecarbonitrile ( 2-2, 48.0 mg, 87.0%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.205 (d, J = 1.09 Hz,1 H); 7.941 (d, J = 8.79 Hz,1 H); 7.681 (dd, J1 = 8.79 Hz, J2 = 1.83 Hz, 1 H); 7.647 (s, 1 H); 7.454-7.503 (m, 2 H); 7.251-7.309 (m, 2 H); 4.935 (s, 2 H); 4.049 (s, 2 H); 3.057 (s, 3 H). LRMS m/z (M+H)+ 375.1 found, 375.1 required. 4-(4-Fluorophenyl)[(3-methyl-2,5-dioxoimidazolidinyl)methyl]quinolinecarboxamide (2-3) 4-(4-Fluorophenyl)[(3-methyl-2,5-dioxoimidazolidinyl)methyl]quinolinecarbonitrile (2- 2, 44.9 mg, 0.120 mmol, 1.0 equiv.) was dissolved in acetone (1.5 mL)/water (0.75 mL) and sodium percarbonate (188.0 mg, 0.600 mmol, 5.0 equiv) was added. The resulting e was d at 50°C for two hours. The mixture was cooled and poured over aqueous NH4Cl (1.0 mL), extracted with ethyl acetate (3 x 5.0 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford 4-(4-fluorophenyl)[(3- -2, 5-dioxoimidazolidinyl)methyl]quinolinecarboxamide (2-3, 35.3 mg, 75.0%) as a colorless solid. 1H NMR (400 MHz, CDCl 3): δ 8.498 (br s, 1 H); 8.221 (d, J= 1.29 Hz,1 H); 8.180 (s, 1 H); 7.947 (d, J = 8.60 Hz,1 H); 7.672 (dd, J1 = 8.79 Hz, J2 = 1.83 Hz, 1 H); 7.532 (br s, 1 H); 7.462-7.512 (m, 2 H); 7.219-7.276 (m, 2 H); 4.918 (s, 2 H); 3.985 (s, 2 H); 3.040 (s, 3 H). LRMS m/z (M+H)+ 393.1 found, 393.1 required.
Scheme 2.2 Example 2.2: Synthesis of 7-((2,5-dioxopyrrolidinyl)methyl)(4-fluorophenyl)quinoline carboxamide (2-7) - 72 – 7-(Bromomethyl)chloroquinolinecarbonitrile (2-4) 4-Chloromethylquinolinecarbonitrile (1-5, 57 g, 0.37 mol,1.0 equiv.), NBS (75 g, 0.42 mol, 1.14 equiv.) and benzoyl peroxide (0.8 g, 3.3 mmol, 0.01 equiv.) were stirred in CH3CN (30 ml, 12.3 M) at room temperature. After 16 h, the solvent was removed and the e was partitioned between AcOEt and water, the c layer was washed with water, dried over MgSO4 and filtered. After removal of the solvent, the e was recrystallized from methanol to give 60 g of desired 7-(bromomethyl) chloroquinolinecarbonitrile (2-4). LRMS m/z (M+H)+ 283.1 found, 282.9 ed. 4-Chloro[(2,5-dioxopyrrolidinyl)methyl]quinolinecarbonitrile (2-5) To a room temperature solution of succinimide (4.22 g, 42.6 mmol, 1.2 equiv.) in anhydrous itrile (89 mL, 0.4 M) was added Hunig's base (12.4 ml, 71.0 mmol, 2.0 equiv.) and 7- (bromomethyl)chloroquinolinecarbonitrile (2-4, 10.0 g, 35.5 mmol). The resulting mixture was warmed in the microwave to 100°C for 1h. The reaction was then cooled to 0°C and a precipitate formed.
The solids were then collected by vacuum filtration and washed with cold acetonitrile to afford 4-chloro- 5-dioxopyrrolidinyl)methyl]quinolinecarbonitrile (2-5) which was taken to the next step without further purification. LRMS m/z (M+H)+ 300.2 found, 300.0 required. 7-[(2,5-Dioxopyrrolidinyl)methyl](4-fluorophenyl)quinolinecarbonitrile (2-6) To a room temperature solution of 4-fluorophenylboronic acid (5.96 g, 42.6 mmol, 1.2 equiv.) in dioxane:water (10:1, 177 mL, 0.2 M) was added sodium bicarbonate (5.96 g, 71.0 mmol, 2.0 equiv.), 4- chloro[(2,5-dioxopyrrolidinyl)methyl]quinolinecarbonitrile (2-5, 10.6 g, 35.5 mmol), and Pd(PPh 3)4 (4.1g, 3.55 mmol, 0.1 equiv.). The resulting mixture was warmed to 100°C for 4 hr. The reaction was then cooled to 0 °C and a precipitate formed. The solids were then collected by vacuum filtration and washed with water and cold itrile to afford 5-dioxopyrrolidinyl)methyl](4- fluorophenyl)quinolinecarbonitrile (2-6) which was taken to the next step without further purification. 1H NMR (400 MHz, CDCl 3): δ 8.115 (d, J = 1.10 Hz,1 H); 7.897 (d, J = 8.79 Hz,1 H); 7.655 (dd, J1 = 8.79 Hz, J2 = 1.83 Hz, 1 H); 7.603 (s, 1 H); 7.439-7.475 (m, 2 H); 7.243-7.286 (m, 2 H); 4.909 (s, 2 H); 2.796 (s, 4 H). LRMS m/z (M+H)+ 360.3 found, 360.1 required. 7-[(2,5-Dioxopyrrolidinyl)methyl](4-fluorophenyl)quinolinecarboxamide (2-7) 7-[(2,5-Dioxopyrrolidinyl)methyl](4-fluorophenyl)quinolinecarbonitrile (2-6, 12.8 g, .5 mmol, 1.0 equiv.) was dissolved in acetone (473 mL)/water (237 mL) and sodium percarbonate (55.7g, 178 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50°C for 1.5 hours. The - 73 – mixture was cooled and poured over aqueous NH4Cl (saturated, 250 mL), extracted with ethyl acetate (3 x 200 mL), dried over , filtered and concentrated to afford 7-[(2,5-dioxopyrrolidinyl)methyl] (4-fluorophenyl)quinolinecarboxamide (2-7, 5.5g, 41% over 3 steps) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.216 (s, 1 H); 8.156 (s, 1 H); 8.091 (br s, 1 H); 7.908 (d, J = 8.69 Hz,1 H); 7.614 (dd, J1 = 8.79 Hz, J2 = 1.71 Hz, 1 H); 7.498 (m, 2 H); 7.211-7.262 (m, 2 H); 5.668 (br s, 1 H); 4.902 (s, 2 H); 2.776 (s, 4 H). LRMS m/z (M+H)+ 378.3 found, 378.1 required.
The following compounds have been prepared according to procedures similar to those found in Scheme 2.1 and 2.2 selecting the appropriate quinoline derivative, phile, and boronic acid derivative and provide examples of nds in the invention and/or as described herein.
Table 2 Exact Mass Example Structure IUPAC Name [M+H]+ O O N NH2 7-[(2,5- O dioxoimidazolidin Calc'd yl)methyl](4- 379.1, fluorophenyl)quinoline- Found 2-8 F 2-carboxamide 379.1 7-[(2,5- dioxopyrrolidin Calc'd yl)methyl](4- 360.1, fluorophenyl)quinoline- Found 2-9 2-carbonitrile 360.3 7-[(4,4-dimethyl-2,6- dioxopiperidin Calc'd yl)methyl](4- 420.2, phenyl)quinoline- Found 2-10 2-carboxamide 420.2 - 74 – 7-[(5,5-dimethyl-2,4- dioxo-1,3-oxazolidin Calc'd yl)methyl](4- 408.1, fluorophenyl)quinoline- Found 2-11 2-carboxamide 408.1 7-[(4,4-dimethyl-2,6- dioxopiperidin Calc'd yl)methyl](4- 402.2, fluorophenyl)quinoline- Found 2-12 2-carbonitrile 402.2 4-(4-fluorophenyl) [(3-methyl-2,5-dioxo Calc'd phenylpyrrolidin 468.2, yl)methyl]quinoline Found 2-13 amide 468.2 ethylmethyl- 2,5-dioxopyrrolidin Calc'd yl)methyl](4- 420.2, fluorophenyl)quinoline- Found 2-14 2-carboxamide 420.2 4-(4-fluorophenyl) [(3,4,4-trimethyl-2,5- Calc'd dioxoimidazolidin 421.2, yl)methyl]quinoline Found 2-15 carboxamide 421.2 - 75 – 7-[(4,4-dimethyl-2,5- dioxoimidazolidin Calc'd hyl](4- 407.2, fluorophenyl)quinoline- Found 2-16 2-carboxamide 407.2 7-[(2,4-dioxo-1,3- oxazolidin Calc'd yl)methyl](4- 362.1, fluorophenyl)quinoline- Found 2-17 onitrile 362.1 7-[(1,3-dioxo azaspiro[4.4]non Calc'd yl)methyl](4- 432.2, fluorophenyl)quinoline- Found 2-18 2-carboxamide 432.2 4-(4-fluorophenyl) [(3-methyl-2,5- Calc'd dioxoimidazolidin 375.1, yl)methyl]quinoline Found 2-19 carbonitrile 375.1 7-[(3,3-dimethyl-2,5- dioxopyrrolidin Calc'd yl)methyl](4- 406.2, fluorophenyl)quinoline- Found 2-20 2-carboxamide 406.2 - 76 – 7-[(2,6-dioxopiperidin- Calc'd 1-yl)methyl](4- 392.1, fluorophenyl)quinoline- Found 2-21 2-carboxamide 392.1 4-(4-fluorophenyl) [(3,3,4-trimethyl-2,5- Calc'd dioxopyrrolidin 420.2, yl)methyl]quinoline Found 2-22 carboxamide 420.2 di-tert-butyl {[2- carbamoyl(4- fluorophenyl)quinolin- Calc'd 7- 496.2, yl]methyl}imidodicarb Found 2-23 onate 496.2 4-(2-chloro fluorophenyl)[(2,5- Calc'd dioxopyrrolidin 412.1, yl)methyl]quinoline Found 2-24 carboxamide 412.1 4-cyclohexenyl- 7-[(2,5- Calc'd dioxopyrrolidin 364.2, yl)methyl]quinoline Found 2-25 carboxamide 364.2 4-cyclohexyl[(2,5- Calc'd yrrolidin 366.2, yl)methyl]quinoline Found 2-26 carboxamide 366.3 - 77 – O O 7-[(2,5- N NH2 dioxopyrrolidin O yl)methyl](4- Calc'd methylcyclohexen- 378.2, 1-yl)quinoline Found 2-27 carboxamide 378.2 7-[(2,5- dioxopyrrolidin Calc'd yl)methyl](4- 380.2, cyclohexyl)quin Found 2-28 olinecarboxamide 380.2 O O N NH2 7-[(2,5- O dioxopyrrolidin Calc'd yl)methyl](4- 374.2, methylphenyl)quinoline Found 2-29 carboxamide 374.2 4-(4-fluorophenyl) Calc'd o-1,3-oxazolidin- 366.1, 3-yl)methyl]quinoline- Found 2-30 2-carboxamide 366.1 4-(4-fluorophenyl) [(3-methyl Calc'd oxoimidazolidin 379.2, yl)methyl]quinoline Found 2-31 carboxamide 379.2 - 78 – tert-butyl {[2- Calc'd carbamoyl(4- 396.2, fluorophenyl)quinolin- Found 2-32 7-yl]methyl}carbamate 396.2 O O O S N N NH2 7-[(1,1-dioxido-1,2- thiazinanyl)methyl]- Calc'd 4-(4- 414.1, fluorophenyl)quinoline- Found 2-33 F 2-carboxamide 414.1 7-[(1,1- dioxidoisothiazolidin- Calc'd ethyl](4- 400.1, fluorophenyl)quinoline- Found 2-34 2-carboxamide 400.1 4-(4-fluorophenyl) Calc'd [(3-oxomorpholin 380.1, yl)methyl]quinoline Found 2-35 carboxamide 380.1 luorophenyl) Calc'd [(2-oxopyrrolidin 346.1, yl)methyl]quinoline Found 2-36 carbonitrile 346.3 - 79 – luorophenyl) Calc'd [(2-oxopiperidin 378.2, yl)methyl]quinoline Found 2-37 carboxamide 378.2 7-[(2,5- dioxopyrrolidin Calc'd yl)methyl](4- 390.1, methoxyphenyl)quinoli Found 2-38 necarboxamide 390.0 7-[(2,5- dioxopyrrolidin yl)methyl](2-fluoro- Calc'd 4- 408.1, methoxyphenyl)quinoli Found 2-39 necarboxamide 408.0 Scheme 3.1 - 80 – N CN Br N Br NH2 2(Na2CO3 1.5H2O2) acetone:H2O, 50 C 2-1 3-1 N N N N NH2 Cs2CO3 DMF, rt Example 3.1: Synthesis of 7-((1H-benzo[d]imidazolyl)methyl)(4-fluorophenyl)quinoline amide (3-2) 7-(Bromomethyl)(4-fluorophenyl)quinolinecarboxamide (3-1) Sodium percarbonate (2.98 g, 9.50 mmol, 3.0 equiv.) in water (52.8 ml) was added dropwise to a solution of 7-(bromomethyl)(4-fluorophenyl)quinolinecarbonitrile (2-1, 1.08 g, 3.17 mmol, 1.0 equiv.) in acetone (106 ml) and the reaction stired for 1 hour at rt. The reaction was quenched with saturated KH2PO4 and the mixture was extracted with EtOAc (3x). The combined c ons were dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (120 g SiO2, 0-100% EtOAc/hexanes) to afford 7-(bromomethyl)- 4-(4-fluorophenyl)quinolinecarboxamide (3-1, 650 mg, 57%) as a white solid. LRMS m/z (M+H)+ 359.05 found, 359.19 ed. 7-((1H-Benzo[d]imidazolyl)methyl)(4-fluorophenyl)quinolinecarboxamide (3-2) Cs2CO3 (91 mg, 0.278 mmol, 2.0 equiv.) was added to a solution of 7-(bromomethyl)(4- fluorophenyl)quinolinecarboxamide (3-1, 50 mg, 0.139 mmol, 1.0 equiv.) and benzimidazole (18.09 mg, 0.153 mmol, 1.1 equiv.) in DMF (696 µl) and the reaction d at rt for 2 hours. The crude residue was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier). A Waters - 81 – Porapak® Rxn CX (6 cc) was conditioned with MeOH (5mL). ons containing the desired product were loaded onto the cartridge and the cartridge was washed with MeOH (10mL). The desired product was eluted with 2M NH3 in MeOH (5mL) and the solvent removed in vacuo to afford 7-((1HBenzo [d]imidazolyl)methyl)(4-fluorophenyl)quinolinecarboxamide (3-2, 23.6 mg, 43 %) as a white solid. 1H NMR (400 MHz, CD 3OD): δ 8.40 (s, 1 H); 8.09 (s, 1 H); 8.00-7.91 (m, 2 H); 7.73-7.70 (m, 1 H); 7.61-7.55 (m, 3 H); 7.47 (dd, J = 7.2, 2.0 Hz, 1 H); 7.33-7.23 (m, 4 H); 5.80 (s, 2 H). LRMS m/z (M+H)+ 397.17 found, 397.42 required.
Scheme 3.2 Example 3.2: Synthesis of 4-(4-fluorophenyl)((5-(1,1,1-trifluorohydroxybutanyl)- 2H-tetrazolyl)methyl)quinolinecarboxamide (3-6) 1,1,1-Trifluoro(2H-tetrazolyl)butanol (3-3) To 1,1,1-trifluorobutanone (5.0 g, 39.7 mmol, 1.0 equiv) was slowly added trimethylsilylcyanide (4.7 g, 47.6 mmol, 1.2 equiv) and the resulting mixture stirred overnight at ambient temperature. To the resulting mixture was added water (80 mL) ed by zinc de (5.4 g, 39.7 mmol, 1.0 equiv) and sodium azide (3.1 g, 47.1 mmol, 1.2 equiv) and the mixture was heated at 80°C for three hours. The mixture was cooled to room temperature and the precipitate was filtered and dried in vacuo to afford 1,1,1-trifluoro(2H-tetrazolyl)butanol (3-3) as a white solid. LRMS m/z (M+H)+ 197.0 found, 197.1 required. - 82 – 4-(4-fluorophenyl){[5-(1,1,1-trifluorohydroxybutanyl)-2H-tetrazol yl]methyl}quinolinecarbonitrile (3-4) 7-(Bromomethyl)(4-fluorophenyl)quinolinecarbonitrile (2-1, 120 mg, 0.35 mmol, 1.0 equiv), 1,1,1-trifluoro(2H-tetrazolyl)butanol (3-3, 83 mg, 0.42 mmol, 1.2 equiv) and potassium carbonate (146 mg, 1.1 mmol, 3.0 equiv) were combined in DMF (1.8 mL) and stirred at ambient temperature for 16 hours. The solids were filtered and the filtrate was purified by reverse phase HPLC (H 2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford 4-(4-fluorophenyl){[5-(1,1,1-trifluoro ybutanyl)-2H-tetrazolyl]methyl}quinolinecarbonitrile (3-4) and 4-(4-fluorophenyl){[5- (1,1,1-trifluorohydroxybutanyl)-1H-tetrazolyl]methyl}quinolinecarbonitrile (3-5). 1H NMR (3-4) (500 MHz, CDCl3): δ 8.26 (d, J = 1.7 Hz, 1 H); 7.99 (d, J = 8.8 Hz, 1 H); 7.68 (s, 1 H); 7.59 (dd, J = 8.8, 1.9 Hz, 1 H); 7.50-7.45 (m, 2 H); 7.31-7.25 (m, 2 H); 6.07 (s, 2 H); 2.33 (dt, J = 14.3, 7.4 Hz, 1 H); 2.24-2.16 (m, 1 H); 0.84 (t, J = 7.5 Hz, 3 H). LRMS m/z (M+H)+ 456.8 found, 457.1 required. 1H NMR (3-5) (500 MHz, CDCl3): δ 8.15 (s, 1 H); 7.94 (d, J = 8.8 Hz, 1 H); 7.65-7.61 (m, 2 H); 7.48- 7.44 (m, 2 H); 7.30-7.24 (m, 2 H); 6.13 (d, J = 15.0 Hz, 1 H); 6.01 (d, J = 15.0 Hz, 1 H); .06 (brs, 1 H); 2.75 (dt, J = 14.8, 7.5 Hz, 1 H); 2.16 (dq, J = 14.7, 7.3 Hz, 1 H); 0.89 (t, J = 7.4 Hz, 3 H). LRMS m/z (M+H)+ 456.8 found, 457.1 required. 4-(4-fluorophenyl){[5-(1,1,1-trifluorohydroxybutanyl)-2H-tetrazol yl]methyl}quinolinecarboxamide (3-6) 4-(4-Fluorophenyl){[5-(1,1,1-trifluorohydroxybutanyl)-2H-tetrazol yl]methyl}quinolinecarbonitrile (3-4, 14 mg, 0.031 mmol, 1.0 equiv) was dissolved in e (0.5 mL)/water (0.25 mL) and sodium percarbonate (48 mg, 0.15 mmol, 5.0 equiv) was added. The resulting mixture was heated to 50°C for two hours. The mixture was cooled and poured over aqueous NH4Cl (1 mL), extracted with ethyl e (3 x 5 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash column tography (SiO2, 12g ISCO column, 0-100% EtOAc/hexanes) to give 4-(4-fluorophenyl){[5-(1,1,1-trifluorohydroxybutanyl)-2H-tetrazol yl]methyl}quinolinecarboxamide (3-6) as a white solid. 1H NMR (3-6) (500 MHz, CDCl 3): δ 8.28 (s, 1 H); 8.17 (s, 1 H); 8.06 (s, 1 H); 7.99 (d, J = 8.7 Hz, 1 H); 7.55-7.44 (m, 3 H); 6.05 (s, 2 H); 5.84 (s, 1 H); 3.92 (s, 1 H); 2.33 (dt, J = 14.4, 7.4 Hz, 1 H); 2.20 (dt, J = 14.3, 7.2 Hz, 1 H); 0.84 (t, J = 7.4 Hz, 3 H). LRMS m/z (M+H) 474.9 found, 475.1 required. 1H NMR (3-7) (500 MHz, CD 3OD): δ 8.12 (s, 1 H); 8.08 (s, 1 H); 7.96 (d, J = 8.8 Hz, 1 H); 7.64-7.55 (m, 3 H); 7.34-7.29 (m, 2 H); 6.25 (d, J = 15.1 Hz, 1 H); 6.15 (d, J = 15.1 Hz, 1 H); 2.57 (dd, J = 14.4, 7.3 Hz, 1 H); 2.13 (dq, J = 14.4, 7.2 Hz, 1 H); 0.78 (t, J = 7.4 Hz, 3 H). LRMS m/z (M+H)+ 474.7 found, 475.1 required. - 83 – Scheme 3.3 N CN N N N CN Br N OHC 2(Na2CO3 1.5H2O2) DIEA acetone:H2O, 50 C CH3CN, 180 C F F 2-1 3-8 O O N N N N N NH2 N NH2 MgBr Dess-Martin Periodinane THF, 0 C CH2Cl2, 0 C F F 3-9 3-10 N N N NH2 3-11 Example 3.3: Synthesis of (cyclopropylcarbonyl)-1 H-pyrazolyl]methyl}(4- fluorophenyl)quinolinecarboxamide (3-11) 4-(4-Fluorophenyl)[(4-formyl-1 H-pyrazolyl)methyl]quinolinecarbonitrile (3-8) 7-(Bromomethyl)(4-fluorophenyl)quinolinecarbonitrile (2-1, 100.0 mg, 0.293 mmol, 1.0 equiv.), DIEA (0.051 ml, 0.293 mmol, 1.0 equiv.), and 1-H-pyrazolecarbaldehyde (33.8 mg, 0.352 mmol, 1.2 ) were added to acetonitrile (1.0 mL) in a microwave reaction vessel and the resulting mixture was irradiated with ave at 180 °C for 30 minutes. The reaction mixture was cooled and concentrated and the residue was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford 4-(4-fluorophenyl)[(4-formyl-1 H-pyrazolyl)methyl]quinolinecarbonitrile (3- 8, 55.0 mg, 52.7%) as a colorless solid. LRMS m/z (M+H)+ 357.1 found, 357.1 required. - 84 – 4-(4-Fluorophenyl)[(4-formyl-1 H-pyrazolyl)methyl]quinolinecarboxamide (3-9) 4-(4-Fluorophenyl)[(4-formyl-1H-pyrazolyl)methyl]quinolinecarbonitrile (3-8), 51 mg, 0.143 mmol, 1.0 equiv.) was dissolved in acetone (1.0 mL)/water (0.5 mL) and sodium percarbonate (225.0 mg, 0.716 mmol, 5.0 equiv) was added. The resulting mixture was d at 50°C for two hours.
