WO2007130468A2 - Pyrido [2, 3-b] pyrazine and [1, 8] -naphthyridine derivatives as alk and c-met inhibitors - Google Patents

Pyrido [2, 3-b] pyrazine and [1, 8] -naphthyridine derivatives as alk and c-met inhibitors Download PDF

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Publication number
WO2007130468A2
WO2007130468A2 PCT/US2007/010656 US2007010656W WO2007130468A2 WO 2007130468 A2 WO2007130468 A2 WO 2007130468A2 US 2007010656 W US2007010656 W US 2007010656W WO 2007130468 A2 WO2007130468 A2 WO 2007130468A2
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WO
WIPO (PCT)
Prior art keywords
tetrahydropyrido
pyrazin
alkyl
benzyl
chloro
Prior art date
Application number
PCT/US2007/010656
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French (fr)
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WO2007130468A3 (en
Inventor
Bruce D. Dorsey
Karen L. Milkiewicz
Douglas A. Pippin
Jay P. Theroff
Theodore L. Underiner
Linda Weinberg
Craig A. Zificsak
Original Assignee
Cephalon, Inc.
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Publication date
Application filed by Cephalon, Inc. filed Critical Cephalon, Inc.
Priority to JP2009509691A priority Critical patent/JP5265525B2/en
Priority to CN2007800159105A priority patent/CN101437819B/en
Priority to AU2007248603A priority patent/AU2007248603B8/en
Priority to EP07776633.5A priority patent/EP2091951B1/en
Priority to MX2008013942A priority patent/MX2008013942A/en
Priority to NZ571309A priority patent/NZ571309A/en
Priority to CA2646128A priority patent/CA2646128C/en
Priority to IN4797KON2008 priority patent/IN266859B/en
Publication of WO2007130468A2 publication Critical patent/WO2007130468A2/en
Publication of WO2007130468A3 publication Critical patent/WO2007130468A3/en
Priority to IL194832A priority patent/IL194832A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Anaplastic Lymphoma Kinase is a cell membrane-spanning receptor tyrosine kinase, which belongs to the insulin receptor subfamily. The most abundant expression of ALK occurs in the neonatal brain, suggesting a possible role for ALK in brain development (Duyster, J. et al., Oncogene, 2001, 20, 5623-5637).
  • ALK is also implicated in the progression of certain tumors. For example, approximately sixty percent of anaplastic large cell lymphomas (ALCL) are associated with a chromosome mutation that generates a fusion protein consisting of nucleophosmin (NMP) and the intracellular domain of ALK.
  • NMP nucleophosmin
  • This mutant protein, NMP-ALK possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic property through activation of downstream effectors.
  • the constitutively activated chimeric ALK has also been demonstrated in about 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growing sarcoma that mainly affects children and young adults. (Lawrence, B. et al., Am. J. Pathol, 2000, 157, 377-384; Duyster et al.).
  • ALK and its putative ligand, pleiotrophin are overexpressed in human glioblastomas (Stoica, G. et al., J. Biol. Chem., 2001, 276, 16772-16779).
  • depletion of ALK reduced glioblastoma tumor growth and prolonged animal survival (Powers, C. et al., J. Biol Chem., 2002, 277, 14153-14158; Mentlein, R. et al, J. Neurochem., 2002, 83, 747-753).
  • an ALK inhibitor would either permit durable cures when combined with current chemotherapy for ALCL, IMT, or glioblastoma, or be used as a single therapeutic agent in a maintenance role to prevent cancer recurrence in those patients.
  • Various ALK inhibitors have been reported, including indazoloisoquinolines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).
  • c-Met is a member of the tyrosine kinase growth factor receptor family.
  • c-Met expression occurs in endothelial, epithelial, and mesenchymal cells. c-Met binding to the endogenous ligand, hepatocyte growth factor (HGF), promotes cell migration, proliferation, and invasion. c-Met is implicated in the progression of certain tumors. c-Met overexpression has been shown in numerous tumor types including colon, breast, renal, lung, hemangiomas, squamous cell myeloid leukemia, melanomas, glioblastomas, and astrocytomas.
  • HGF hepatocyte growth factor
  • a c-Met inhibitor would have potent anti-tumor effects in many cancers.