The mixture was cooled and poured over aqueous NH4Cl (saturate,1.0 mL), extracted with Ethyl Acetate (3 x 5.0 mL), dried over MgSO4, filtered and concentrated. The residue was ed by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA er) to afford 4-(4-Fluorophenyl)[(4-formyl-1 H- pyrazolyl)methyl]quinolinecarbonitrile (3-9, 40.0 mg, 74.7%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ 9.879 (s, 1 H); 8.262 (s, 1 H); 8.056 (br s, 2 H); 8.021 (br s, 2 H); 7.972 (d, J= 8.80 Hz,1 H); 7.462-7.512 (m, 3 H); 7.216-7.259 (m, 2 H); 5.705 (br s, 1 H); 5.589 (s, 2 H). LRMS m/z (M+H) + 375.1 found, 375.1 required.
[Cyclopropyl(hydroxy)methyl]-1 H-pyrazolyl}methyl)(4-fluorophenyl)quinoline carboxamide (3-10 ) To a 0°C solution of 4-(4-fluorophenyl)[(4-formyl-1H-pyrazolyl)methyl]quinoline carboxamide (3-9, 36.0 mg, 0.0960 mmol, 1.0 equiv.) in anhydrous THF, under nitrogen was added dropwise 0.5 M cyclopropylmagnesium bromide in THF (0.769 mL, 0.385 mmol, 4.0 equiv.). The resulting e was stirred at 0°C for 1 hour, ed with sat. aqueous NH4Cl, extracted with ethyl acetate (3 x 5.0 mL), dried over MgSO4, filtered and concentrated. The residue was ed by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford 7-({4- [cyclopropyl(hydroxy)methyl]-1 H-pyrazolyl}methyl)(4-fluorophenyl)quinolinecarboxamide (3- , 25.0 mg, 62.4%) as a colorless solid. 1H NMR (400 MHz, CDCl 3): δ 8.228 (s, 1 H); 8.084 (br s, 1 H); 7.995 (s, 1 H); 7.929 (d, J= 8.81 Hz,1 H); 7.625 (s, 1 H); 7.515 (s, 1 H); 7.442-7.506 (m, 3 H); 7.206- 7.249 (m, 2 H); 5.777 (br s, 1 H); 5.526 (s, 2 H); 4.044 (d, J= 8.48 Hz,1 H); 1.185-1.258 (m, 1 H); 0.599-0.638 (m, 2 H); 0.331-0.454 (m, 2 H). LRMS m/z (M+H)+ 417.2 found, 417.2 required. 7-{[4-(Cyclopropylcarbonyl)-1H-pyrazolyl]methyl}(4-fluorophenyl)quinolinecarboxamide (3- 11 ) To a room ature solution of 7-({4-[cyclopropyl(hydroxy)methyl]-1 H-pyrazol yl}methyl)(4-fluorophenyl)quinolinecarboxamide (3-10 , 22 mg, 0.053 mmol, 1.0 equiv.) in methylene chloride (1.0 mL) was added Dess-Martin Periodinane (67.2 mg, 0.158 mmol, 3.0 equiv.) and the mixture was stirred at room temperature overnight. Aqueous Na2S2O3 ate, 2.0 mL) and aqueous sodium hydrogen carbonate (saturate, 5.0 mL) were added and the mixture was extracted with ethyl - 85 – acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford (cyclopropylcarbonyl)-1H-pyrazolyl]methyl}(4-fluorophenyl)quinoline carboxamide (3-11, 3.30 mg, 15.1%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ 8.239 (s, 1 H); 8.179 (br s, 1 H); 8.088 (s, 1 H); 8.039 (s, 1 H); 8.017 (s, 1 H); 7.965 (d, J= 8.81 Hz,1 H); 7.466-7.510 (m, 3 H); 7.219-7.263 (m, 2 H); 6.369 (br s, 1 H); 5.585 (s, 2 H); 2.283-2.345 (m, 1 H); 1.187-1.225 (m, 2 H); 0.958-1.004 (m, 2 S m/z (M+H)+ 415.2 found, 415.2 required.
Scheme 3.4 Example 3.4: 4-(o-Tolyl)((4-(1,1,1-trifluorohydroxybutanyl)-1H-1,2,3-triazol yl)methyl)quinolinecarboxamide (3-15) 7-(Azidomethyl)chloroquinolinecarbonitrile (3-12) Sodium azide (1.690 g, 26.0 mmol, 1.3 equiv.) was added to a stirred solution of 7- (bromomethyl)chloroquinolinecarbonitrile (2-4, 5.63 g, 20.00 mmol) in 100 ml of EtOH, and the - 86 – resulting slurry mixture was refluxed for 1 h. The mixture was cooled to rt, water (100 ml) was added, and the slurry was stirred at rt for 30 min. The resulting solid was collected by filtration and air dried to afford domethyl)chloroquinolinecarbonitrile (3-12 , 4.75 g, 97%) as a white solid. LRMS m/z (M+H) + 244.1 found, 244.65 required. (1-((4-Chlorocyanoquinolinyl)methyl)-1H-1,2,3-triazolyl)-1,1,1-trifluorobutanyl 4- enzoate (3-13 ) To a solution of 7-(azidomethyl)chloroquinolinecarbonitrile (3-12, 1 g, 4.10 mmol, 1 equiv.) and (S)(trifluoromethyl)pentynyl 4-nitrobenzoate (1.360 g, 4.51 mmol, 1.1 equiv.) in THF (20.5 mL) was added DIEA (3.58 ml, 20.52 mmol, 5 equiv.) and copper (I) iodide (1.172 g, 6.16 mmol, 1.5 equiv.), then stirred at rt for 2h. The reaction was d by addition of saturated NH4Cl. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO 4, filtered and concentrated. The residue was treated with MeOH. The resulting solid was collected by filtration, washed with MeOH, and air dried to afford (S)(1-((4-chlorocyanoquinolinyl)methyl)- 1H-1,2,3-triazolyl)-1,1,1-trifluorobutanyl 4-nitrobenzoate (3-13 , 1.58 g, 71%) as a colorless solid.
LRMS m/z (M+H)+ 545.4 found, 545.9 required. 4-Chloro((4-[(2S)-(1,1,1-trifluorohydroxybutanyl)]-1H-1,2,3-triazolyl)methyl)quinoline carboxamide (3-14 ) To (S)(1-((4-chlorocyanoquinolinyl)methyl)-1H-1,2,3-triazolyl)-1,1,1- trifluorobutanyl 4-nitrobenzoate (3-13 , 1.58 g, 2.90 mmol, 1 equiv.) in e/H2O (38.7 ml/19.33 mL) was added sodium percarbonate (4.55 g, 14.50 mmol, 5 equiv.) and the mixture was heated to 50 °C ght. The reaction was incomplete. Sodium percarbonate (4.55 g, 14.50 mmol, 5 equiv.) was added and stirred for an additional 5 hr. The mixture was cooled, water was added, and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried ), filtered, and the solvent was evaporated under reduced pressure to afford 4-chloro((4-[(2S)-(1,1,1-trifluoro hydroxybutanyl)]-1H-1,2,3-triazolyl)methyl)quinolinecarboxamide (3-14 , 1.09 g, 91%) as light yellow solid. LRMS m/z (M+H)+ 414.3 found, 414.8 required. 7-({4-[(1S)hydroxy(trifluoromethyl)propyl]-1H-1,2,3-triazolyl}methyl)(2- methylphenyl)quinolinecarboxamide (3-15 ) 4-chloro({4-[(2S)-1,1,1-trifluorohydroxybutanyl]-1H-1,2,3-triazol yl}methyl)quinolinecarboxamide (3-14 , 8 mg, 0.02 mmol, 1.0 equiv.), (2-methylphenyl)boronic acid (5 mg, 0.04 mmol, 2 equiv.), Pd(PPh3)4 (0.7 mg, 0.0006 mmol, 0.03 equiv.) and 2M aqueous Na 2CO 3 - 87 – (0.02 mL, 0.05 mmol, 2.5 equiv.) were suspended in Dioxane (0.4 mL) and the reaction mixture was heated overnight at 100 °C. The crude mixture was filtered, concentrated and purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford [(1S)hydroxy (trifluoromethyl)propyl]-1H-1,2,3-triazolyl}methyl)(2-methylphenyl)quinolinecarboxamide (3- 15). LRMS m/z (M+H)+ 470.1 found, 470.2 required.
Scheme 3.5 Example 3.5: sis of 4-(5-fluoropyridinyl)({4-[(2S)-1,1,1-trifluorohydroxybutanyl]- 1H-1,2,3-triazolyl}methyl)quinolinecarboxamide (3-16) 4-(5-Fluoropyridinyl)({4-[(2S)-1,1,1-trifluorohydroxybutanyl]-1H-1,2,3-triazol hyl)quinolinecarboxamide (3-16) ro({4-[(2S)-1,1,1-trifluorohydroxybutanyl]-1H-1,2,3-triazol yl}methyl)quinolinecarboxamide (3-14, 16.0 mg, 0.039 mmol, 1.0 equiv), (5-fluoropyridin yl)boronic acid (22 mg, 0.097 mmol, 2.5 equiv), cesium carbonate (25 mg, 0.077 mmol, 2.0 equiv), DPPF (2.1 mg, 0.004 mmol, 0.1 equiv), copper(I) chloride (3.8 mg, 0.039 mmol, 1.0 equiv) and palladium(II) acetate (0.43 mg, 0.002 mmol, 0.05 equiv) were ed and purged with argon. DMF (0.4 mL) was added and the mixture was heated at 100°C for 14 hours. The mixture was filtered purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford 4-(5-fluoropyridinyl)({4- [(2S)-1,1,1-trifluorohydroxybutanyl]-1H-1,2,3-triazolyl}methyl)quinolinecarboxamide (3-16) as a white solid. LRMS m/z (M+H)+ 475.1 found, 475.2 required The following nds have been prepared according to procedures similar to those found in Scheme 2.1, 3.1, 3.2, 3.3, 3.4, and 3.5 selecting the appropriate quinoline derivative, nucleophile, and boronic acid derivative and provide examples of compounds in the invention. - 88 – Table 3 Exact Mass Example Structure IUPAC Name [M+H]+ 4-(6- fluoropyridin yl)({4-[(1R) hydroxy N N N N NH2 (trifluoromethyl)p HO F ropyl]-1H-1,2,3- F triazol Calc'd 475.2, F N yl}methyl)quinoli Found 3-17 F necarboxamide 475.2 4-(2- fluorophenyl) ({4-[(1S) hydroxy (trifluoromethyl)p ropyl]-1H-1,2,3- triazol Calc'd 474.2, hyl)quinoli Found 3-18 necarboxamide 474.1 4-(2- fluoropyridin yl)({4-[(1S) hydroxy (trifluoromethyl)p ropyl]-1H-1,2,3- l Calc'd 475.2, yl}methyl)quinoli Found 3-19 necarboxamide 475.1 - 89 – 4-(4- chlorophenyl) ({4-[(1S) hydroxy (trifluoromethyl)p ropyl]-1H-1,2,3- triazol Calc'd 490.1, yl}methyl)quinoli Found 3-20 necarboxamide 490.0 ethyl 1-{[2- carbamoyl(4- fluorophenyl)quin olinyl]methyl}- Calc'd 419.2, 1H-pyrazole Found 3-21 carboxylate 419.2 ethyl 1-{[2- oyl(4- fluorophenyl)quin olinyl]methyl}- (trifluoromethyl)- Calc'd 487.1, 1H-pyrazole Found 3-22 carboxylate 487.1 7-({4- [cyclopentyl(hydr oxy)methyl]-1H- pyrazol yl}methyl)(4- fluorophenyl)quin Calc'd 445.2, 2- Found 3-23 carboxamide 445.2 - 90 – methyl 1-{[2- carbamoyl(4- phenyl)quin olinyl]methyl}- Calc'd 405.1, 1H-pyrazole Found 3-24 carboxylate 405.1 7-[(4-bromo-1H- imidazol yl)methyl](4- fluorophenyl)quin Calc'd 425.0, oline Found 3-25 carboxamide 425.0 methyl 1-{[2- carbamoyl(4- fluorophenyl)quin -yl]methyl}- Calc'd 405.1, 1H-imidazole Found 3-26 carboxylate 405.1 methyl 1-{[2- carbamoyl(4- fluorophenyl)quin olinyl]methyl}- Calc'd 405.1, 1H-imidazole Found 3-27 carboxylate 405.1 1-{[2-carbamoyl- 4-(4- fluorophenyl)quin olinyl]methyl}- Calc'd 392.1, 1H-1,2,3-triazole- Found 3-28 4-carboxylic acid 392.1 - 91 – 4-(4- fluorophenyl) (1H-imidazol Calc'd 347.1, yl)quinolin Found 3-29 ecarboxamide 347.1 4-(4- fluorophenyl) {[2-(1- methylethyl)-1H- imidazol Calc'd 389.2, yl]methyl}quinoli Found 3-30 necarboxamide 389.2 4-(4- fluorophenyl) [(2-methyl-1H- ol Calc'd 361.1, yl)methyl]quinoli Found 3-31 necarboxamide 361.1 7-[(2-chloro-1H- imidazol yl)methyl](4- fluorophenyl)quin Calc'd 381.1, oline Found 3-32 carboxamide 381.1 4-(4- fluorophenyl) (3H-imidazo[4,5- b]pyridin Calc'd 398.1, ylmethyl)quinolin Found 3-33 ecarboxamide 398.1 - 92 – 4-(4- fluorophenyl) (1H-imidazo[4,5- b]pyridin Calc'd 398.1, ylmethyl)quinolin Found 3-34 ecarboxamide 398.1 1-{[2-carbamoyl- O S O O N 4-(4- N N NH2 fluorophenyl)quin olinyl]methyl}- 1H- Calc'd 477.1, benzimidazole Found 3-35 F sulfonic acid 477.1 N 4-(4- N fluorophenyl) N N NH2 ridinyl- 1H-benzimidazol- 1- Calc'd 474.2, yl)methyl]quinoli Found 3-36 F arboxamide 474.2 4-(4- N fluorophenyl) N N NH2 [(2-pyridinyl- 1H-benzimidazol- 1- Calc'd 474.2, yl)methyl]quinoli Found 3-37 F necarboxamide 474.2 4-(4- fluorophenyl) {[2-(2,2,2- trifluoroethyl)- Calc'd 480.1, 1H-benzimidazol- Found 3-38 1- 480.1 - 93 – yl]methyl}quinoli necarboxamide N 7-[(2-cyclopropyl- N N NH2 1H-benzimidazol- 1-yl)methyl](4- fluorophenyl)quin Calc'd 437.2, oline Found 3-39 F carboxamide 437.2 N 7-[(2-cyclobutyl- N N NH2 1H-benzimidazol- 1-yl)methyl](4- fluorophenyl)quin Calc'd 451.2, oline Found 3-40 F carboxamide 451.2 N 7-[(2-cyclopentyl- N N NH2 zimidazol- 1-yl)methyl](4- fluorophenyl)quin Calc'd 465.2, 2- Found 3-41 F carboxamide 465.2 4-(4- fluorophenyl) [(2-methyl-1H- benzimidazol Calc'd 411.2, yl)methyl]quinoli Found 3-42 necarboxamide 411.2 - 94 – 4-(4- N fluorophenyl) N N NH2 {[2-(1- methylethyl)-1H- benzimidazol Calc'd 439.2, yl]methyl}quinoli Found 3-43 F necarboxamide 439.2 4-(4- fluorophenyl) ({4-[(1S) hydroxy uoromethyl)p ropyl]-1H- imidazol Calc'd 473.2, yl}methyl)quinoli Found 3-44 necarboxamide 473.2 4-(4- fluorophenyl) ({4-[(1R) hydroxy (trifluoromethyl)p -1H- imidazol Calc'd 473.2, yl}methyl)quinoli Found 3-45 necarboxamide 473.2 F 4-(3,4- N OH dimethoxyphenyl) ({4-[1- N O N y (trifluoromethyl)p ropyl]-1H- imidazol O yl}methyl)quinoli Calc'd 515.2, 3-46 O necarboxamide Found 515.3 - 95 – F 7-({4-[1-hydroxy- F 1- N OH (trifluoromethyl)p ropyl]-1H- N O N imidazol yl}methyl)(4- methoxy methylphenyl)qui noline Calc'd 499.2, 3-47 O amide Found 499.3 4-(2-fluoro methoxyphenyl)- 7-({4-[1-hydroxy- uoromethyl)p ropyl]-1H- imidazol yl}methyl)quinoli Calc'd 503.2, 3-48 necarboxamide Found 503.2 4-(3-fluoro methoxyphenyl)- 7-({4-[1-hydroxy- F F O F 1- N NH2 (trifluoromethyl)p ropyl]-1H- ol F yl}methyl)quinoli Calc'd 503.2, 3-49 O necarboxamide Found 503.2 4-(2-fluoro F F O F methoxyphenyl)- N NH2 7-({4-[1-hydroxy- (trifluoromethyl)p ropyl]-1H- Calc'd 503.2, 3-50 O imidazol Found 503.2 - 96 – hyl)quinoli necarboxamide 7-({4-[1-hydroxy- (trifluoromethyl)p F F O F ropyl]-1H- N NH2 imidazol yl}methyl)(4- methoxyphenyl)q uinoline Calc'd 485.2, 3-51 O carboxamide Found 485.4 Scheme 4.1 Example 4.1: Synthesis of 4-(4-fluorophenyl)(morpholinylmethyl)quinolinecarboxamide (4- 4-(4-Fluorophenyl)(morpholinylmethyl)quinolinecarboxamide (4-1) To a room temperature solution of 7-(bromomethyl)(4-fluorophenyl)quinolinecarbonitrile (2-1, 311.0 mg, 0.895 mmol, 1.0 equiv.) in acetonitrile (10.0 mL) was added ine (85.77 mg, 0.985 mmol, 1.1 equiv.) and 5.0 M aqueous NaOH (2.69 mL, 13.43 mmol, 15 equiv.), and the resulting mixture was d at 50 °C for 4 days. After cooling to room temperature, water (100.0 mL) was added and the mixture was stirred for 30 minutes. A yellow solid was collected via suction filtration, washed with water, dried in vacuo. The solid was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA er) to afford 4-(4-fluorophenyl)(morpholinylmethyl)quinolinecarboxamide (4-1, 291.0 mg, 80.0%) as a colorless solid. 1H NMR (500 MHz, CDCl 3): δ 8.216 (s, 1 H); 8.098 (br s, 2 H); 7.911 (d, J= - 97 – 8.54 Hz,1 H); 7.642 (d, J= 8.55 Hz,1 H); 7.529 (m, 2 H); 7.219-7.263 (m, 2 H); 5.798 (br s, 1 H); 3.734 (br s, 6 H); 2.528 (br s, 2 H). LRMS m/z (M+H)+ 366.2 found, 366.2 required.
Scheme 4.2 Example 4.2: sis of 4-(1-methyl-1H-pyrazolyl)(((2R,6R)methyl (trifluoromethyl)morpholino)methyl)quinolinecarboxamide (4-9) (R)(Benzylamino)-1,1,1-trifluoropropanol (4-2) To a solution of lithium trifluoromethanesulfonate (1.43 g, 9.17 mmol) in CH3CN (30 ml) was added (R)-(+)-3,3,3-trifluoro-1,2-epoxypropane (10.77 g, 96 mmol) slowly at -10 °C. After 5 minutes benzylamine (10 ml, 92 mmol) was added slowly. The mixture was allowed to warm as the bath warmed to rt overnight. The mixture was concentrated. The crude product was subjected to silica gel chromatography (330g, 0-50% EtOAc/hexanes, 10 minute gradient) to afford (R)(benzylamino)-1,1,1- trifluoropropanol (4-2, 15.9 g, 79%) as a white solid. LRMS m/z (M+H)+ 220.2 calc.; 220.1 found. - 98 – (S)-N-Benzylhydroxy-N-((R)-3,3,3-trifluorohydroxypropyl)propanamide (4-3) To a solution of (R)(benzylamino)-1,1,1-trifluoropropanol (4-2, 5 g, 22.81 mmol) in CH 3CN (200 ml) was added DIEA (12 ml, 68.7 mmol), chloropropionic acid (2.4 ml, 27.4 mmol), then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (16.3 ml, 27.4 mmol) slowly at rt.
After 2.5 hr the mixture was trated. The material was taken up in EtOAc and washed with saturated NaHCO3, H2O, and brine. The organic layer was filtered through a pad of silica gel g with ethyl acetate then concentrated to afford (S)-N-benzylhydroxy-N-((R)-3,3,3-trifluoro hydroxypropyl)propanamide (4-3) as a clear oil which was sufficiently pure for use in the next step.
)Benzylmethyl(trifluoromethyl)morpholinone (4-4) A solution of (S)-N-benzylhydroxy-N-((R)-3,3,3-trifluorohydroxypropyl)propanamide (4- 3) in THF (200 ml) was cooled to 0 °C. To this was added NaH (60% dispersion in mineral oil, 1.05 g, 26.3 mmol) portionwise as a solid. After 1 hr the cooling bath was removed and the mixture allowed to warm to rt. After an additional hour the mixture was quenched with brine. The mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford (2R,6R)benzylmethyl(trifluoromethyl)morpholinone (4-4) as a clear oil which was iently pure for use in the next step. (2R,6R)Benzylmethyl(trifluoromethyl)morpholine ( 4-5) To a solution of (2R,6R)benzylmethyl(trifluoromethyl)morpholinone (4-4) was added 1M LAH (48 ml, 48.0 mmol) in THF slowly at rt. After the on was complete the mixture was heated to reflux. After 1 hr the mixture was cooled to rt then 0 °C. The mixture was slowly quenched with 2M NaOH until gas evolution had ceased and a fine white precipitate formed. Anhydrous MgSO4 was added and the mixture stirred for 15 minutes The slurry was filtered through a pad of celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (120 g, 0- % EtOAc/hexanes, 15 minute gradient) to give a afford (2R,6R)benzylmethyl uoromethyl)morpholine (4-5, 4.1 g, 66% over 3 steps) as clear oil. 1H NMR (400 MHz, CDCl 3): δ 7.35-7.26 (m, 5 H); 4.02 (dqd, J = 10.7, 6.4, 2.5 Hz, 1 H); 3.76-3.69 (m, 1 H); 3.60-3.48 (m, 2 H); 2.89 (d, J = 11.1 Hz, 1 H); 2.73-2.68 (m, 1 H); 2.16-2.04 (m, 1 H); 1.91-1.79 (m, 1 H); 1.19 (d, J = 6.3 Hz, 3 (2R,6R)Methyl(trifluoromethyl)morpholine hydrochloride (4-6) - 99 – To a on of (2R,6R)benzylmethyl(trifluoromethyl)morpholine (4-5, 4.1 g, 15.81 mmol) in MeOH (80 ml) was added concentrated HCl (6.6 ml, 79 mmol). This mixture was transfered to a Parr bottle containing 10% Pd/C (1.7 g, 1.597 mmol). The mixture was hydrogenated (45 psi) overnight. The mixture was filtered through a pad of Celite washing with MeOH then concentrated. The residue was taken up in MeOH and trated (3x) to afford (2R,6R)methyl (trifluoromethyl)morpholine hydrochloride (4-6, 3.34 g, 103%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 4.59 (bs, 2 H); 4.27 (bs, 2 H); 3.01 (bs, 1 H); 2.79 (bs, 1 H); 1.33 (s, 3 H). 4-Chloro(((2R,6R)methyl(trifluoromethyl)morpholino)methyl)quinolinecarbonitrile (4-7) (2R,6R)Methyl(trifluoromethyl)morpholine hloride (4-6, 500 mg, 2.432 mmol) and K2CO 3 (739 mg, 5.35 mmol) were combined in CH3CN (10 ml) at rt. To this was added 7- (bromomethyl)chloroquinolinecarbonitrile (2-4, 753 mg, 2.68 mmol) all at once as a solid then the mixture was heated to 60 °C overnight. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc (3x). The combined organic layers were filtered h a pad of Celite washing with EtOAc then concentrated. The crude product was subjected to silica gel tography (50g, 0-10% EtOAc/hexanes, 15 minute gradient) to afford 4-chloro(((2R,6R)methyl (trifluoromethyl)morpholino)methyl)quinolinecarbonitrile (4-7, 859, 96%) as a white foam. 1H NMR (400 MHz, : δ 8.26 (d, J = 8.7 Hz, 1 H); 8.11 (s, 1 H); 7.83 (dd, J = 8.6, 1.6 Hz, 1 H); 7.78 (s, 1 H); 4.09-4.01 (m, 1 H); 3.79 (m, 3 H); 2.90 (d, J = 10.9 Hz, 1 H); 2.73 (d, J = 11.4 Hz, 1 H); 2.28-2.17 (m, 1 H); 2.03-1.92 (m, 1 H); 1.20 (d, J = 6.2 Hz, 3 H). 4-(1-Methyl-1H-pyrazolyl)(((2R,6R)methyl(trifluoromethyl)morpholino)methyl)quinoline carbonitrile (4-8) 4-Chloro(((2R,6R)methyl(trifluoromethyl)morpholino)methyl)quinolinecarbonitrile (4-7, 859 mg, 2.323 mmol), 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (725 mg, 3.48 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), and X-Phos (111 mg, 0.232 mmol) were combined in THF (10 ml). To this was added 1M K3PO 4 (7 ml, 7.00 mmol). The mixture was ed (3 x pump/N 2) then heated to 70 °C overnight. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc (3x). The combined organic layers were filtered through a pad of Celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (100g, 50% EtOAc/hexanes) to afford 4-(1-methyl-1H-pyrazolyl)(((2R,6R)methyl (trifluoromethyl)morpholino)methyl)quinolinecarbonitrile (4-8, 650 mg, 67%) as a white solid. 1H NMR (399 MHz, CDCl3): δ 8.22 (d, J = 8.7 Hz, 1 H); 8.10 (s, 1 H); 7.86 (s, 1 H); 7.78 (s, 1 H); 7.71 - 100 – (dd, J = 8.7, 1.7 Hz, 1 H); 7.63 (s, 1 H); 4.07 (m, 3 H); 3.78 (m, 3 H); 2.92 (d, J = 11.0 Hz, 1 H); 2.75 (d, J = 11.4 Hz, 1 H); 2.22 (t, J = 10.8 Hz, 1 H); 1.97 (t, J = 10.8 Hz, 1 H); 1.20 (d, J = 6.3 Hz, 3 H). 4-(1-Methyl-1H-pyrazolyl)(((2R,6R)methyl(trifluoromethyl)morpholino)methyl)quinoline carboxamide (4-9) 4-(1-Methyl-1H-pyrazolyl)(((2R,6R)methyl (trifluoromethyl)morpholino)methyl)quinolinecarbonitrile (4-8, 650 mg, 1.565 mmol) was taken up in trated HCl (10 ml) and stirred at rt. After 3 hrs the mixture was quenched by slow addition of it to a solution of K2CO 3 (17 g) in 100 ml H2O. The reaction flask was rinsed into the quench with H2O bringing the total volume to 150 mL H2O. The resulting mixture was stirred at rt for 1 hr. The off-white solid was ted by filtration, washed with H2O, and air dried. The crude product was subjected to silica gel chromatography (40 g, 100% EtOAc) to afford 4-(1-methyl-1H-pyrazolyl)(((2R,6R) methyl(trifluoromethyl)morpholino)methyl)quinolinecarboxamide (4-9, 592 mg, 87%) as a white foam. 1H NMR (399 MHz, CDCl 3): δ 8.27-8.22 (m, 2 H); 8.10 (bs, 1 H); 8.04 (s, 1 H); 7.90 (s, 1 H); 7.80 (s, 1 H); 7.65 (dd, J = 8.7, 1.7 Hz, 1 H); 5.67 (bs, 1 H); 4.06 (m, 3 H); 3.82-3.74 (m, 3 H); 2.95 (d, J = 11.0 Hz, 1 H); 2.77 (d, J = 11.5 Hz, 1 H); 2.21 (t, J = 10.8 Hz, 1 H); 2.05 (s, 1 H); 1.96 (t, J = 10.8 Hz, 1 H); 1.20 (d, J = 6.3 Hz, 3 H); LRMS m/z (M+H)+ 434.4 calc.; 434.3 found.
Scheme 4.3 - 101 – KOtBu TFAA, TEA EtO2C SH CHO + NO2 THF, t-BuOH HO NO2 CH2Cl2, 0 C NO2 TEA, THF 4-10 4-11 N CN Zn Br S NO2 S NH S NH HOAc, 70 C THF EtO2C O 4-12 4-13 4-14 N CN N N N NH2 K2CO3 S conc. HCl CH3CN, 60 C rt N N N N 4-15 4-16 Example 4.3: Synthesis of 7-((2-cyclopropylthiomorpholino)methyl)(1-methyl-1H-pyrazol yl)quinolinecarboxamide (4-16) 1-Cyclopropylnitroethanol (4-10) A mixture of THF (10 ml) and t-BuOH (10.00 ml) was cooled to 0 ºC. To this was added cyclopropanecarboxaldehyde (1.1 ml, 14.60 mmol) and nitromethane (1.18 ml, 21.88 mmol). After stirring 5 minutes 1M KOtBu (2.92 ml, 2.92 mmol) in THF was added slowly. During the addition a white solid formed. The e was allowed to warm as the bath warmed to rt overnight. The mixture was d with saturated aqueous NH4Cl and extracted with CH2Cl2 (3x). The combined c layers were dried (MgSO4), filtered, and concentrated (no heat) to afford 1-cyclopropylnitroethanol (4-10, 1.9 g, 99%) as a clear oil which was sufficiently pure for use in the next step. 1H NMR (399 MHz, CDCl 3): δ 4.56-4.52 (m, 2 H); 3.72-3.64 (m, 1 H); 2.42 (d, J = 3.9 Hz, 1 H); 0.99-0.90 (m, 1 H); 0.68-0.59 (m, 2 H); 0.52-0.44 (m, 1 H); 0.39-0.32 (m, 1 H).
(E)-(2-Nitrovinyl)cyclopropane (4-11) Crude 1-cyclopropylnitroethanol (4-10, 1.9 g, 14.49 mmol) was taken up in CH2Cl2 (20 ml) then cooled to 0 °C. To this was added TFAA (2.3 ml, 16.28 mmol) followed by a slow addition of TEA - 102 – (4.5 ml, 32.3 mmol). The mixture was allowed to warm as the bath warmed to rt. After 3 hr the mixture was filtered through a pad of silica gel washing with CH2Cl 2. The filtrate was concentrated (no heat) to a yellow oil. The oil was taken up in 20% Et2O/hexanes and ed through a pad of silica gel washing with 20% Et2O/hexanes. The filtrate was concentrated (no heat) to afford (E)-(2-nitrovinyl)cyclopropane (4-11 , 1.49 g, 91%) as a very pale yellow oil which was sufficiently pure for use in the next step. 1H NMR (399 MHz, : δ 7.14 (d, J = 13.2 Hz, 1 H); 6.79 (dd, J = 13.2, 10.8 Hz, 1 H); 1.68-1.58 (m, 1 H); 1.19-1.11 (m, 2 H); 0.84-0.78 (m, 2 H).
Ethyl 2-((1-cyclopropylnitroethyl)thio)acetate (4-12 ) (E)-(2-Nitrovinyl)cyclopropane (4-11 , 750 mg, 6.63 mmol) was taken up in THF (20 mL). To this was added ethyl thioglycolate (0.88 mL, 7.98 mmol) then TEA (1.2 mL, 8.61 mmol) at rt. After ng overnight the mixture was concentrated. The crude product was subjected to silica gel chromatography (40 g, 0-20% EtOAc/hexanes, 10 minute gradient) to afford ethyl 2-((1-cyclopropyl nitroethyl)thio)acetate (4-12 , 1.46 g, 94%) as a clear oil. 1H NMR (399 MHz, CDCl 3): δ 4.73-4.58 (m, 2 H); 4.21 (q, J = 7.1 Hz, 2 H); 3.34 (d, J = 6.2 Hz, 2 H); 2.93 (dt, J = 9.9, 7.2 Hz, 1 H); 1.30 (t, J = 7.1 Hz, 3 H); 1.00-0.90 (m, 1 H); 0.69 (dd, J = 8.0, 1.6 Hz, 2 H); 0.47-0.36 (m, 2 H). 6-Cyclopropylthiomorpholinone (4-13 ) Ethyl 2-((1-cyclopropylnitroethyl)thio)acetate (4-12 , 1.46 g, 6.26 mmol) was taken up in AcOH (30 ml). To this was added zinc powder (4093 mg, 62.6 mmol) then the mixture was heated to 70 ºC. After stirring overnight the mixture was cooled to rt, diluted with AcOH, filtered h a pad of Celite washing with AcOH, and concentrated. The crude product was subjected to silica gel chromatography (40 g, 0-100% EtOAc/hexanes, 10 minute gradient) to afford 6- cyclopropylthiomorpholinone (4-13 , 355 mg, 36%) as an amber oil which solidified slowly under vacuum. 1H NMR (399 MHz, CDCl 3): δ 6.65 (s, 1 H); 3.65 (dt, J = 13.2, 4.4 Hz, 1 H); 3.54-3.46 (m, 1 H); 3.32 (s, 2 H); .39 (m, 1 H); 0.98-0.89 (m, 1 H); 0.67-0.58 (m, 2 H); 0.41-0.25 (m, 2 H). opropylthiomorpholine (4-14 ) A solution of opropylthiomorpholinone (4-13 , 355 mg, 2.258 mmol) in THF (10 ml) was cooled to 0 °C. To this was added 2M LAH (2.3 ml, 4.60 mmol) slowly. After the addition was complete the cooling bath was removed and the mixture allowed to warm to rt. After stirring overnight the mixture was cooled to 0ºC and slowly quenched with 2M NaOH until gas evolution had ceased and a fine white precipitate formed. Anhydrous Na2SO 4 was added and the mixture d for 15 minutes. The slurry was filtered through a pad of Celite washing with THF and the filtrate concentrated to afford 2- - 103 – cyclopropylthiomorpholine (4-14 , 242 mg, 75%) as a pale yellow oil which was used in subsequent steps as is. 7-((2-Cyclopropylthiomorpholino)methyl)(1-methyl-1H-pyrazolyl)quinolinecarbonitrile (4-15 ) To a solution of crude 2-cyclopropylthiomorpholine (4-14 , 100 mg, 0.698 mmol) in CH3CN (3 ml) was added K2CO 3 (289 mg, 2.094 mmol) then 7-(bromomethyl)(1-methyl-1H-pyrazol yl)quinolinecarbonitrile (251 mg, 0.768 mmol) all at once as solid. The resulting mixture was heated to 60 °C ght. The mixture was cooled to rt, diluted with EtOAc, filtered h a pad of Celite washing with EtOAc, and concentrated. The crude product was subjected to silica gel chromatography (25 g, 0-100% EtOAc/hexanes, 10 minute nt) to afford 7-((2-Cyclopropylthiomorpholino)methyl)- 4-(1-methyl-1H-pyrazolyl)quinolinecarbonitrile (4-15 , 123 mg, 45%) as a light orange foam. 1H NMR (399 MHz, CDCl3): δ 8.19 (d, J = 8.7 Hz, 1 H); 8.09 (s, 1 H); 7.85 (s, 1 H); 7.77 (s, 1 H); 7.71 (d, J = 8.8 Hz, 1 H); 7.61 (s, 1 H); 4.07 (s, 3 H); .70 (m, 2 H); 3.16 (dd, J = 11.6, 2.7 Hz, 1 H); 3.01 (d, J = 11.6 Hz, 1 H); 2.83 (ddd, J = 13.4, 10.6, 2.7 Hz, 1 H); 2.61-2.53 (m, 1 H); 2.45-2.34 (m, 2 H); 2.20-2.13 (m, 1 H); 0.88-0.80 (m, 1 H); 0.61-0.44 (m, 2 H); 0.36-0.27 (m, 1 H); 0.23-0.16 (m, 1 7-((2-Cyclopropylthiomorpholino)methyl)(1-methyl-1H-pyrazolyl)quinolinecarboxamide (4-16 ) 7-((2-Cyclopropylthiomorpholino)methyl)(1-methyl-1H-pyrazolyl)quinolinecarbonitrile (4-15 , 40 mg, 0.103 mmol) was taken up in trated HCl (0.6 ml) and stirred at rt. After 4 hr the mixture was quenched by slow addition of it to saturated NaHCO3. The resulting mixture was extracted with CH2Cl 2 (3x). The combined organic layers were filtered through a pad of Celite washing with CH 2Cl 2 then concentrated. The crude product was subjected to silica gel tography (25 g, 100% EtOAc) to afford 7-((2-cyclopropylthiomorpholino)methyl)(1-methyl-1H-pyrazolyl)quinoline carboxamide (4-16 , 28 mg, 67%) as an off-white foam. 1H NMR (399 MHz, CDCl 3): δ 8.22 (m, 2 H); 8.10 (s, 1 H); 8.04 (s, 1 H); 7.89 (s, 1 H); 7.80 (s, 1 H); 7.65 (d, J = 8.7 Hz, 1 H); 5.62 (s, 1 H); 4.05 (s, 3 H); 3.87-3.68 (m, 2 H); 3.19 (d, J = 11.6 Hz, 1 H); 3.04 (d, J = 11.6 Hz, 1 H); 2.91-2.79 (m, 1 H); 2.61-2.53 (m, 1 H); 2.46-2.35 (m, 2 H); 2.23-2.15 (m, 1 H); 0.88-0.79 (m, 1 H); 0.60-0.46 (m, 2 H); 0.36-0.27 (m, 1 H); 0.26-0.18 (m, 1 H). LRMS m/z (M+H)+ 408.5 calc.; 408.3 found.