  • Various c-Met inhibitors have been reported, including aminoheteroaryl compounds (WO 2004/076412; WO 2005/082411; US 2005/0009840), 5-6 bicyclic heterocycles (WO 2005/028475), monocyclic heterocycles (US 2005/0245530), bicyclic heterocycles (US 2005/0239820), triazolotriazine compounds (WO 2005/010005; US 2005/0075340), triarylimidazoles (US 2005/0085473), indolinone hydrazides (WO 2005/005378), tetracyclic compounds (WO 2005/004808), imidazole derivatives (WO 2005/040154), quinolines and quinazolines (WO 2005/030140), and quinolinoxynaphthalenes (WO 2005/070891).
  • aminoheteroaryl compounds WO 2004/076412; WO 2005/08
  • the present invention provides a compound of Formula I
  • the compounds of Formula I have ALK and/or c-Met inhibitory activity, and may be used to treat ALK- or c-Met-mediated disorders or conditions.
  • the present invention further provides a pharmaceutical composition comprising at least one compound of the present invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient therefor.
  • the present invention provides a method of treating a subject suffering from an ALK- or c-Met-mediated disorder or condition comprising: administering to the subject the pharmaceutical composition of the present invention.
  • Alkyl or “alkyl group” includes both straight and branched chain aliphatic hydrocarbon groups.
  • straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.
  • branched-chain alkyl groups include, but are not limited to, isopropyl, tert-butyl, isobutyl, etc.
  • C x - y indicates the number of carbon atoms in a group.
  • a "Ci- ⁇ - alkyl” is an alkyl group having from one (1) to six (6) carbon atoms.
  • x 0, i.e., "Co-y”.
  • the term “Co- y " indicates that the group may be absent or present, and if present, defines the number of carbon atoms in the group.
  • Alkenyl or “alkenyl group” includes straight and branched chain unsaturated alkyl groups which have two (2) or more carbon atoms and at least one double bond. Examples include, but are not limited to, ethenyl, 3-buten-l-yl, 2-ethenylbutyl, and 3-hexen-l-yl.
  • Alkynyl or “alkynyl group” includes straight and branched chain unsaturated alkyl groups which have two (2) or more carbon atoms and at least one triple bond. Examples include, but are not limited to, ethynyl, 3-butyn-l-yl, propynyl, 2-butyn-l-yl, and 3-pentyn-l- yi.
  • Haloalkyl or “haloalkyl group” refers to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms.
  • "Halogen" includes fluorine, chlorine, bromine and iodine atoms.
  • 'Tseudohalogen refers to -OCN, -SCN, -CF 3 , and -CN.
  • Cycloalkyl or “cycloalkyl group” includes monocyclic, bicyclic, and tricyclic non- aromatic carbocyclic rings, which may be saturated or unsaturated. Examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, and norbornenyl.
  • Heterocycloalkyl or “heterocycloalkyl group” includes 3-15 membered monocyclic, bicyclic, and tricyclic non-aromatic rings, which may be saturated or unsaturated, and which contain, in addition to carbon atoms, at least one heteroatom, such as nitrogen, oxygen or sulfur.
  • Examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S- dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, di
  • heterocycloalkyl groups can be C- attached or N-attached where such is possible and results in the creation of a stable structure.
  • piperidinyl can be piperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).
  • Aryl or “aryl group” includes phenyl and 9-15 membered bicyclic or tricyclic hydrocarbon ring systems in which at least one of the rings is aromatic. Examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, and 6,7,8,9-tetrahydro- 5H-benzocycloheptenyl.
  • Heteroaryl or “heteroaryl group” includes (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 8-15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atoms, at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic.
  • Examples include, but are not limited to, 2,3- dihydrobenzofuranyl, 1 ,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, A-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl
  • Linker or “linker group” refers to a bond, atom, or group of atoms that connects other atoms or groups of atoms within a molecule.
  • L 1 is a linker group that connects the groups A and R 1 in a compound of Formula I (A-L 1 -R 1 ).
  • Linker groups are identified herein as an atom or group of atoms between two dashed lines (— ).
  • an oxygen atom linker is identified herein as -O— .
  • “Chemically stable” or “stable” refers to a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture, and then incorporated into a pharmaceutical composition. The present invention is directed only to stable compounds.