Scheme 4.4 - 104 – O Sodium triacetoxy CF3 CF3 borohydride OH H OH N O H NH H2N O DCM NH O O 4-17 CF3 CF3 I2, PPh3 I TFA I N TFA N O H DCM H imidazole, DCM NH NH2 4-18 4-19 N CN 2-1 F3C N CN K2CO3 N NH HN Acetonitrile HN Acetonitrile, DMA, DIEA, 34 C 4-20 4-21 O O F3C N F3C N conc HCl N NH2 N NH2 HN HN Chiral HPLC 4isomer A 4isomer B F F Example 4.4: sis of 4-(4-fluorophenyl)(((2S)methyl-5(R or S)- (trifluoromethyl)piperazinyl)methyl)quinolinecarboxamide (4-22) Tert-butyl ((2S)((1,1,1-trifluorohydroxypropanyl)amino)propanyl)carbamate (4-17) To a stirred solution of (S)-tert-butyl (1-oxopropanyl)carbamate (3.15 g, 18.18 mmol), and DCM (91 ml) was added 2-amino-3,3,3-trifluoropropanol (2.230 g, 17.28 mmol). d at ambient temperature for 10 minutes and then added sodium triacetoxyborohydride (5.78 g, 27.3 mmol).
The mixture was stirred overnight. The reaction was diluted with DCM and then washed with 1 N - 105 – NaOH, brine dried over MgSO4, filtered and the solvent removed to provide 4.0 grams of utyl ((2S)- 1-((1,1,1-trifluorohydroxypropanyl)amino)propanyl)carbamate as a colorless oil that was used without further purification. LRMS m/z (M+H)+ 287.3 found, 287.3 required.
Tert-butyl ((2S)((1,1,1-trifluoroiodopropanyl)amino)propanyl)carbamate (4-18 ) To a stirred mixture of triphenylphosphine (resin bound, 1.88 ram,7.70 g, 14.67 mmol) in DCM (48.9 ml) was added iodine (3.72 g, 14.67 mmol). Stirred for 15 minutes. Added imidazole (1.332 g, 19.56 mmol) and stirred for 15 minutes, then added tert-butyl ((2S)((1,1,1-trifluoro hydroxypropanyl)amino)propanyl)carbamate (2.8g, 9.78 mmol), dissolved in DCM (48 ml), and then the mixture was heated to reflux for 3 hours. Cooled to room temperature and filtered through celite.
The resulting solution was washed with saturated sodium thiosulfate, dried over MgSO4, filtered and trated. The crude residue was purified by column chromatography on silica gel eluting with s to EtOAc to provide tert-butyl ((2S)((1,1,1-trifluoroiodopropanyl)amino)propan yl)carbamate as a colorless oil. LRMS m/z (M+H)+ 397.1 found, 397.2 required. (2S)-N1-(1,1,1-trifluoroiodopropanyl)propane-1,2-diamine 2,2,2-trifluoroacetate (4-19 ) To a stirred solution of utyl ((2S)((1,1,1-trifluoroiodopropanyl)amino)propan yl)carbamate (1.6g, 4.04 mmol) and DCM (8.08 ml) was added TFA (6.22 ml, 81 mmol). Stirred for 1 hour at t temperature and then the solution was concentrated. The residue was azeotroped with toluene (3 x 10 ml) to provide (2S)-N1-(1,1,1-trifluoroiodopropanyl)propane-1,2-diamine 2,2,2- trifluoroacetate as a yellow oil that was used without furter purification. LRMS m/z (M+H)+ 297.1 found, 297.0 required. 4-(4-Fluorophenyl)(((2S)methyl(trifluoromethyl)piperazinyl)methyl)quinolinecarbonitrile (4-21 ) 1-(1,1,1-trifluoroiodopropanyl)propane-1,2-diamine 2,2,2-trifluoroacetate (1.66g, 4.05 mmol) and acetonitrile (20.24 ml) were combined and then added potassium carbonate (1.678 g, 12.14 mmol). The mixture was stirred for 4 hours at ambient temperature and then was filtered through a celite pad and trated to 1/3 of original volume.
To the solution of (2S)methyl(trifluoromethyl)piperazine (4-20 ) was added DMA (1.76 ml), DIEA (0.614 ml, 3.52 mmol) followed by 7-(bromomethyl)(4-fluorophenyl)quinolinecarbonitrile (300 mg, 0.879 mmol) . The reaction was heated to 50 °C for 4 hours. The reaction was diluted with EtOAc and then washed with H2O, brine, dried ) and trated. The residue was purified by column chromatography on silica gel eluting with hexanes to EtOAc to provide 4-(4-fluorophenyl) - 106 – (((2S)methyl(trifluoromethyl)piperazinyl)methyl)quinolinecarbonitrile as a colorless solid.
LRMS m/z (M+H)+ 429.2 found, 429.4 required. 4-(4-Fluorophenyl)(((2S)methyl-5(R or S)-(trifluoromethyl)piperazinyl)methyl)quinoline carboxamide (4-22) 4-(4-fluorophenyl)(((2S)methyl(trifluoromethyl)piperazinyl)methyl)quinolinecarbonitrile (275 mg, 0.642 mmol) was dissolved in conc HCl (2636 µl, 32.1 mmol) and then stirred at ambient temperture for 4 hours. The yellow solution was slowly poured into aq potassium carbonate (12.8 ml, 5M, 64 mmol) at 0°C. The resulting mixture was extracted with chloroform. The c portion was dried over MgSO4 and trated. The residue was purified by preparative HPLC Chiralpak AD, 5 cm x 500 cm, 50 ml/min eluting with 20% IPA/hexanes + 0.1% EtWNH, to e isomers A and B of 4-(4- fluorophenyl)(((2S)methyl-5(R or S)-(trifluoromethyl)piperazinyl)methyl)quinoline carboxamide as colorless foams. Isomer A, LRMS m/z (M+H)+ 447.3 found, 447.4 required 1H NMR (500 MHz, CDCl 3):8.22 (1 H, s), 8.10 (2 H, d, J = 12.11 Hz), 7.91 (1 H, d, J = 8.69 Hz), 7.65 (1 H, dd, J = 8.72, 1.66 Hz), 7.52 (2 H, dd, J = 8.44, 5.36 Hz), 5.64 (1 H, s), 3.89 (1 H, d, J = 13.93 Hz), 3.77 (1 H, d, J = 13.94 Hz), 3.39-3.34 (1 H, m), 3.08-3.04 (1 H, m), 2.94-2.87 (2 H, m), 2.73 (1 H, dd, J = 11.54, 8.93 Hz), 2.60 (1 H, dd, J = 11.55, 3.62 Hz), 1.17 (3 H, d, J = 6.41 Hz).
Isomer B, LRMS m/z (M+H)+ 447.3 found, 447.4 required 1H NMR (500 MHz, CDCl 3):8.21 (1 H, s), 8.10 (2 H, d, J = 14.50 Hz), 7.91 (1 H, d, J = 8.70 Hz), 7.65 (1 H, d, J = 8.75 Hz), 7.52 (2 H, dd, J = 8.22, 5.34 Hz), 5.74 (1 H, s), 3.89 (1 H, d, J = 13.95 Hz), 3.77 (1 H, d, J = 13.95 Hz), 3.37 (1 H, t, J = 7.88 Hz), 3.09-2.98 (2 H, m), 2.91 (2 H, d, J = 11.86 Hz), 2.73 (1 H, t, J = 10.19 Hz), 2.60 (1 H, dd, J = 11.55, 3.52 Hz), 1.17 (3 H, d, J = 6.36 Hz).
Chiral HPLC Analytical data: 1 ml/ min 20% IPa/hexanes, 4.6 x 250 mm AD column Isomer A: 7.63 minutes Isomer B: 8.63 minutes The following compounds have been prepared according to procedures similar to those found in Scheme 4.1, 4.2, 4.3, and 4.4 selecting the appropriate quinoline derivative, nucleophile, and c acid tive and provide examples of compounds in the invention.
Table 4 Exact Mass Example Structure IUPAC Name [M+H]+ - 107 – Exact Mass Example Structure IUPAC Name [M+H]+ O O N NH2 methyl 1-{[2- carbamoyl(4- Calc'd phenyl)quino 408.2, linyl]methyl}-L- Found 4-23 F prolinate 408.2 O O N 7-{[(2S) N NH2 carbamoylpyrrolidi nyl]methyl} Calc'd (4- 393.2, fluorophenyl)quino Found 4-24 F linecarboxamide 393.2 7-[(3,3- difluoropyrrolidin- Calc'd 1-yl)methyl](4- 386.1, fluorophenyl)quino Found 4-25 linecarboxamide 386.1 4-(4-fluorophenyl)- 7-{[(3R) Calc'd pyrrolidin 368.2, yl]methyl}quinolin Found 4-26 ecarboxamide 368.2 F O N 4-(4-fluorophenyl)- N NH2 7-{[2- (trifluoromethyl)py Calc'd rrolidin 418.2, yl]methyl}quinolin Found 4-27 F ecarboxamide 418.2 - 108 – Exact Mass Example Structure IUPAC Name [M+H]+ luorophenyl)- 7-[(3-oxopiperazin- Calc'd 1- 379.2, yl)methyl]quinoline Found 4-28 carboxamide 379.2 O N 4-(4-fluorophenyl)- N NH2 {[methoxy(methyl) Calc'd amino]methyl}quin 340.1, oline Found 4-29 F carboxamide 340.1 O N 4-(4-fluorophenyl)- N NH2 7-{[(2- methoxyethyl)(met Calc'd hyl)amino]methyl} 368.2, quinoline Found 4-30 F carboxamide 368.2 H2N N N NH2 7-{[(2-amino oxoethyl)(methyl)a Calc'd mino]methyl}(4- 367.2, phenyl)quino Found 4-31 F linecarboxamide 367.2 7-{[(2S) cyanopyrrolidin Calc'd yl]methyl}(4- 375.2, fluorophenyl)quino Found 4-32 linecarboxamide 375.2 - 109 – Exact Mass Example Structure IUPAC Name [M+H]+ N 4-(4-fluorophenyl)- O N NH2 7-{[(3S) methoxypyrrolidin- Calc'd 1- 380.2, yl]methyl}quinolin Found 4-33 F ecarboxamide 380.2 7-{[3- hylamino)py rrolidin Calc'd yl]methyl}(4- 393.2, fluorophenyl)quino Found 4-34 -carboxamide 393.2 O N 7-{[3- HN N NH2 (acetylamino)pyrrol idinyl]methyl}- Calc'd 4-(4- 407.2, fluorophenyl)quino Found 4-35 F linecarboxamide 407.2 7-[(2-carbamoyl hydroxypyrrolidin- Calc'd 1-yl)methyl](4- 409.2, fluorophenyl)quino Found 4-36 linecarboxamide 409.2 N NH2 7-[(2,6- dimethylmorpholin Calc'd yl)methyl](4- 394.2, fluorophenyl)quino Found 4-37 F linecarboxamide 394.2 - 110 – Exact Mass Example Structure IUPAC Name [M+H]+ N 4-(4-fluorophenyl)- N NH2 7-{[(3S) morpholin- Calc'd 4- 380.2, yl]methyl}quinolin Found 4-38 F ecarboxamide 380.2 N 4-(4-fluorophenyl)- N NH2 7-{[(2S) methylmorpholin- Calc'd 4- 380.2, yl]methyl}quinolin Found 4-39 F ecarboxamide 380.2 4-(4-fluorophenyl)- 7-[(4- hydroxypiperidin- Calc'd 1- 380.2, yl)methyl]quinoline Found 4-40 boxamide 380.2 N NH2 HO 7-[(4,4- HO dihydroxypiperidin Calc'd yl)methyl](4- 396.2, fluorophenyl)quino Found 4-41 F linecarboxamide 396.2 N 7-[(1,1- N NH2 O dioxidothiomorphol O inyl)methyl] Calc'd (4- 414.1, fluorophenyl)quino Found 4-42 F linecarboxamide 414.1 - 111 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(4-fluorophenyl)- 7-[(4- Calc'd methylpiperazin 379.2, yl)methyl]quinoline Found 4-43 carboxamide 379.2 4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl)pi Calc'd peridin 432.2, yl]methyl}quinolin Found 4-44 rboxamide 432.2 4-(4-fluorophenyl)- Calc'd 7-(piperazin 365.2, ylmethyl)quinoline- Found 4-45 2-carboxamide 365.2 luorophenyl)- 7-{[2- (trifluoromethyl)m Calc'd orpholin 434.1, yl]methyl}quinolin Found 4-46 ecarboxamide 434.1 4-(4-fluorophenyl)- 7-{[4-(4-methyl- 1H-imidazol Calc'd yl)piperidin 444.2, yl]methyl}quinolin Found 4-47 ecarboxamide 444.3 - 112 – Exact Mass Example Structure IUPAC Name [M+H]+ N O 4-(4-fluorophenyl)- NH2 7-{[3-(1H-1,2,4- triazol Calc'd yl)piperidin 431.2, yl]methyl}quinolin Found 4-48 F ecarboxamide 431.2 luorophenyl)- 7-{[2- (trifluoromethyl)- ,6- dihydroimidazo[1,2 Calc'd -a]pyrazin-7(8H)- 470.2, yl]methyl}quinolin Found 4-49 ecarboxamide 470.2 7-[(4- aminopiperidin Calc'd hyl](4- 379.2, fluorophenyl)quino Found 4-50 linecarboxamide 379.2 4-(2-methyl-1,3- thiazolyl){[2- (trifluoromethyl)m Calc'd orpholin 437.1, yl]methyl}quinolin Found 4-51 ecarboxamide 437.2 - 113 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(4-fluorophenyl)- 7-(2-oxa Calc'd ro[4.5]dec 420.2, yl)quinoline- Found 4-52 2-carboxamide 420.2 4-(1-methyl-1H- pyrazolyl) {[(2S) (trifluoromethyl)m Calc'd orpholin 420.2, yl]methyl}quinolin Found 4-53 rboxamide 420.1 4-(1-methyl-1H- pyrazolyl) {[(2R) (trifluoromethyl)m Calc'd orpholin 420.2, yl]methyl}quinolin Found 4-54 ecarboxamide 420.5 4-(2-methoxy-1,3- thiazolyl){[2- (trifluoromethyl)m Calc'd orpholin 453.1, yl]methyl}quinolin Found 4-55 ecarboxamide 453.2 7-[(2,2- dimethylmorpholin yl)methyl](1- Calc'd methyl-1H-pyrazol- 380.2, 4-yl)quinoline Found 4-56 carboxamide 380.3 - 114 – Exact Mass Example Structure IUPAC Name [M+H]+ dimethylmorpholin yl)methyl](1- Calc'd methyl-1H-pyrazol- 380.2, 4-yl)quinoline Found 4-57 carboxamide 380.3 7-{[2- (methoxymethyl)m orpholin yl]methyl}(1- Calc'd methyl-1H-pyrazol- 396.2, 4-yl)quinoline Found 4-58 carboxamide 396.3 7-{[(3S) methylmorpholin- 4-yl]methyl}(1- Calc'd methyl-1H-pyrazol- 366.2, 4-yl)quinoline Found 4-59 carboxamide 366.2 7-{[(3R) methylmorpholin- 4-yl]methyl}(1- Calc'd methyl-1H-pyrazol- 366.2, 4-yl)quinoline Found 4-60 carboxamide 366.2 7-{[(2R) morpholin- 4-yl]methyl}(1- Calc'd methyl-1H-pyrazol- 366.2, 4-yl)quinoline Found 4-61 carboxamide 366.2 - 115 – Exact Mass Example Structure IUPAC Name [M+H]+ 7-{[(2S) methylmorpholin- 4-yl]methyl}(1- Calc'd methyl-1H-pyrazol- 366.2, 4-yl)quinoline Found 4-62 carboxamide 366.2 7-{[(3R,5R)-3,5- ylmorpholin yl]methyl}(1- Calc'd methyl-1H-pyrazol- 380.2, 4-yl)quinoline Found 4-63 carboxamide 380.2 7-{[3-(2- methylpropyl)morp holinyl]methyl}- ethyl-1H- Calc'd pyrazol 408.2, yl)quinoline Found 4-64 carboxamide 408.2 4-(1-methyl-1H- pyrazolyl) 6S) methyl (trifluoromethyl)m Calc'd orpholin 434.2, yl]methyl}quinolin Found 4-65 ecarboxamide 434.3 4-(1-methyl-1H- pyrazolyl) Calc'd {[(2R,6S) 434.2, methyl Found 4-66 (trifluoromethyl)m 434.3 - 116 – Exact Mass Example Structure IUPAC Name [M+H]+ orpholin yl]methyl}quinolin ecarboxamide 4-(1H-pyrazol yl){[2- (trifluoromethyl)m Calc'd in 406.1, yl]methyl}quinolin Found 4-67 ecarboxamide 406.2 7-[(4- fluoropiperidin yl)methyl](1- Calc'd methyl-1H-pyrazol- 368.2, 4-yl)quinoline Found 4-68 carboxamide 368.2 7-[(4,4- difluoropiperidin yl)methyl](1- Calc'd methyl-1H-pyrazol- 386.2, 4-yl)quinoline Found 4-69 carboxamide 386.2 4-(1-methyl-1H- lyl) {[4- (trifluoromethyl)pi Calc'd peridin 418.2, yl]methyl}quinolin Found 4-70 ecarboxamide 418.2 - 117 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(1-methyl-1H- lyl) {[3- (trifluoromethyl)pi Calc'd peridin 418.2, yl]methyl}quinolin Found 4-71 ecarboxamide 418.2 7-[(3- fluoropiperidin yl)methyl](1- Calc'd -1H-pyrazol- 368.2, 4-yl)quinoline Found 4-72 carboxamide 368.3 difluoropiperidin yl)methyl](1- Calc'd methyl-1H-pyrazol- 386.2, 4-yl)quinoline Found 4-73 carboxamide 386.3 4-(2-ethyl-1,3- thiazolyl){[2- (trifluoromethyl)m Calc'd orpholin 451.1, yl]methyl}quinolin Found 4-74 ecarboxamide 451.3 4-[2-(1- methylethyl)-1,3- thiazolyl]{[2- (trifluoromethyl)m Calc'd orpholin 465.2, yl]methyl}quinolin Found 4-75 ecarboxamide 465.3 - 118 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(2-cyclopropyl- 1,3-thiazolyl) {[2- (trifluoromethyl)m Calc'd orpholin 463.1, yl]methyl}quinolin Found 4-76 ecarboxamide 463.3 4-(1-ethyl-1H- pyrazolyl) {[2- (trifluoromethyl)m Calc'd orpholin 434.2, yl]methyl}quinolin Found 4-77 ecarboxamide 434.3 4-[1-(1- methylethyl)-1H- pyrazolyl] {[2- (trifluoromethyl)m Calc'd orpholin 448.2, yl]methyl}quinolin Found 4-78 ecarboxamide 448.3 2,2,2- trifluoroethyl)-1H- F O N pyrazolyl] F N NH2 {[2- uoromethyl)m Calc'd orpholin 488.2, N N F yl]methyl}quinolin Found 4-79 F ecarboxamide 488.3 - 119 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-[1- (fluoromethyl)-1H- lyl] {[2- (trifluoromethyl)m Calc'd orpholin 438.2, yl]methyl}quinolin Found 4-80 ecarboxamide 438.3 4-(2-methyl-1,3- oxazolyl){[2- (trifluoromethyl)m Calc'd orpholin 421.1, hyl}quinolin Found 4-81 ecarboxamide 421.3 4-(1-cyclopropyl- 1H-pyrazolyl) {[2- (trifluoromethyl)m Calc'd orpholin 446.2, yl]methyl}quinolin Found 4-82 ecarboxamide 446.3 4-(1H-pyrazol yl){[(2R) (trifluoromethyl)m Calc'd orpholin 406.1, yl]methyl}quinolin Found 4-83 ecarboxamide 406.3 - 120 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-[1- (difluoromethyl)- 1H-pyrazolyl] {[2- uoromethyl)m Calc'd orpholin 456.1, yl]methyl}quinolin Found 4-84 ecarboxamide 456.3 4-[1- (fluoromethyl)-1H- pyrazolyl] {[(2S) (trifluoromethyl)m Calc'd in 438.2, yl]methyl}quinolin Found 4-85 ecarboxamide 438.3 4-[1- (fluoromethyl)-1H- pyrazolyl] {[(2R) (trifluoromethyl)m Calc'd orpholin 438.2, yl]methyl}quinolin Found 4-86 ecarboxamide 438.3 4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl)pi Calc'd perazin 433.2, yl]methyl}quinolin Found 4-87 ecarboxamide 433.3 - 121 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl)pi Calc'd perazin 433.2, yl]methyl}quinolin Found 4-88 rboxamide 433.3 4-(4-fluorophenyl)- 7-{[2- (trifluoromethyl)pi Calc'd perazin 433.2, yl]methyl}quinolin Found 4-89 ecarboxamide 433.3 ethyl-1H- pyrazolyl) {[(2R,5R) methyl (trifluoromethyl)m Calc'd orpholin 434.2, yl]methyl}quinolin Found 4-90 ecarboxamide 434.3 4-(1-methyl-1H- pyrazolyl) {[(2R,5S) methyl (trifluoromethyl)m Calc'd orpholin 434.2, yl]methyl}quinolin Found 4-91 ecarboxamide 434.2 - 122 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(1-methyl-1H- pyrazolyl) {[(2S,6R) methyl (trifluoromethyl)m Calc'd in 434.2, yl]methyl}quinolin Found 4-92 ecarboxamide 434.3 7-{[4-ethyl (trifluoromethyl)pi perazin Calc'd yl]methyl}(4- 461.2, fluorophenyl)quino Found 4-93 linecarboxamide 461.3 4-(4-fluorophenyl)- 7-{[4-methyl (trifluoromethyl)pi Calc'd n 447.2, yl]methyl}quinolin Found 4-94 ecarboxamide 447.3 7-{[(6R)-2,2- dimethyl (trifluoromethyl)m in yl]methyl}(1- Calc'd methyl-1H-pyrazol- 448.2, 4-yl)quinoline Found 4-95 carboxamide 448.3 - 123 – Exact Mass Example Structure IUPAC Name [M+H]+ 7-{[(2R)-5,5- yl (trifluoromethyl)m orpholin yl]methyl}(1- Calc'd methyl-1H-pyrazol- 448.2, 4-yl)quinoline Found 4-96 carboxamide 448.3 7-{[(2R,6R) methyl uoromethyl)m orpholin yl]methyl}(1H- Calc'd pyrazol 420.2, yl)quinoline Found 4-97 carboxamide 420.2 4-(1-methyl-1H- pyrazolyl) ,2,2- trifluoroethyl)morp Calc'd holin 434.2, yl]methyl}quinolin Found 4-98 ecarboxamide 434.3 7-[(2- ethylmorpholin yl)methyl](1- Calc'd methyl-1H-pyrazol- 380.2, 4-yl)quinoline Found 4-99 carboxamide 380.3 - 124 – Exact Mass Example Structure IUPAC Name [M+H]+ 7-{[2-(2- methylpropyl)morp holinyl]methyl}- 4-(1-methyl-1H- Calc'd pyrazol 408.2, noline Found 4-100 carboxamide 408.3 4-(4-fluorophenyl)- 7-{[(2R)methyl- (trifluoromethyl)pi Calc'd perazin 447.2, yl]methyl}quinolin Found 4-101 ecarboxamide 447.3 4-(4-fluorophenyl)- 7-{[(2R)methyl- (trifluoromethyl)pi Calc'd perazin 447.2, hyl}quinolin Found 4-102 ecarboxamide 447.3 4-(4-fluorophenyl)- 7-{[(3R) Calc'd methylpiperazin 379.2, yl]methyl}quinolin Found 4-103 ecarboxamide 379.3 - 125 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-(4-fluorophenyl)- 7-{[(3S) Calc'd methylpiperazin 379.2, yl]methyl}quinolin Found 4-104 ecarboxamide 379.3 N 4-(4-fluorophenyl)- N NH2 7-[(8aR)- hexahydropyrrolo[1 Calc'd ,2-a]pyrazin-2(1H)- 405.2, ylmethyl]quinoline- Found 4-105 F 2-carboxamide 405.3 F O N 7-{[3- F N NH2 (difluoromethyl)pip Calc'd yl]methyl}(4- 415.2, phenyl)quino Found 4-106 F linecarboxamide 415.2 F O N 7-{[3- F N NH2 (difluoromethyl)pip erazin Calc'd yl]methyl}(4- 415.2, fluorophenyl)quino Found 4-107 F linecarboxamide 415.2 N NH2 7-[(3-tert- butylpiperazin Calc'd yl)methyl](4- 421.2, fluorophenyl)quino Found 4-108 F linecarboxamide 421.3 - 126 – Exact Mass Example Structure IUPAC Name [M+H]+ N 4-(4-fluorophenyl)- N NH2 7-{[3-(1- methylethyl)pipera Calc'd zin 407.2, yl]methyl}quinolin Found 4-109 F ecarboxamide 407.3 N 7-[(3- N NH2 cyclopropylpiperazi nyl)methyl] Calc'd (4- 405.2, fluorophenyl)quino Found 4-110 F -carboxamide 405.3 7-{[3- (fluoromethyl)piper azinyl]methyl}- Calc'd 4-(4- 397.2, fluorophenyl)quino Found 4-111 linecarboxamide 397.3 4-(4-fluorophenyl)- 7-{[3-methyl (trifluoromethyl)pi Calc'd perazin 447.2, yl]methyl}quinolin Found 4-112 ecarboxamide 447.3 4-(4-fluorophenyl)- 7-{[3-methyl (trifluoromethyl)pi Calc'd perazin 447.2, hyl}quinolin Found 4-113 ecarboxamide 447.3 - 127 – Exact Mass Example ure IUPAC Name [M+H]+ 4-(4-fluorophenyl)- 7-{[3-methyl (trifluoromethyl)pi Calc'd perazin 447.2, yl]methyl}quinolin Found 4-114 ecarboxamide 447.3 4-(4-fluorophenyl)- methyl (trifluoromethyl)pi Calc'd n 447.2, yl]methyl}quinolin Found 4-115 ecarboxamide 447.3 4-[2- (fluoromethyl)-1,3- thiazolyl] {[(2R,6R) methyl (trifluoromethyl)m Calc'd orpholin 469.1, yl]methyl}quinolin Found 4-116 ecarboxamide 469.2 4-[2- (difluoromethyl)- 1,3-thiazolyl] {[(2R,6R) methyl (trifluoromethyl)m Calc'd orpholin 487.1, yl]methyl}quinolin Found 4-117 ecarboxamide 487.2 - 128 – Exact Mass Example Structure IUPAC Name [M+H]+ 4-[1- (difluoromethyl)- 1H-pyrazolyl] {[(2R,6R) methyl (trifluoromethyl)m Calc'd orpholin 470.2, yl]methyl}quinolin Found 4-118 ecarboxamide 470.2 ethyl-1H- pyrazolyl) {[2- (trifluoromethyl)thi Calc'd omorpholin 436.1, yl]methyl}quinolin Found 4-119 ecarboxamide 436.2 7-(5- azaspiro[2.5]oct ylmethyl)(1- Calc'd methyl-1H-pyrazol- 376.2, 4-yl)quinoline Found 4-120 carboxamide 376.3 7-{[(3R) hydroxypiperidin- 1-yl]methyl}(1- Calc'd methyl-1H-pyrazol- 366.2, uinoline Found 4-121 carboxamide 366.3 - 129 – Exact Mass Example Structure IUPAC Name [M+H]+ 7-{[(3S) hydroxypiperidin- 1-yl]methyl}(1- Calc'd methyl-1H-pyrazol- 366.2, 4-yl)quinoline Found 4-122 carboxamide 366.3 4-(4-fluorophenyl)- 7-{[3- (trifluoromethyl)pi Calc'd peridin 432.2, yl]methyl}quinolin Found 4-123 Isomer A ecarboxamide 432.3 4-(4-fluorophenyl)- 7-{[3- uoromethyl)pi Calc'd peridin 432.2, yl]methyl}quinolin Found 4-124 Isomer B ecarboxamide 432.3 ethyl-1,3- thiazolyl) {[(2R,6R) methyl (trifluoromethyl)m Calc'd orpholin 451.1, yl]methyl}quinolin Found 4-125 ecarboxamide 451.2 - 130 – Exact Mass Example ure IUPAC Name [M+H]+ 4-(3- methylisothiazol yl){[(2R,6R) methyl (trifluoromethyl)m Calc'd orpholin 451.1, yl]methyl}quinolin Found 4-126 ecarboxamide 451.2 7-[(2-cyclopropyl- 1,1- dioxidothiomorphol inyl)methyl] (1-methyl-1H- Calc'd pyrazol 440.2, yl)quinoline Found 4-127 amide 440.3 4-(2-amino-1,3- thiazolyl) {[(2R,6R) methyl (trifluoromethyl)m Calc'd orpholin 452.1, yl]methyl}quinolin Found 4-128 ecarboxamide 452.2 4-(3-methyl-1,2,4- thiadiazolyl) {[(2R,6R) methyl (trifluoromethyl)m Calc'd orpholin 452.1, yl]methyl}quinolin Found 4-129 ecarboxamide 452.2 - 131 – Exact Mass Example Structure IUPAC Name [M+H]+ 7-(6- azaspiro[2.5]oct ylmethyl)(1- Calc'd methyl-1H-pyrazol- 376.2, 4-yl)quinoline Found 4-130 carboxamide 376.3 7-{[2- (fluoromethyl)piper idinyl]methyl}- 4-(1-methyl-1H- Calc'd pyrazol 382.2, yl)quinoline Found 4-131 carboxamide 382.3 7-(4- azaspiro[2.5]oct N NH2 yl)(1- Calc'd methyl-1H-pyrazol- 376.2, 4-yl)quinoline Found 4-132 N N carboxamide 376.3 4-(1,5-dimethyl- 1H-pyrazolyl) {[(2R,6R) methyl Calc'd (trifluoromethyl)m 448.5, orpholin Found yl]methyl}quinolin 448.4 4-133 rboxamide 7-{[(2R,6R) Calc'd methyl 462.5, uoromethyl)m Found orpholin 462.4 4-134 yl]methyl} - 132 – Exact Mass Example Structure IUPAC Name [M+H]+ -trimethyl- 1H-pyrazol yl)quinoline carboxamide 4-(1,3-dimethyl- 1H-pyrazolyl) {[(2R,6R) methyl Calc'd (trifluoromethyl)m 448.5, orpholin Found yl]methyl}quinolin 448.4 4-135 ecarboxamide Scheme 5 Example 5: Synthesis of 4-(4-fluorophenyl)(pyrrolidinylcarbonyl)quinolinecarboxamide (5- 4) - 133 – 7-(Dibromomethyl)(4-fluorophenyl)quinolinecarbonitrile (5-1) 4-(4-Fluorophenyl)methylquinolinecarbonitrile (1-6, 7.86 g, 30.0 mmol, 1.0 equiv.) was dissolved in carbon tetrachloride (150.0 mL, 0.2 M). NBS (5.44 g, 30.6 mmol, 1.02 equiv) and AIBN (148.0 mg, 0.899 mmol, 0.03 equiv.) were added and the mixture was heated to reflux for 5 hours. The mixture was cooled to room temperature and the white precipitate was filtered off. The filtrate was trated and the e was purified by column tography on a silica gel column, eluting with EtOAc/Isohexane (0-50%) to afford 7-(dibromomethyl)(4-fluorophenyl)quinolinecarbonitrile (5-1, 1.27 g, 10.1%). LRMS m/z (M+H)+ 421.1 found, 421.1 required. 4-(4-Fluorophenyl)formylquinolinecarboxamide (5-2) To a solution of 7-(dibromomethyl)(4-fluorophenyl)quinolinecarbonitrile (5-1, 1.27 g, 3.02 mmol, 1.0 equiv.) in 1, 4-dioxane (40.0 mL, 0.075 M) was added a slurry of silver nitrate (2.05 g, 12.1 mmol, 4.0 equiv.) in water (20.0 mL). The resulting e was heated to reflux for 24 hours, then cooled, and filtered through a pad of celite. The te was washed with ethyl acetate, the layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give 4-(4-fluorophenyl)formylquinolinecarboxamide (5-2, 850.0 mg, 96.0%) as a white solid.
LRMS m/z (M+H)+ 295.1 found, 295.1 required. 2-(Aminocarbonyl)(4-fluorophenyl)quinolinecarboxylic acid (5-3) To a solution of 4-(4-fluorophenyl)formylquinolinecarboxamide (5-2, 200.0 mg, 0.680 mmol, 1.0 equiv.) and 2-methylbutene (3.96 mL, 37.4 mmol, 55 equiv.) in t-BuOH (14.0 mL, 0.05 M) was added a solution of sodium chlorite (553.0 mg, 6.12 mmol, 9 equiv.) and sodium dihydrogen phosphate monohydrate (559.0 mg, 4.08 mmol, 6 equiv.) in water (6.5 mL). The resulting e was stirred at room temperature for 1 hour. A white solid precipitated. Water (100.0 ml) was added and the mixture stirred for 30 minutes. The solid was collected via suction filtration, washed with water, dried in vacuo to give 2-(aminocarbonyl)(4-fluorophenyl)quinolinecarboxylic acid (5-3, 150.0 mg, 71.1%) as a white solid. LRMS m/z (M+H)+ 311.1 found, 311.1 required. 4-(4-Fluorophenyl)(pyrrolidinylcarbonyl)quinolinecarboxamide (5-4) 2-(Aminocarbonyl)(4-fluorophenyl)quinolinecarboxylic acid (5-3, 50.0 mg, 0.161 mmol, 1.0 equiv), idine (11.5 mg, 0.161 mmol, 1.0 equiv.), BOP (93.0 mg, 0.209 mmol, 1.3 equiv.), and TEA (0.0670 mL, 0.483 mmol, 3 equiv) were dissolved into DMF (1.0 mL) and stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride, washed with water, brine, dried over MgSO4, filtered and concentrated. The crude residue was ed by reverse phase HPLC (H2O/ - 134 – CH3CN nt w/ 0.1% TFA modifier) to afford 4-(4-Fluorophenyl)(pyrrolidin ylcarbonyl)quinolinecarboxamide (5-4, 50.0 mg, 85.0%) as a colorless solid. ¹H NMR (500 MHz, CDCl₃): δ 8.324 (d, J= 1.47 Hz,1 H); 8.273 (s, 1 H); 8.251 (br s, 1 H); 8.026 (d, J= 8.78 Hz,1 H); 7.762 (dd, J1= 8.54 Hz, J2= 1.71 Hz,1 H); 7.501-7.529 (m, 2 H); 7.246-7.286 (m, 2 H); 6.750 (br s, 1 H); 3.765 (tr, J= 6.95 Hz, 2 H); 3.567 (tr, J= 6.68 Hz, 2 H); 2.055 (quint, J= 6.78 Hz,2 H); 1.962 (quint, J= 6.65 Hz,2 H). LRMS m/z (M+H)+ 364.1 found, 364.1 required.
The following compounds have been prepared according to procedures similar to those found in Scheme selecting the appropriate quinoline derivative and boronic acid derivatives and e examples of nds in the invention.
Table 5 Exact Mass Example Structure IUPAC Name [M+H]+ 4-(4-fluorophenyl) Calc'd (piperidin 378.2, ylcarbonyl)quinoline Found -5 carboxamide 378.2 4-(4-fluorophenyl) Calc'd (morpholin 380.1, ylcarbonyl)quinoline Found -6 carboxamide 380.3 Scheme 6.1 - 135 – N O N CN N B N CN B(OH)2 Br O N N N Pd(dppf)Cl2-CH2Cl2 adduct 115 C K3PO4, Dioxane:H2O, 100 C N N N NH2 2(Na2CO3 1.5H2O2) e:H2O, rt Example 6.1: Synthesis of 7-((2-cyclopropylpyrimidinyl)methyl)(1-methyl-1H-pyrazol yl)quinolinecarboxamide (6-2) 7-((2-Cyclopropylpyrimidinyl)methyl)(1-methyl-1H-pyrazolyl)quinolinecarbonitrile (6-1) After degassing with N2, a mixture of 7-(bromomethyl)chloroquinolinecarbonitrile (2-4, 650 mg, 2.31 mmol), 2-cyclopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrimidine (580 mg, 2.36 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (94 mg, 0.11 mmol), and K3PO4 (1960 mg, 9.24 mmol) in 1,4- dioxane (13.7 mL) and H2O (1.7 mL) was heated at 100oC for 30 min under microwave condition. The mixture was cooled to room temperature, and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1H-pyrazole (528 mg, 2.54 mmol) was added. After degassing with N2, the mixture was then heated at 115oC for 30 min under ave condition. The reaction mixture was cooled, diluted with H2O (10 mL) and the mixture was extracted with ethyl acetate (2x 50 mL). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the t was ated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with EtOAc/Hexane (0- 100%) to afford 7-((2-cyclopropylpyrimidinyl)methyl)(1-methyl-1H-pyrazolyl)quinoline carbonitrile (6-1, 649 mg, 77%). LRMS m/z (M+H)+ 367.3 found, 367.2 required. 7-((2-Cyclopropylpyrimidinyl)methyl)(1-methyl-1H-pyrazolyl)quinolinecarboxamide (6-2) 7-((2-Cyclopropylpyrimidinyl)methyl)(1-methyl-1H-pyrazolyl)quinolinecarbonitrile (5-1, 71.3 mg, 0.19 mmol.) was dissolved in acetone (6.5 mL) and sodium bonate (85 mg, 0.58 mmol.) in H2O (3.24 mL) was added slowly. The resulting mixture was d at room temperature for one hour. Saturated NH4Cl (1.5 mL) was added, followed by H2O (30 mL) to give a white precipitation. - 136 – The solid was collected by filtration, washed with H 2O and then Hexane, and dried under vacuum to provide 7-((2-cyclopropylpyrimidinyl)methyl)(1-methyl-1H-pyrazolyl)quinolinecarboxamide (6-2, 72.1 mg, 96.0%) as a white solid. LRMS m/z (M+H)+ 385.3 found, 385.2 required.
Scheme 6.2 Example 6.2: Synthesis of 4-(4-fluorophenyl)(pyrimidinylmethyl)quinolinecarboxamide (6- 4-(4-Fluorophenyl)(pyrimidinylmethyl)quinolinecarboxamide (6-3) Degassed DME (1237 µl)/Water (619 µl) was added to 7-(bromomethyl)(4-fluorophenyl)quinoline carboxamide (3-1, 100 mg, 0.278 mmol), pyrimidinylboronic acid (41.4 mg, 0.334 mmol), 3)4 (16.09 mg, 0.014 mmol), and Na2CO3 (62.0 mg, 0.585 mmol). The reaction was heated at 100 °C in the microwave for 10minutes. The reaction was quenched with water and the mixture was extracted with ethyl acetate ( x 3). The combined organic ons were dried (MgSO4), ed and the solvent was evaporated under reduced pressure. The crude material was purified by flash column chromatography (12 g SiO2, 0-100% EtOAc/hexanes) to afford impure product. The material was purified further by reverse phase HPLC (20 x 150 mm, Waters Sunfire, Solvent A = 0.1% TFA/H2O, Solvent B = 0.1% TFA/MeCN, ml/min) to afford, after basic workup, 4-(4-fluorophenyl)(pyrimidinylmethyl)quinoline amide (6-3, 8.16 mg, 8.18 % yield) as a white solid. 1H NMR (500 MHz, CDCl 3): δ 9.14 (s, 1 H); 8.68 (s, 2 H); 8.23 (s, 1 H); 8.05 (s, 1 H); 7.97 (s, 1 H); 7.93 (d, J = 8.7 Hz, 1 H); 7.50 (dd, J = 8.5, 5.4 Hz, 2 H); 7.42 (dd, J = 8.7, 1.8 Hz, 1 H); 7.24 (t, J = 8.5 Hz, 2 H); 5.64 (s, 1 H); 4.22 (s, 2 H). LRMS m/z (M+H)+ 359.2 found, 359.4 required.