  • “Pharmaceutical composition” refers to a composition suitable for administration in medical or veterinary use.
  • “Therapeutically effective amount” refers to an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit, halt, or cause an improvement in a disorder or condition being treated in a particular subject or subject population.
  • a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.
  • Subject refers to a member of the class Mammalia.
  • mammals include, without limitation, humans, primates, chimpanzees, rodents, mice, rats, rabbits, horses, livestock, dogs, cats, sheep, and cows.
  • Treatment refers to the acute or prophylactic diminishment or alleviation of at least one symptom or characteristic associated or caused by a disorder being treated.
  • treatment can include diminishment of several symptoms of a disorder or complete eradication of a disorder.
  • administering refers to the method of contacting a compound with a subject.
  • Modes of “administering” include, but are not limited to, methods that involve contacting the compound intravenously, intraperitoneally, intranasally, transde ⁇ nally, topically, via implantation, subcutaneously, parentally, intramuscularly, orally, systemically, and via adsorption.
  • the present invention provides a compound of Formula I
  • A is chosen from N and CH;
  • X is chosen from -L 2 G 1 L 3 G 2 L 4 R 7 and R 8 ;
  • R 2 and R 3 are independently chosen from H, OH, and Ci- 6 -alkyl, or R 2 and R 3 together form a carbonyl group;
  • R 4 and R 5 are independently chosen from H and Ci- 6 -alkyl, or R 4 and R 5 together form a carbonyl group, or one of R 4 and R 5 forms a double bond with R 6 ;
  • R 6 is chosen from H and Ci- 6 -alkyl, or R 6 forms a double bond with R 4 or R s ;
  • A is N, i.e., a compound of Formula ICa):
  • A is CH, i.e., a compound of Formula ICb):
  • L 1 is -Co- 3 -alkyl-NR IO -Co- 3 -alkyl-, -Qw-alkyl-O-Coo-alkyl-, or -Ci ⁇ -alkyl-. More " preferably, when A is CH, L 1 is -NR 10 -Co- 3 - alkyl-, -O-Co- 3 -alkyl-, or -CH 2 -. More preferably, when A is CH, L 1 is -NR 10 -, -0-C 0-3 - alkyl-, or -CH 2 -.
  • L 1 is -Co- 3 -alkyl-O-Co-s-alkyl- or -Ci- 6 - alkyl-. More preferably, when A is CH, L 1 is -Coo-alkyl-O-Co-s-alkyl- or -CH 2 -. More preferably, when A is CH, L 1 is -O-Co- 3 -alkyl— , or -CH 2 -. More preferably, when A is CH, L 1 is -O- or -CH 2 -.
  • R 10 at each occurrence is independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ - haloalkyl. More preferably, R 10 at each occurrence is independently chosen from H and Ci- ⁇ - alkyl. More preferably, R 10 at each occurrence is H.
  • R 1 is an optionally mono- or polysubstituted group chosen from aryl and heteroaryl. More preferably, R 1 is an optionally mono- or polysubstituted aryl group. More preferably, R 1 is an optionally mono- or polysubstituted group chosen from phenyl, pyridinyl, and furanyl. More preferably, R 1 is an optionally mono- or polysubstituted group chosen from phenyl, pyridin-3-yI, and furan-2-yl.
  • R 1 is chosen from 2-chloro-3,6-difluorophenyl, phenyl, 2,5-difluorophenyl, 2,4,5-trifluorophenyl, 5-chloro-2-(trifluoromethyl)phenyl, 2-chloro-5 -(trifluoromethyl)phenyl, 2-chlorophenyl, 2,5-dichlorophenyl, 5-fluoro-2-(trifluoromethyl)phenyl, 2,6-dichlorophenyl, 3- fluoro-2-(trifluoromethyl)phenyl, 3-chlorophenyl, 3,5-dichlorophenyl, pyridin-3-yl, 2-acetyl-5- fluorophenyl, 2-cyano-3,6-difluorophenyl, 5-(trifluoromethyl)furan-2-yl, 2- (trifluoromethoxy)phenyl, and 2-chloropyridin-3-yl.