The following compounds have been prepared according to procedures similar to those found in Scheme 6.1 and 6.2 selecting the appropriate quinoline derivative and boronic acid derivatives and provide examples of compounds in the invention. - 137 – Table 6 IUPAC Exact Mass Example Structure Name [M+H]+ 4-(1-methyl- 1H-pyrazol yl){[2- (trifluorometh yl)pyridin yl]methyl}qui Calc'd 394.1, noline Found 6-4 carbonitrile 394.1 N 4-(4- fluorophenyl) N (pyridin ylmethyl)quin Calc'd 358.1, oline Found 6-5 F carboxamide 358.2 7-[(6- cyanopyridin- 3-yl)methyl]- 4-(4- fluorophenyl) Calc'd 383.1, quinoline Found 6-6 carboxamide 383.1 4-(4- phenyl) (hydroxymeth yl)pyridin yl]methyl}qui Calc'd 388.1, noline Found 6-7 carboxamide 388.1 - 138 – 7-[(3-chloro- methoxypyrid in yl)methyl] fluorophenyl) Calc'd 422.1, quinoline Found 6-8 carboxamide 422.1 4-(4- fluorophenyl) [(2- methoxypyri midin yl)methyl]qui Calc'd 389.1, noline Found 6-9 carboxamide 389.1 4-(4- fluorophenyl) N [(4- methylpyridin N yl)methyl]qui Calc'd 372.2, noline Found 6-10 F carboxamide 372.1 4-(4- fluorophenyl) methoxypyri midin yl)methyl]qui Calc'd 389.1, noline Found 6-11 carboxamide 389.1 - 139 – 4-(4- fluorophenyl) O N [(5- methoxypyrid N in yl)methyl]qui Calc'd 388.1, noline Found 6-12 F amide 388.1 4-(4- O fluorophenyl) NH2 (4- methoxybenz yl)quinoline- Calc'd 387.2, 2- Found 6-13 F carboxamide 387.1 4-(4- fluorophenyl) [(2- ypyrid in yl)methyl]qui Calc'd 388.1, noline Found 6-14 carboxamide 388.1 7-[(2- Cl chloropyrimid N N in yl)methyl] N (1-methyl- 1H-pyrazol yl)quinoline- Calc'd 379.1, 2- Found 6-15 N N carboxamide 379.1 - 140 – 7-[(2- F fluoropyrimid N N in yl)methyl] N (1-methyl- 1H-pyrazol yl)quinoline- Calc'd 363.1, 2- Found 6-16 N N carboxamide 363.1 7-[(6- O methoxypyrid N in yl)methyl] N hyl- 1H-pyrazol yl)quinoline- Calc'd 374.2, 2- Found 6-17 N N carboxamide 374.2 F F 7-[4-fluoro F (trifluorometh zyl] N (1-methyl- 1H-pyrazol yl)quinoline- Calc'd 429.1, 2- Found 6-18 N N carboxamide 429.1 7-[(2- methoxypyri midin yl)methyl] (1-methyl- 1H-pyrazol yl)quinoline- Calc'd 375.2, 2- Found 6-19 carboxamide 375.1 - 141 – 7-[(2- cyanopyridin- 4-yl)methyl]- 4-(1-methyl- 1H-pyrazol yl)quinoline- Calc'd 369.1, 2- Found 6-20 carboxamide 369.1 F 4-(1-methyl- N 1H-pyrazol yl){[2- N (trifluorometh idin yl]methyl}qui Calc'd 412.1, noline Found 6-21 N N carboxamide 412.3 4-(1-methyl- 1H-pyrazol yl){[2- (trifluorometh yl)pyridin yl]methyl}qui Calc'd 412.1, noline Found 6-22 carboxamide 412.1 ethyl- 1H-pyrazol {[6- (trifluorometh yl)pyridin yl]methyl}qui Calc'd 412.1, noline Found 6-23 carboxamide 412.1 - 142 – 7-[(2,6- dimethylpyrid in hyl] (1-methyl- 1H-pyrazol yl)quinoline- Calc'd 372.2, 2- Found 6-24 carboxamide 372.3 7-{[2-chloro- (trifluorometh yl)pyridin yl]methyl} (1-methyl- 1H-pyrazol yl)quinoline- Calc'd 446.1, 2- Found 6-25 carboxamide 446.2 7-{[2- cyclopropyl- (trifluorometh yl)pyridin yl]methyl} (1-methyl- 1H-pyrazol noline- Calc'd 452.2, 2- Found 6-26 carboxamide 452.3 Scheme 7.1 - 143 – F F DMAD H Eaton's Reagent N CO2Me NH2 N CO2Me MeOH CO2Me 7-1 7-2 N CO2H (HO)2B F POBr3 N CO2Me Toluene:CH3CN Pd(PPh3)4, Na2CO3 Br Dioxane:H2O, 100 C 7-3 7-4 F O NH4HCO2 BOP, TEA DMF, rt e 7.1: Synthesis of ro(4-fluorophenyl)quinolinecarboxamide (7-5) Dimethyl (2E)[(2-fluorophenyl)amino]butenedioate (7-1) To a solution 2-fluoroaniline (1.00 g, 9.00 mmol) in MeOH (11.1 mL) at 0 °C was added yl acetylenedicarboxylate (DMAD, 1.34 mL, 10.8 mmol). The reaction was stirred at room ature for 2 h. The mixture was concentrated and the residue was purified by silica gel flash chromatography (gradient 0-25% EtOAc in Hexanes) to give dimethyl (2E)[(2- fluorophenyl)amino]butenedioate (7-1, 1.9 g, 83%). LRMS m/z (M+H)+ 254.4 found, 254.4 required. 8-Fluorohydroxyquinolinecarboxylate (7-2) Dimethyl (2E)[(2-fluorophenyl)amino]butenedioate (7-1, 1.90 g, 7.50 mmol) was dissolved in Eaton’s reagent (8.00 mL, 50.4 mmol) and heated at 55 ºC for 1 h. The LC-MS showed clean conversion. The reaction mixture was cooled to room temperature and slowly poured into a cold saturated solution of NaHCO3. The light-yellow precipitate formed was collected by filtration, washed with H2O and dried in vacuum to provide methyl 8-fluorohydroxyquinolinecarboxylate (7-2). LRMS m/z (M+H)+ 222.4 found, 222.4 required. - 144 – Methyl 4-bromofluoroquinolinecarboxylate (7-3) To a solution of 8-fluorohydroxyquinolinecarboxylate (7-2, 0.860 g, 3.89 mmol) in a mixture of acetonitrile (0.884 mL) and toluene (8.84 ml) was added orus oxybromide (1.23 g, 4.28 mmol). The reaction mixture was heated at 75 °C for 0.5 h. A second n of phosphorus oxybromide (0.50 g) was added and heated at 75 °C for another 30 min. The LC-MS showed ted reaction. The on was cooled and carefully quenched with ice-water. The mixture was extracted with CH2Cl 2 and EtOAc consecutively. The combined organic layers were dried and concentrated. The residue was purified by silica gel flash chromatography (gradient 0-25% EtOAc in hexanes) to give methyl o- 8-fluoroquinolinecarboxylate (7-3). LRMS m/z (M+H)+ 284.3 found, 284.3 required. 8-Fluoro(4-fluorophenyl)quinolinecarboxylic acid (7-4) Methyl 4-bromofluoroquinolinecarboxylate (7-3, 100.0 mg, 0.352 mmol), 4- Fluorophenylboronic acid (59.1 g, 0.422 mmol), Tetrakis (20.3 mg, 0.0180 mmol), and Na2CO 3 (0.704 ml, 0.704 mmol) were added into 1,4-Dioxane (1.0 mL) in a microwave reaction vessel. The mixture was irradiated with microwave at 100 °C for 30 min. Cooled to room temperature, aqueous Sodium Hydrogen Carbonate (saturate, 2.0 mL) was added and extracted with Ethyl Acetate ( 2 x 10.0 mL). The combined organic fractions were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to give 8-Fluoro(4-fluorophenyl)quinolinecarboxylic acid (7-4 , 100.0 mg, 100.0% . LRMS m/z (M+H)+ 286.2 found, 286.2 required. 8-Fluoro(4-fluorophenyl)quinolinecarboxamide (7-5) 8-Fluoro(4-fluorophenyl)quinolinecarboxylic acid (7-4, 100.0 mg, 0.351 mmol), ammonium formate (88.0 mg, 1.40 mmol), BOP (202.0 mg, 0.456 mmol), and triethylamine (0.147 ml, 1.052 mmol) were dissolved into DMF (1.0 mL), and the resulting mixture was stirred at 60°C for 5 hours. The mixture was cooled and diluted with ene Chloride, washed with water, brine, dried over MgSO 4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/ CH3CN gradient w/ 0.1% TFA modifier) to afford 8-Fluoro(4-fluorophenyl)quinolinecarboxamide (7-5, 9.00 mg, 9.0%) as a ess solid. ¹H NMR (400 MHz, CDCl₃): δ 8.209 (s, 1 H); 8.138 (br s, 1 H); 8.658 (d, J= 8.62 Hz,1 H); 7.379-7.493 (m, 4 H); 7.145-7.214 (m, 2 H); 6.004 (br s, 1 H). LRMS m/z (M+H) 285.1 found, 285.1 required.
Scheme 7.2 - 145 – O CO2Me F F CO2Me microwave N CO2Me NH2 N CO2Me cat. TsOH DMA, 240 C toluene CO2Me Dean-Stark OH 7-6 7-7 N CO2Me (HO)2B F POCl3 N CO2Me 100 C Pd(PPh3)4, Na2CO3 Cl e:EtOH, 75 C F O O F N CO2Me NH N CO2Me Br N NBS O (PhCO2)2 Cs2CO3, DMF, rt CCl4, reflux F F 7-10 7-11 O F O F O N CO2H N N N NH2 6M HCl NH4OH, HATU, TEA O O HOAc, 55 C DMF, rt F F 7-12 7-13 Example 7.2: Synthesis of 7-[(2,5-dioxopyrrolidinyl)methyl]fluoro(4- fluorophenyl)quinolinecarboxamide (7-13) Dimethyl (2E)[(2-fluoromethylphenyl)imino]butanedioate (7-6) 3-Aminofluorotoluene (4.89 g, 39.1 mmol), dimethyl 2-oxobutanedioate (6.26 g, 39.1 mmol), and TosicAcid (0.223 g, 1.172 mmol) were heated at reflux under tark conditions for 1 hour. The solvent was removed in vacuo and the residue purified by column chromatography on a silica gel column, - 146 – eluting with EtOAc/hexane (0-15%) to afford Dimethyl (2E)[(2-fluoro methylphenyl)imino]butanedioate (7-6, 5.48 g, 53 % yield) as a clear oil, LCMS shows the compound is 100% pure, LRMS m/z (M+H)+ 268.2 found, 268.1 required.
Methyl 8-fluoromethyloxo-1,4-dihydroquinolinecarboxylate (7-7) Dimethyl (2E)[(2-fluoromethylphenyl)imino]butanedioate (7-6, 3.27 g, 12.24 mmol) in DMA (24.47 ml) was heated at 240 °C in the microwave for 5min. The solvent was evaporated under reduced pressure and the residue triturated with ether to afford a tan solid. The desired product was filtered off and washed with ether till the ether ran colorless affording Methyl 8-fluoromethyloxo- 1,4-dihydroquinolinecarboxylate (7-7, 1.23 g, 43 % yield) as a tan solid, LCMS shows 93% pure, LRMS m/z (M+H)+ 236.1 found, 236.1 required.
Methyl 4-chlorofluoromethylquinolinecarboxylate ( 7-8) Methyl 8-fluoromethyloxo-1,4-dihydroquinolinecarboxylate (7-7, 1.23 g, 5.23 mmol) in POCl 3 (11 ml) was heated at 100 °C for 1hour. The excess POCl3 was removed in vacuo. The resulting residue was triturated with ether, then filtered and washed with ether till no brown color remained in the ether. The remaining solid was Methyl 4-chlorofluoromethylquinolinecarboxylate (7-8, 993 mg, 75 % yield) 100% pure by LCMS, LRMS m/z (M+H)+ 254.0 found, 254.1 required.
Methyl ro(4-fluorophenyl)methylquinolinecarboxylate (7-9) Methyl 4-chlorofluoromethylquinolinecarboxylate ( 7-8, 993 mg, 3.91 mmol), (4- Fluorophenyl)boronic acid (575 mg, 4.11 mmol), and Pd(Ph 3P) 4 (226 mg, 0.196 mmol) were dissolved in degassed toluene (25mL). Degasses EtOH (2.7mL) was added followed by degassed 2M aq. Sodium Carbonate (4.31 mL, 8.61 mmol). The on was heated at 75 °C overnight then quenched with water and the mixture was extracted with ethyl acetate ( x 3). The combined c fractions were dried (MgSO 4), filtered and the solvent was ated under reduced pressure. The residue was triturated with ether to afford Methyl 8-fluoro(4-fluorophenyl)methylquinolinecarboxylate (7-9, 991 mg, 81 % yield) as a tan solid, LCMS shows the compound is 89% pure, LRMS m/z (M+H)+ 314.1 found, 314.0 required.
Methyl momethyl)fluoro(4-fluorophenyl)quinolinecarboxylate (7-10) Methyl 8-fluoro(4-fluorophenyl)methylquinolinecarboxylate 7-9 (991 mg, 3.16 mmol), l peroxide (102 mg, 0.316 mmol), and NBS (591 mg, 3.32 mmol) were heated at reflux in CCl4 for 5 hours. The solvent was removed in vacuo and the residue purified by column chromatography on a - 147 – silica gel column, eluting with EtOAc/hexane (0-50%) to afford Methyl 7-(bromomethyl)fluoro(4- fluorophenyl)quinolinecarboxylate 7-10 (1.05 g, 85 % yield) as a white solid, LCMS shows the compound is 67% pure, LRMS m/z (M+H)+ 392.0 found, 392.1 required.
Methyl 7-[(2,5-dioxopyrrolidinyl)methyl]fluoro(4-fluorophenyl)quinolinecarboxylate (7-11) Cs 2CO 3 (1.745 g, 5.35 mmol) was added to a solution of imide (0.292 g, 2.94 mmol) and methyl 7-(bromomethyl)fluoro(4-fluorophenyl)quinolinecarboxylate 7-10 (1.05 g, 2.68 mmol) in DMF (13.39 ml) and the reactant stirred at rt for 30min. The reaction was quenched with KH2PO 4 (saturated) and the mixture was extracted with ethyl acetate (x 3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The solvent was removed in vacuo and the residue purified by column tography on a silica gel column, eluting with hexane (0-100%) to afford Methyl 7-[(2,5-dioxopyrrolidinyl)methyl]fluoro(4- fluorophenyl)quinolinecarboxylate 7-11 as a white solid, LCMS shows the compound is 90% pure, LRMS m/z (M+H)+ 411.2 found, 411.1 required. 7-[(2,5-Dioxopyrrolidinyl)methyl]fluoro(4-fluorophenyl)quinolinecarboxylic acid (7-12 ) 6M HCl (2964 µl) was added to a on of methyl 7-[(2,5-dioxopyrrolidinyl)methyl] fluoro(4-fluorophenyl)quinolinecarboxylate 7-11 (629 mg, 1.482 mmol) in Acetic Acid (2964 µl) and the reaction heated at 120 °C for 10min in the microwave. The reaction was quenched with KH2PO4 (saturated) and the mixture was extracted with ethyl acetate (x3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford 7-[(2,5- dioxopyrrolidinyl)methyl]fluoro(4-fluorophenyl)quinolinecarboxylic acid 7-12 (499 mg, 85 % yield) as a white solid, 100% pure by LCMS, LRMS m/z (M+H)+ 397.2 found, 397.1 required. 7-[(2,5-dioxopyrrolidinyl)methyl]fluoro(4-fluorophenyl)quinolinecarboxamide (7-13) TEA (105 µl, 0.757 mmol) was added to a solution of 7-[(2,5-dioxopyrrolidinyl)methyl] fluoro(4-fluorophenyl)quinolinecarboxylic acid 7-12 (100 mg, 0.252 mmol) and HATU (96 mg, 0.252 mmol) in DMF (1262 µl). Ammonium Hydroxide (50.5 µl, 0.757 mmol) was added and the on stirred for 15min at rt. The reaction was quenched with s sodium hydrogen carbonate (saturated) and the e was extracted with ethyl acetate (x 3). The combined c fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel , eluting with EtOAc/hexane (0-100%) to afford 7- [(2,5-dioxopyrrolidinyl)methyl]fluoro(4-fluorophenyl)quinolinecarboxamide 7-13 (63 mg, 63 % yield) as a white solid, LCMS shows the nd is 100% pure ¹H NMR (500 MHz, CDCl₃): δ 8.28 - 148 – (1 H, s), 8.14 (1 H, s), 7.68 (1 H, d, J = 8.85 Hz), 7.54 (1 H, dd, J = 8.86, 6.65 Hz), 7.50-7.46 (2 H, m), 7.25-7.20 (2 H, m), 5.69 (1 H, s), 4.99 (2 H, s), 2.78 (4 H, S m/z (M+H)+ 396.2 found, 396.1 required.
Scheme 7.3 - 149 – F F DMAD H Eaton's Reagent N CO2Me NH2 N CO2Me MeOH CO2Me 50 C 7-14 7-15 O F B N N CO2Me POBr3 N CO2Me O N Toluene:CH3CN Pd(dppf)Cl2-CH2Cl2 adduct 75 C K3PO4, e:H2O 7-16 7-17 F F3C N CO2Me Br O NH NBS Chiral Separation (PhCO2)2 Cs2CO3, DMF CCl4, 80 C N N 7-18 F F O F3C N CO2Me F3C N N N NH2 7M NH3 in MeOH O O MeOH N N N N 7-19a 7-20a F F O F3C N CO2Me F3C N N N NH2 7M NH3 in MeOH O O MeOH N N N N 7-19b 7-20b Example 7.3: Synthesis of (R)- and (S)- (S)fluoro(1-methyl-1H-pyrazolyl)((2- (trifluoromethyl)morpholino)methyl)quinolinecarboxamide (7-20a and 7-20b) - 150 – (E)-dimethyl 2-(2-fluoromethylphenylimino)succinate (7-14 ) At 0°C, dimethyl acetylenedicarboxylate (8.70 mL, 70.4 mmol) was added se to a solution 2- fluoromethylaniline (7.34 g, 58.7 mmol) in MeOH (58.7 mL). After stirring at room temperature overnight, the reaction mixture was concentrated to dryness. The e was purified by silica gel flash chromatography (gradient 0-60% EtOAc/Hexanes) to give (E)-dimethyl 2-(2-fluoro methylphenylimino)succinate (7-14, 14.59 g, 93%). LRMS m/z (M+H)+ 268.3 found, 268.1 required.
Methyl 8-fluorohydroxymethylquinolinecarboxylate (7-15 ) A mixture of (E)-dimethyl 2-(2-fluoromethylphenylimino)succinate (7-14 , 14.59 g, 54.6 mmol) and Eaton's reagent (52.0 mL, 328 mmol) was heated at 50 oC for 1h. After cooling to room temperature, the mixture was added slowly to a cold sat. NaHCO3 solution (gas released!), followed by EtOAc extraction (twice). The combined organic fractions were washed with brine, dried (Na2SO 4), ed and the solvent was evaporated under reduced pressure to afford methyl 8-fluorohydroxymethylquinoline carboxylate (7-15, 11.9 g). LRMS m/z (M+H)+ 236.2 found, 236.1 required.
Methyl 4-bromofluoromethylquinolinecarboxylate (7-16 ) A mixture of (methyl 8-fluorohydroxymethylquinolinecarboxylate (7-15 , 842.1 mg, 3.58 mmol) and POBr3 (1129 mg, 3.94 mmol) in Toluene (8.14 mL) and CH3CN (0,81 mL) was heated at 75oC for 1h. After cooling to room ature, the mixture was poured to a mixture of ice-H2O, followed by CH 2Cl 2 tion (twice). The combined organic fractions were dried (Na2SO 4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash tography (gradient 0-50% Hexanes) to afford methyl 4-bromofluoromethylquinolinecarboxylate (7-16, 710 mg). LRMS m/z (M+H)+ 298.1 found, 298.0 required.
Methyl 8-fluoromethyl(1-methyl-1H-pyrazolyl)quinolinecarboxylate (7-17 ) After ing with N2, a mixture of methyl 4-bromofluoromethylquinolinecarboxylate (7-16, 650 mg, 2.18 mmol.), 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (544 mg, 2.62 mmol) Pd(dppf)Cl2-CH 2Cl 2 adduct (89 mg, 0.11 mmol), and K3PO 4 (1388 mg, 6.54 mmol) in 1,4- dioxane (12.9 mL) and H2O (1.6 mL) was heated at 100oC for 20 min under microwave condition. After cooling to room temperature, the reaction mixture was filtered and trated. The residue was purified by column chromatography on silica gel, eluting with Hexane (0-100%) to afford methyl 8-fluoromethyl(1-methyl-1H-pyrazolyl)quinolinecarboxylate (7-17 , 481 mg, 74%). LRMS m/z (M+H)+ 300.3 found, 300.1 require. - 151 – Methyl momethyl)fluoro(1-methyl-1H-pyrazolyl)quinolinecarboxylate (7-18 ) After degassing with N2, a mixture of methyl 8-fluoromethyl(1-methyl-1H-pyrazolyl)quinoline- 2-carboxylate (7-17 , 169.2 mg, 0.57 mmol), NBS (106 mg, 0.59 mmol) and benzoyl peroxide (13.7 mg, 0.057 mmol) in CCl4 (2.8 ml) was stirred at 80oC. After 5 h, the solvent was removed and the residue was partitioned between EtOAC and sat. NaHCO3. The organic layer was washed with water, dried over Na 2SO 4 and filtered. tration afforded the crude methyl 7-(bromomethyl)fluoro(1-methyl-1H- pyrazolyl)quinolinecarboxylate, which was used without further purification (7-18 ). LRMS m/z (M+H) + 378.2 found, 378.0 required.
(R)-Methyl 8-fluoro(1-methyl-1H-pyrazolyl)((2-(trifluoromethyl)morpholino)methyl)quinoline- 2-carboxylate (7-19a ) and (S)-Methyl 8-fluoro(1-methyl-1H-pyrazolyl)((2- (trifluoromethyl)morpholino)methyl)quinolinecarboxylate (7-19b ) Cs 2CO 3 (345 mg, 1.06 mmol) was added to a mixture of methyl 7-(bromomethyl)fluoro(1-methyl- 1H-pyrazolyl)quinolinecarboxylate (7-18, 160 mg, 0.42 mmol) and 2-(trifluoromethyl)morpholine (79 mg, 0.51 mmol) in DMF (4.2 mL). After stirring at room temperature for 2h, the mixture was diluted with EtOAc, washed with H2O, then brine. The organic layer was dried over Na2SO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexane (0-100%) to afford methyl 8-fluoromethyl(1-methyl-1H-pyrazolyl)quinoline carboxylate as racemic e (31.4mg, 16%). LRMS m/z (M+H)+ 453.3 found, 453.1 ed. Chiral separation using SFC chromatography ed (R)-methyl 8-fluoro(1-methyl-1H-pyrazolyl)((2- (trifluoromethyl)morpholino)methyl)quinolinecarboxylate (7-19a ,15 mg)and (S)-methyl 8-fluoro(1- methyl-1H-pyrazolyl)((2-(trifluoromethyl)morpholino)methyl)quinolinecarboxylate (7-19b, 14.3 mg).
(R)Fluoro(1-methyl-1H-pyrazolyl)((2-(trifluoromethyl)morpholino)methyl)quinoline carboxamide (7-20a ) A mixture of (R)fluoro(1-methyl-1H-pyrazolyl)((2- uoromethyl)morpholino)methyl)quinolinecarboxamide (7-19a , 15.3 mg) in 7 N NH3 in MeOH (372 uL) was d at room temperature for 2h. Concentration and washing with the solid with hexane provided (R)fluoro(1-methyl-1H-pyrazolyl)((2- (trifluoromethyl)morpholino)methyl)quinolinecarboxamide (7-20a , 12.8 mg) as white solid. LRMS m/z (M+H)+ 438.3 found, 438.3 required. - 152 – (S)Fluoro(1-methyl-1H-pyrazolyl)((2-(trifluoromethyl)morpholino)methyl)quinoline carboxamide (7-20b) By applying the same synthetic ure for 7-20a, , from (S)fluoro(1-methyl-1H-pyrazolyl) ((2-(trifluoromethyl)morpholino)methyl)quinolinecarboxamide (7-19b, 14 mg), (S)fluoro(1- methyl-1H-pyrazolyl)((2-(trifluoromethyl)morpholino)methyl)quinolinecarboxamide (7-20b, 13 mg) was prepared as white solid. LRMS m/z (M+H)+ 438.3 found, 438.3 ed.
The following compounds have been prepared according to procedures r to those found in Scheme 7.1, 7.2, and 7.3 selecting the appropriate aniline derivative, boronic acid derivatives, and nucleophile and provide examples of compounds in the invention.
Table 7 Exact Mass Example Structure IUPAC Name [M+H]+ 7-[(2,5- dioxopyrrolidin yl)methyl]fluoro Calc'd (4- 396.1, fluorophenyl)quinoline- Found 7-21 2-carboxamide 396.1 7-[(2,5- yrrolidin yl)methyl]fluoro Calc'd (4- 396.1, fluorophenyl)quinoline- Found 7-22 2-carboxamide 396.1 - 153 – 8-fluoro(4- fluorophenyl)[(2- Calc'd methoxypyrimidin 407.1, yl)methyl]quinoline Found 7-23 carboxamide 407.1 8-fluoro(4- fluorophenyl)({4-[1- hydroxy (trifluoromethyl)propyl Calc'd ]-1H-imidazol 491.2, yl}methyl)quinoline Found 7-24 amide 491.2 7-[(2- ropylpyrimidin- -yl)methyl]fluoro- Calc'd 4-(4- 417.2, fluorophenyl)quinoline- Found 7-25 2-carboxamide 417.1 8-fluoro(4- fluorophenyl){[6- (hydroxymethyl)pyridi Calc'd n 406.1, yl]methyl}quinoline Found 7-26 carboxamide 406.1 8-fluoro[(4- fluoropiperidin yl)methyl](1- Calc'd methyl-1H-pyrazol 386.2, yl)quinoline Found 7-27 carboxamide 386.3 - 154 – 8-fluoro(3-fluoro methoxyphenyl)({4- [1-hydroxy (trifluoromethyl)propyl Calc'd ]-1H-imidazol 521.2, yl}methyl)quinoline Found 7-28 carboxamide 521.2 8-fluoro(2-fluoro methoxyphenyl)({4- [1-hydroxy (trifluoromethyl)propyl Calc'd ]-1H-imidazol 521.2, yl}methyl)quinoline Found 7-29 carboxamide 521.2 8-fluoro[(2- methoxypyridin yl)methyl](1- Calc'd methyl-1H-pyrazol 392.2, noline Found 7-30 carboxamide 392.1 8-fluoro(1-methyl- 1H-pyrazolyl){[6- (trifluoromethyl)pyridi Calc'd n 430.1, yl]methyl}quinoline Found 7-31 amide 430.1 7-[(4,4-dimethyl-2,5- dioxoimidazolidin yl)methyl]fluoro Calc'd (1-methyl-1H-pyrazol- 411.2, 4-yl)quinoline Found 7-32 carboxamide 411.1 - 155 – 7-[(2- cyclopropylpyrimidin- -yl)methyl]fluoro- Calc'd 4-(1-methyl-1H- 403.2, pyrazolyl)quinoline- Found 7-33 oxamide 403.2 7-[(2,6- dimethylpyridin yl)methyl]fluoro Calc'd (1-methyl-1H-pyrazol- 390.2, 4-yl)quinoline Found 7-34 carboxamide 390.2 8-fluoro[(2- methoxy methylpyridin yl)methyl](1- Calc'd methyl-1H-pyrazol 406.2, noline Found 7-35 carboxamide 406.2 8-fluoro(1-methyl- 1H-pyrazolyl){[3- (trifluoromethyl)piperid Calc'd in 436.2, yl]methyl}quinoline Found 7-36 carboxamide 436.2 7-[(6- cyclopropylpyridin yl)methyl]fluoro Calc'd (1-methyl-1H-pyrazol- 402.2, 4-yl)quinoline Found 7-37 carboxamide 402.2 - 156 – 8-fluoro[(6- methoxypyridin yl)methyl](1- Calc'd methyl-1H-pyrazol 392.2, yl)quinoline Found 7-38 carboxamide 392.1 Scheme 8.1 Example 8.1: Synthesis of 7-[2-(6-chloropyridinyl)-1(R or S)-hydroxyethyl](4- fluorophenyl)quinolinecarboxamide (8-1 (Isomer A), 8-2 (Isomer B)) 7-[2-(6-Chloropyridinyl)-1(R or S)-hydroxyethyl](4-fluorophenyl)quinolinecarboxamide (8-1, 8- To a stirred solution of 4-(4-fluorophenyl)formylquinolinecarboxamide (275 mg, 0.934 mmol) and THF (2336 µl) was added (2-chloropyridyl)methylzinc de (0.5M THF, 9345 µl, 4.67 mmol) dropwise over 1 minute. The solution was heated to 50°C for 20 minutes. d to cool to ambient temperture and then was quenched with saturated NH4Cl. The e was xtracted with EtOAc. The organic portion was washed with brine, dried (MgSO4) and concentrated. The residue was purified by - 157 – column tography on silica gel, g with CHCl3 to 70:25:5 CHCl3/EtOAc/MeOH to give the racemic amide as a colorless solid. The racemic amide was purified by preparative HPLC Chiralpak AD, eluting with 60% EtOH/hexanes+ 0.1% Et₂NH, 50 ml/min to give 8-1 (isomer A, 38 mg, 0.090 mmol, 9.64 % yield) as a colorless solid and 8-2 (isomer B, 43 mg, 0.102 mmol, 10.91 % yield) as a colorless solid. 8-1 (LCMS, LRMS m/z (M+H)+ 422.2 found, 422.8 required. 8-2 LCMS, LRMS m/z (M+H)+ 422.2 found, 422.8 required.
Scheme 8.2 Example 8.2: Synthesis of 7-[2-(6-cyanopyridinyl)ethyl](2-fluoro methoxyphenyl)quinolinecarboxamide (8-7) 7-Chloro(2-fluoromethoxyphenyl)quinolinecarbonitrile (8-3) - 158 – To a stirred on of 4,7-dichloroquinolinecarbonitrile (6 g, 26.9 mmol), (2-fluoro methoxyphenyl)boronic acid (5.03 g, 29.6 mmol), 2M sodium carbonate (29.6 ml, 59.2 mmol) in 10:1 toluene (48.9 ml) ethanol (4.89 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.777 g, 0.672 mmol). The mixture was stirred at 75 °C under N2 for 18 hours. The reaction was allowed to cool to ambient temperture. The cooled reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was mostly dissolved in warm EtOAc ( 100 ml), added 100 ml of Et2O, allowed to stand at t temperture for 1 hour. The solid was collected and washed with cold Et2O (50 ml) to give ro(2-fluoromethoxyphenyl)quinolinecarbonitrile (4.4g, 14.07 mmol, 52.3 % yield) as a yellow solid.
(LCMS, LRMS m/z (M+H)+ 313.1 found, 313.7 ed.
Methyl 7-chloro(2-fluoromethoxyphenyl)quinolinecarboxylate (8-4) 7-Chloro(2-fluoromethoxyphenyl)quinoline carbonitrile (4.4g, 14.07 mmol) was suspended in MeOH (70.3 ml), added 200 ml sat HCl/MeOH and then heated to 60 °C for 4 hours. The on was allowed to cool to ambient temperature and then was concentrated. The e was dissolved in EtOAc and then washed with 1:1 1N NaOH/sat NaHCO3, brine, dried ) and concentrated to afford methyl 7-chloro(2-fluoromethoxyphenyl)quinolinecarboxylate (4.4g, 12.73 mmol, 90 % yield) as a yellow solid.
(LCMS, LRMS m/z (M+H)+ 346.2 found, 346.8 required.
Methyl 7-ethenyl(2-fluoromethoxyphenyl)quinolinecarboxylate (8-5) Methyl 7-chloro(2-fluoromethoxyphenyl)quinolinecarboxylate (1.8g, 5.21 mmol) was dissolved in dioxane (23.43 ml), degassed 10 minutes with N2. Added potassium vinyltrifluoroborate (1.395 g, .41 mmol), palladium(II) acetate (0.088 g, 0.390 mmol), 2-bicyclohexylphosphino-2',6'- dimethoxybiphenyl (0.321 g, 0.781 mmol) and cesium carbonate (5.09 g, 15.62 mmol) followed by degassed water (2.60 ml). Degassed with N2 for another 10 minutes and then the mixture was stirred at 85 °C for 1 hour. Reaction was complete. The reaction mixture was cooled to ambient temperture and then diluted with EtOAc. Partitioned EtOAc with water, washed EtOAc t with brine, dried using anhy. MgSO4 and then concentrated. The residue was purified by column chromatography on silica gel, eluting with hexanes to EtOAc to afford methyl 7-ethenyl(2-fluoromethoxyphenyl)quinoline carboxylate (1.25g, 3.71 mmol, 71.2 % yield) as a yellow solid.
(LCMS, LRMS m/z (M+H)+ 338.3 found, 338.3 required.
Methyl 7-[2-(6-cyanopyridinyl)ethyl](2-fluoromethoxyphenyl)quinolinecarboxylate (8-6) - 159 – Methyl 7-ethenyl(2-fluoromethoxyphenyl)quinolinecarboxylate (250 mg, 0.741 mmol) was dissolved in THF (1.3 ml) , heated to 60°C and then added 9-BBN (0.5M THF, 1.85 ml, 0.93 mmol) dropwise over 5 minutes. After 1 hour, allowed to cool to ambient. Added 5-bromopyridine carbonitrile (203 mg, 1.112 mmol), Pd2(dba) 3 (33.9 mg, 0.037 mmol), butyldiadamantylphosphine (26.6 mg, 0.074 mmol), potassium carbonate (410 mg, 2.96 mmol) and water (135 µl), degassed 5 minutes with N2 and then heated to 90oC in a sealed tube for 30 minutes. Reaction proceeded, allowed to cool to ambient. Added brine and then EtOAc. The organic portion was collected, dried (MgSO4) and concentrated. The residue was ed by column chromatography on silica gel, eluting with hexanes to EtOAc to afford methyl 7-[2-(6-cyanopyridinyl)ethyl](2-fluoromethoxyphenyl)quinoline carboxylate (160 mg, 0.362 mmol, 48.9 % yield) as an orange oil.
(LCMS, LRMS m/z (M+H)+ 442.3 found, 442.4 required. 7-[2-(6-Cyanopyridinyl)ethyl](2-fluoromethoxyphenyl)quinolinecarboxamide (8-7) A stirred solution of methyl 7-[2-(6-cyanopyridinyl)ethyl](2-fluoromethoxyphenyl)quinoline carboxylate (160 mg, 0.362 mmol) and MeOH (1450 µl) was treated with 5 ml 7N OH and then heated to 60 °C in a sealed tube for 30 minutes. The reaction was d to cool to ambient ature and then was concentrated. The solid was trituated with EtOH, collected, washed with 5 ml Et2O and then dried in vacuo to afford 7-[2-(6-cyanopyridinyl)ethyl](2-fluoromethoxyphenyl)quinoline amide (105 mg, 0.246 mmol, 67.9 % yield) as a colorless solid.
(LCMS, LRMS m/z (M+H)+ 427.3 found, 427.4 required.
¹H NMR (500 MHz, DMSO): 8.68 (1 H, s), 8.27 (1 H, s), 8.01 (1 H, s), 7.97 (3 H, s), 7.83 (1 H, s), 7.64 (2 H, d, J = 4.55 Hz), 7.49 (1 H, t, J = 8.59 Hz), 7.09 (1 H, d, J = 12.11 Hz), 7.02 (1 H, d, J = 8.60 Hz), 3.89 (3 H, s), 3.19 (4 H, dd, J = 18.34, 7.14 Hz).
Scheme 8.3 - 160 – Cl N CO2Me N CO2Me BF3-K+ 1. 9-BBN, THF, 60 C F F Pd(OAc)2, BTBPF 2. Suzuki N K3PO4, H2O OMe Dioxane, 85 C OMe Br 8-4 8-8 N N N N N CO2Me NH3/MeOH 60 C OMe 8-10 N N 8-11 Example 8.3: Synthesis of 4-(2-fluoromethoxyphenyl)[1-(2-methylpyrimidinyl)propan-2(R or S)-yl]quinolinecarboxamide (8-10, 8-11) Methyl luoromethoxyphenyl)(propenyl)quinolinecarboxylate (8-8) penylboronic acid pinacol ester (2.67 g, 15.91 mmol), methyl 7-chloro(2-fluoro methoxyphenyl)quinolinecarboxylate (5 g, 14.46 mmol), potassium phosphate tribasic (9.21 g, 43.4 mmol) and dioxane (43.8 ml)/water (4.38 ml) were combined and then degassed with nitrogen for 5 minutes. Added palladium(II) acetate (0.243 g, 1.085 mmol) and 1,1'-bis(di-tert- butylphosphino)ferrocene(0.515 g, 1.085 mmol) and then heated to 85oC for 4 hours. Reaction was - 161 – complete and was allowed to cool to ambient temperture. The mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel, eluting with hexanes to EtOAc to afford methyl 4-(2-fluoro methoxyphenyl)(propenyl)quinolinecarboxylate (3.3g, 9.39 mmol, 64.9 % yield) as a yellow solid.
(LCMS, LRMS m/z (M+H)+ 352.3 found, 352.4 required.
Methyl 4-(2-fluoromethoxyphenyl)[1-(2-methylpyrimidinyl)propanyl]quinolinecarboxylate (8-9) Methyl 4-(2-fluoromethoxyphenyl)(propenyl)quinolinecarboxylate (1.5g, 4.27 mmol) was dissolved in THF (7.8 ml), heated to 60°C and then added 9-BBN (0.5M THF, 10.7 ml, 5.35 mmol) dropwise over 5 minutes. After 1 hour, d to cool to ambient. Added 5-bromomethylpyrimidine (0.886 g, 5.12 mmol), Pd2(dba) 3 (0.195 g, 0.213 mmol), butyldiadamantylphosphine (0.153 g, 0.427 mmol), potassium carbonate (2.360 g, 17.08 mmol) and water (0.776 ml), degassed 5 minutes with en and then heated to 90oC in a sealed tube for 30 s. The reaction was allowed to cool to ambient temperture. To the mixture was added brine and then EtOAc. The organic portion was collected, dried (MgSO4) and then concentrated. The residue was purified by column chromatography on silica gel, eluting with CHCl3 to 5 CHCl3/EtOAc/MeOH to afford methyl luoro methoxyphenyl)[1-(2-methylpyrimidinyl)propanyl]quinolinecarboxylate (335 mg, 0.752 mmol, 17.62 % yield) as an orange oil.
(LCMS, LRMS m/z (M+H)+ 446.4 found, 446.5 required. 4-(2-Fluoromethoxyphenyl)[1-(2-methylpyrimidinyl)propan-2(R or S)-yl]quinoline carboxamide (8-10 , 8-11 ) A stirred solution of methyl 4-(2-fluoromethoxyphenyl)[1-(2-methylpyrimidinyl)propan yl]quinolinecarboxylate (335 mg, 0.752 mmol) and MeOH (3008 µl) was treated with 5 ml 7N NH 3/MeOH and then heated to 60 °C in a sealed tube for 30 s. The reaction was allowed to cool to ambient temperature and then was concentrated. The solid was azeotroped with 5 ml Et2O and then dried in vacuo to give racemic product as a colorless foam.
The residue was purified by preparative HPLC Chiralpak AD, 5 cm, 40 ml/min, eluting with 100% EtOH, to afford 8-10 (isomer A, 95 mg, 0.221 mmol, 58.7 % yield) as a colorless foam and 8-11 (isomer B, 85 mg, 0.197 mmol, 52.5 % yield) as a colorless foam. 8-10, Isomer A (LCMS, LRMS m/z (M+H)+ 431.3 found, 431.5 required. 1H NMR (500 MHz, CDCl 2 (2 H, s), 8.21 (1 H, s), 8.05 (1 H, s), 7.89 (1 H, s), 7.73 (1 H, d, J = 8.58 Hz), 7.41 (1 H, d, J = 8.42 Hz), 7.34 (1 H, t, J = 8.40 Hz), 6.89-6.85 (1 H, m), 6.80 (1 H, dd, J = 11.53, 2.48 Hz), 5.61 (1 H, s), 3.90 (3 H, s), 3.26-3.21 (1 H, m), 3.00-2.92 (2 H, m), 2.65 (3 H, s). - 162 – 8-11, Isomer B (LCMS, LRMS m/z (M+H)+ 431.4 found, 431.5 required.
¹H NMR (500 MHz, CDCl3):8.32 (2 H, s), 8.21 (1 H, s), 8.05 (1 H, s), 7.89 (1 H, s), 7.73 (1 H, dd, J = 8.63, 2.83 Hz), 7.41 (1 H, d, J = 8.49 Hz), 7.34 (1 H, t, J = 8.43 Hz), 6.87 (1 H, dd, J = 8.51, 2.54 Hz), 6.80 (1 H, dd, J = 11.56, 2.53 Hz), 5.61 (1 H, s), 3.90 (3 H, s), 3.26-3.21 (1 H, m), 3.01-2.90 (2 H, m), 2.65 (3 H, s).
The following nds have been prepared according to procedures similar to those found in Scheme 8.1, 8.2, and 8.3 selecting the riate quinoline derivative, boronic acid derivatives, and aryl or aryl halide and provide examples of compounds in the invention.
Table 8 Exact Mass Example Structure IUPAC Name [M+H]+ 4-(4-fluorophenyl) Calc'd (2-pyridin 372.2, ylethyl)quinoline Found 8-12 carboxamide 372.2 4-(4-fluorophenyl) Calc'd (2-pyrimidin 355.1, ylethyl)quinoline Found 8-13 carbonitrile 355.1 4-(4-fluorophenyl) Calc'd (2-pyridin 372.2, ylethyl)quinoline Found 8-14 carboxamide 372.2 - 163 – 4-(4-fluorophenyl) Calc'd (2-pyrimidin 373.1, ylethyl)quinoline Found 8-15 carboxamide 373.1 4-(4-fluorophenyl) Calc'd (2-pyridin 372.2, l)quinoline Found 8-16 carboxamide 372.2 4-(4-fluorophenyl) (1-hydroxy Calc'd n 388.1, ylethyl)quinoline Found 8-17 carboxamide 388.1 4-(4-fluorophenyl) (1-hydroxy Calc'd pyridin 388.1, ylethyl)quinoline Found 8-18 carboxamide 388.1 4-(4- methoxyphenyl) [2-(2- Calc'd methylpyrimidin 399.2, yl)ethyl]quinoline Found 8-19 carboxamide 399.1 - 164 – 7-[2-(6- chloropyridinyl)- Calc'd 1-hydroxyethyl](4- 434.1, methoxyphenyl)quino Found 8-20 linecarboxamide 434.0 4-(4-fluorophenyl) [1-hydroxy(6- Calc'd pyridin 402.2, yl)ethyl]quinoline Found 8-21 carboxamide 402.2 4-(4-fluorophenyl) [1-hydroxy(6- Calc'd methylpyridin 402.2, yl)ethyl]quinoline Found 8-22 carboxamide 402.2 4-(4-fluorophenyl) Calc'd (1-methylpyridin- 386.2, 3-ylethyl)quinoline- Found 8-23 oxamide 386.2 4-(4-fluorophenyl) Calc'd (1-methylpyridin- 386.2, 3-ylethyl)quinoline- Found 8-24 2-carboxamide 386.2 - 165 – 4-(4-fluorophenyl) [1-methyl(6- Calc'd methylpyridin 400.2, yl)ethyl]quinoline Found 8-25 carboxamide 400.2 4-(4-fluorophenyl) [1-methyl(6- Calc'd methylpyridin 400.2, yl)ethyl]quinoline Found 8-26 carboxamide 400.2 7-[2-(6- pyridinyl)- Calc'd 1-hydroxyethyl](4- 434.1, methoxyphenyl)quino Found 8-27 linecarboxamide 434.5 7-[2-(6- chloropyridinyl)- Calc'd 1-hydroxyethyl](4- 434.1, methoxyphenyl)quino Found 8-28 linecarboxamide 434.5 4-(2-fluoro methoxyphenyl) [2-(2- Calc'd methylpyrimidin 417.2, yl]quinoline Found 8-29 carboxamide 417.2 - 166 – 7-[2-(2- aminopyridin Calc'd yl)ethyl](4- 399.2, methoxyphenyl)quino Found 8-30 linecarboxamide 399.4 7-[2-(2- aminopyridin yl)ethyl](2-fluoro- Calc'd 4- 417.2, methoxyphenyl)quino Found 8-31 linecarboxamide 417.4 7-[2-(2- cyanopyrimidin Calc'd yl)ethyl](4- 410.2, methoxyphenyl)quino Found 8-32 linecarboxamide 410.5 cyanopyrimidin yl](2-fluoro- Calc'd 4- 428.2, methoxyphenyl)quino Found 8-33 linecarboxamide 428.4 - 167 – 7-[2-(2- cyanopyrimidin yl)methylethyl] Calc'd (4- 424.2, methoxyphenyl)quino Found 8-34 linecarboxamide 424.5 7-[2-(4- aminopyrimidin Calc'd yl)ethyl](4- 400.2, methoxyphenyl)quino Found 8-35 linecarboxamide 400.5 7-[2-(2- yridinyl) Calc'd methylethyl](4- 413.2, methoxyphenyl)quino Found 8-36 linecarboxamide 413.5 7-[2-(2- aminopyridinyl) Calc'd methylethyl](4- 413.2, methoxyphenyl)quino Found 8-37 -carboxamide 413.5 7-[2-(2- aminopyridinyl) methylethyl](2- Calc'd fluoro 431.2, methoxyphenyl)quino Found 8-38 linecarboxamide 431.5 - 168 – 7-[2-(2- aminopyridinyl) methylethyl](2- Calc'd fluoro 431.2, methoxyphenyl)quino Found 8-39 linecarboxamide 431.5 4-(4- methoxyphenyl) Calc'd hylpyridin- 398.2, 3-ylethyl)quinoline- Found 8-40 2-carboxamide 398.4 4-(4- methoxyphenyl) Calc'd (1-methylpyridin- 398.2, 3-ylethyl)quinoline- Found 8-41 2-carboxamide 398.4 4-(4- methoxyphenyl) [1-methyl(6- Calc'd methylpyridin 412.2, yl)ethyl]quinoline Found 8-42 carboxamide 412.4 4-(4- methoxyphenyl) [1-methyl(6- Calc'd methylpyridin 412.2, yl)ethyl]quinoline Found 8-43 carboxamide 412.4 - 169 – 4-(2-fluoro methoxyphenyl) Calc'd (1-methylpyridin- 416.2, 3-ylethyl)quinoline- Found 8-44 2-carboxamide 416.4 4-(2-fluoro methoxyphenyl) Calc'd (1-methylpyridin- 416.2, hyl)quinoline- Found 8-45 2-carboxamide 416.4 7-{2-[6- (fluoromethyl)pyridin yl] Calc'd methylethyl}(4- 430.2, methoxyphenyl)quino Found 8-46 linecarboxamide 430.4 7-{2-[6- (fluoromethyl)pyridin yl] Calc'd methylethyl}(4- 430.2, methoxyphenyl)quino Found 8-47 linecarboxamide 430.4 luoro methoxyphenyl) {2-[6- (fluoromethyl)pyridin Calc'd yl] 448.2, methylethyl}quinolin Found 8-48 ecarboxamide 448.4 - 170 – 4-(2-fluoro methoxyphenyl) {2-[6- (fluoromethyl)pyridin Calc'd yl] 448.2, methylethyl}quinolin Found 8-49 ecarboxamide 448.4 4-(3-fluoro methoxyphenyl) [2-(2- Calc'd methylpyrimidin 417.2, yl)ethyl]quinoline Found 8-50 carboxamide 417.3 -difluoro yphenyl) [2-(2- Calc'd methylpyrimidin 435.2, yl)ethyl]quinoline Found 8-51 carboxamide 435.3 4-(4-methoxy methylphenyl)[2- Calc'd (2-methylpyrimidin- 413.2, -yl)ethyl]quinoline- Found 8-52 2-carboxamide 413.3 - 171 – 4-(4-methoxy-2,6- dimethylphenyl) [2-(2- Calc'd methylpyrimidin 427.2, yl)ethyl]quinoline Found 8-53 carboxamide 427.3 4-(3,5-difluoro methoxyphenyl) [2-(2- Calc'd methylpyrimidin 435.2, yl)ethyl]quinoline Found 8-54 carboxamide 435.3 4-(3,4- dimethoxyphenyl) [2-(2- Calc'd methylpyrimidin 429.2, yl)ethyl]quinoline Found 8-55 carboxamide 429.4 ICAL ASSAYS The utility of the compounds in accordance with the present invention as antagonists of tropic glutamate receptor activity, in particular mGluR2 activity, may be demonstrated by methodology known in the art. Antagonist constants are determined as follows. The compounds of the present invention were tested in a fluorescence laser imaging plate reader based assay. This assay is a common onal assay to monitor Ca2+ mobilization in whole cells expressing recombinant receptor coupled with a cuous G-protein. CHO dhfr- cells stably expressing recombinant human mGluR2 and Gα16 loaded with Fluo-4 AM (Invitrogen, Carlsbad CA) are treated with various concentrations of nists of compounds and the Ca2+ response is monitored on a FLIPR384 (Molecular Devices, ale CA) for agonist activity. Then 2,500 nM glutamate is added and the nist response is monitored. The maximum calcium response at each concentration of compound for agonist or antagonist were plotted as dose responses and the curves were fitted with a four parameter logistic equation giving IC50 and Hill cient using the iterative non linear curve fitting software ADA (Merck & Co). In - 172 – particular, the compounds of the es shown in the tables above had activity in antagonizing the mGluR2 receptor in the aforementioned assays, with an IC50 of less than about 700 nM, indicating their activity as antagonists of mGluR2 function. Specific IC 50 values for respresentative example compounds of the invention are provided in the table below: Example IC50 Value e IC50 Value Example IC50 Value (nM) (nM) (nM) 1-7 159 2-12 475 3-2 46 1-9 171 2-13 71 3-6 21 1-10 660 2-14 30 3-7 24 1-11 822 2-15 64 3-10 63 1-12 678 2-16 59 3-11 31 1-13 641 2-17 398 3-15 85 1-14 667 2-18 28 3-16 21 1-15 169 2-19 588 3-17 74 1-16 681 2-20 27 3-18 36 1-17 368 2-21 23 3-19 112 1-18 58 2-22 47 3-20 21 1-19 100 2-23 456 3-21 40 1-20 139 2-24 12 3-22 47 1-21 124 2-25 16 3-23 192 1-22 505 2-26 29 3-24 31 1-23 135 2-27 7 3-25 43 1-24 169 2-28 17 3-26 25 1-25 407 2-29 5 3-27 23 1-26 217 2-30 123 3-28 84 1-27 377 2-31 109 3-29 64 1-28 393 2-32 129 3-30 31 1-29 190 2-33 42 3-31 54 2-3 21 2-34 105 3-32 23 2-7 9 2-35 228 3-33 69 2-8 38 2-36 3059 3-34 55 2-9 416 2-37 59 3-35 27 2-10 21 2-38 27 3-36 189 2-11 25 2-39 8 3-37 42 - 173 – Example IC50 Value e IC50 Value Example IC50 Value (nM) (nM) (nM) 3-38 24 4-36 274 4-68 149 3-39 73 4-37 55 4-69 46 3-40 81 4-38 57 4-70 114 3-41 89 4-39 42 4-71 25 3-42 46 4-40 392 4-72 243 3-43 66 4-41 118 4-73 30 3-44 15 4-42 56 4-74 91 3-45 19 4-43 252 4-75 1090 3-46 206 4-44 59 4-76 261 3-47 67 4-45 136 4-77 15 3-48 16 4-46 24 4-78 81 3-49 16 4-47 170 4-79 159 3-50 15 4-48 53 4-80 15 3-51 10 4-49 38 4-81 1629 4-1 163 4-50 381 4-82 188 4-9 11 4-51 9 4-83 513 4-16 13 4-52 93 4-84 11 4A 9 4-53 25 4-85 15 4 B 11 4-54 12 4-86 9 4-23 137 4-55 33 4-87 14 4-24 78 4-56 88 4-88 14 4-25 61 4-57 237 4-89 235 4-26 118 4-58 163 4-90 8 4-27 183 4-59 394 4-91 8 4-28 82 4-60 196 4-92 17 4-29 82 4-61 166 4-93 66 4-30 241 4-62 252 4-94 63 4-31 84 4-63 46 4-95 11 4-32 478 4-64 73 4-96 8 4-33 138 4-65 17 4-97 260 4-34 330 4-66 16 4-98 52 4-35 187 4-67 1153 4-99 55 - 174 – Example IC50 Value e IC50 Value Example IC50 Value (nM) (nM) (nM) 4-100 24 4-132 149 7-5 338 4-101 10 4-133 272 7-13 13 4-102 10 4-134 86 7A 14 4-103 114 4-135 8 7B 21 4-104 120 5-4 299 7-21 21 4-105 172 5-5 125 7-22 74 4-106 50 5-6 987 7-23 10 4-107 25 6-2 21 7-24 17 4-108 161 6-3 55 7-25 20 4-109 116 6-4 145 7-26 15 4-110 90 6-5 47 7-27 169 4-111 80 6-6 13 7-28 10 4-112 23 6-7 8 7-29 8 4-113 24 6-8 56 7-30 21 4-114 15 6-9 10 7-31 28 4-115 34 6-10 31 7-32 214 4-116 14 6-11 14 7-33 36 4-117 53 6-12 31 7-34 39 4-118 13 6-13 76 7-35 14 4-119 18 6-14 18 7-36 13 4-120 238 6-15 34 7-37 30 4-121 >1000 6-16 76 7-38 39 4-122 931 6-17 48 8-1 10 4-123 49 6-18 35 8-2 15 4-124 48 6-19 41 8-7 13 4-125 76 6-20 15 8-10 7 4-126 13 6-21 6 8-11 6 4-127 97 6-22 42 8-12 86 4-128 142 6-23 28 8-13 170 4-129 >1000 6-24 25 8-14 44 4-130 245 6-25 7 8-15 7 4-131 112 6-26 12 8-16 10 - 175 – Example IC50 Value Example IC50 Value Example IC50 Value (nM) (nM) (nM) 8-17 5 8-30 9 8-43 10 8-18 5 8-31 9 8-44 8 8-19 22 8-32 7 8-45 10 8-20 12 8-33 6 8-46 10 8-21 19 8-34 8 8-47 8 8-22 14 8-35 7 8-48 10 8-23 21 8-36 15 8-49 9 8-24 20 8-37 16 8-50 4 8-25 21 8-38 33 8-51 5 8-26 19 8-39 14 8-52 27 8-27 11 8-40 10 8-53 52 8-28 6 8-41 5 8-54 11 8-29 6 8-42 12 8-55 96 The following abbreviations may be used throughout the text: Me = methyl; Et = ethy; t-Bu: = tert-butyl; Ar: = aryl; Ph = phenyl; Bn = benzyl; DCE = dichloroethylene; HMDS = hexamethyldisilazane; DMF:= dimethylformamide; DMFDMA = N,N- dimethylformamide dimethylacetal; THF = tetrahydrofuran; BOP:= benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate; Boc = tert-butyloxycarbonyl; TEA = triethylamine; TPAP = tetra-n-propyl ammonium perruthenate; NMO = N-methyl morpholine N-oxide; CIZn = zinc; dppf = diphenylphosphorousferrocenyl; PMB = p-methoxybenzyl; Ms = mesyl; Ac = acetyl; DMSO = dimethylsulfoxide; DCM = dichloromethane; m-CPBA = meta-chloroperoxybenzoic acid; DMEM = Dulbecco's ed Eagle Medium (High Glucose); FBS = fetal bovine serum; rt = room temperature; aq = aqueous; HPLC = high mance liquid chromatography; MS = mass spectrometry While the invention has been described and illustrated with reference to certain ular embodiments thereof, those d in the art will appreciate that s adaptations, changes, modifications, tutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable. - 176 –

Claims (34)

What is claimed is:
1. A compound selected from the group consisting of: , , , , and 5 , or a pharmaceutically acceptable salt of said compound.
2. A nd according to claim 1, having a structure: 10
3. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable r.
4. A compound according to claim 1, having a structure: - 177 – in the form of a pharmaceutically acceptable salt.
5. A pharmaceutical composition sing the compound of claim 4 in the form of a 5 pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
6. A compound according to claim 1, having a structure: 10
7. A ceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier.
8. A compound according to claim 1, having a structure: 15 in the form of a pharmaceutically acceptable salt.
9. A pharmaceutical composition comprising the compound of claim 8 in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. - 178 –
10. A compound according to claim 1, having a structure:
11. A pharmaceutical composition comprising the compound of claim 10 and a ceutically 5 acceptable carrier.
12. A compound according to claim 1, having a structure: in the form of a pharmaceutically acceptable salt.
13. A pharmaceutical composition comprising the compound of claim 12 in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
14. A nd according to claim 1, having a structure: 15 .
15. A pharmaceutical composition comprising the nd of claim 14 and a pharmaceutically acceptable carrier. 20
16. A compound according to claim 1, having a structure: - 179 – in the form of a pharmaceutically acceptable salt.
17. A pharmaceutical ition comprising the compound of claim 16 in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
18. A compound ing to claim 1 having a structure:
19. A pharmaceutical composition comprising the compound of claim 18 and a pharmaceutically 10 acceptable carrier.
20. A compound according to claim 1 having a structure: in the form of a pharmaceutically acceptable salt.
21. A pharmaceutical composition sing the compound of claim 20 in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
22. The use of a compound selected from the group consisting of: - 180 – , , , , and , or a pharmaceutically able salt of said compound, for the manufacture of a medicament for the treatment of a disease or disorder mediated by the mGluR2 receptor, 5 wherein said disease or disorder is mer’s disease, cognitive impairment, phrenia, mood disorder, pain, or sleep disorder.
23. The use according to claim 22, wherein said compound is:
24. The use according to claim 23, wherein said compound is in the form of a pharmaceutically acceptable salt.
25. The use according to claim 22, wherein said compound is: - 181 –
26. The use according to claim 25, wherein said compound is in the form of a pharmaceutically acceptable salt.
27. The use according to claim 22, wherein said compound is:
28. The use according to claim 27, wherein said compound is in the form of a pharmaceutically 10 acceptable salt.
29. The use according to claim 22, wherein said compound is: 15
30. The use according to claim 27, wherein said compound is in the form of a ceutically acceptable salt.
31. The use according to claim 22, wherein said compound is: - 182 –
32. The use according to claim 31, wherein said compound is in the form of a pharmaceutically acceptable salt.
33. Use according to any one of claims 22 to 32, wherein said disease or disorder is Alzheimer’s disease.
34. Use ing to any one of claims 22 to 32, wherein said disease or disorder is cognitive 10 impairment.
NZ624596A 2011-11-03 2012-10-26 QUINOLINE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE NZ624596B2 (en)

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PCT/US2012/062027 WO2013066736A1 (en) 2011-11-03 2012-10-26 QUINOLINE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE

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