  • R 20 and R 21 at each occurrence are independently chosen from H, Ci- 6 -alkyl, and Ci- 6 -haloalkyl. More preferably, R 20 and R 21 at each occurrence are independently chosen from H and Ci- ⁇ -alkyl. More preferably, R 20 and R 21 at each occurrence are H.
  • R 2 and R 3 are independently chosen from H and Ci- ⁇ -alkyl, or R 2 and R 3 together form a carbonyl group. More preferably, R 2 and R 3 are H, or R 2 and R 3 together form a carbonyl group. More preferably, R 2 and R 3 together form a carbonyl group. More preferably, R 2 and R 3 are H.
  • R 2 and R 3 together form a carbonyl group
  • R 4 and R 5 are independently chosen from H and Ci- ⁇ -alkyl, or one of R 4 and R 5 forms a double bond with R 6 .
  • R 4 and R 5 are H, or one of R 4 and R 5 forms a double bond with R 6 . More preferably, R 4 and R 5 are H.
  • R 6 is H, or R 6 forms a double bond with R 4 or R 5 . More preferably, R 6 is H.
  • X is -L 2 G 1 L 3 G 2 L 4 R 7 , i.e., a compound of Formula I(c): I(c)
  • R 30 at each occurrence is independently chosen from H, Ci- 6 -alkyl, and Ci . 6 - haloalkyl. More preferably R 30 at each occurrence is independently chosen from H and Ci - 6 - alkyl. More preferably, R 30 at each occurrence is H.
  • G 1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl. More preferably, G 1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl and heteroaryl. More preferably, G 1 is a bond or an optionally mono- or polysubstituted aryl group.
  • G 1 is a bond, or an optionally mono- or polysubstituted group chosen from phenyl, pyridinyl, piperazinyl, pyrimidinyl, tetrahydropyridinyl, pyrazolyl, pyrrolyl, piperidinyl, 4-carbonyl- 1,3,8- triazaspiro[4.5]decanyl, pyrrolidinyl, and thiazolyl.
  • each G 1 substituent is independently chosen from halogen, —OR 40 , Ci -3 -alkyl, and Ci -3 -haloalkyl. More preferably, each G 1 substituent is independently chosen from halogen, -OR 40 , and C 1-3 - haloalkyl. More preferably, each G 1 substituent is independently chosen from halogen and — OR 40 . More preferably, each G 1 substituent is independently chosen from halogen and hydroxyl. More preferably, each G 1 substituent is independently chosen from chloro, fluoro, and hydroxyl. More preferably, G 1 is unsubstituted.
  • R 40 and R 41 at each occurrence are independently chosen from H, Ci-6-alkyl, and Ci-6-haloalkyl. More preferably, R 40 and R 41 at each occurrence are independently chosen from H and Ci- 6 -alkyl. More preferably, R 40 and R 41 at each occurrence are H.
  • R 50 at each occurrence is independently chosen from H, Ci- ⁇ -alkyl, and Ci- 6 - haloalkyl. More preferably, R 50 at each occurrence is independently chosen from H and Q - 6 - alkyl. More preferably, R 50 at each occurrence is H.
  • G 2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl. More preferably, G 2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl and heteroaryl. More preferably, G 2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl and heterocycloalkyl. More preferably, G 2 is a bond or an optionally mono- or polysubstituted aryl group. More preferably, G 2 is a bond or an optionally mono- or polysubstituted heterocycloalkyl group.
  • G 2 is a bond or an optionally mono- or polysubstituted heteroaryl group. More preferably, G 2 is a bond, or an optionally mono- or polysubstituted group chosen from piperazinyl, pyrrolidinyl, piperidinyl, phenyl, 4-carbonyl-l,3,8-triazaspiro[4.5]decanyl, and thiazolyl.
  • each G 2 substituent is independently chosen from halogen, -OR 60 , Ci -3 -alkyl, and Ci- 3 -haloalkyl. More preferably, each G 2 substituent is independently chosen from halogen, -OR 60 , and C1. 3 - haloalkyl. More preferably, each G 2 substituent is independently chosen from halogen and - OR 60 . More preferably, each G 2 substituent is independently chosen from halogen and hydroxyl. More preferably, each G 2 substituent is independently chosen from chloro, fluoro, and hydroxyl. More preferably, each G 2 substituent is hydroxyl. More preferably, G 2 is unsubstituted.
  • R 60 and R 61 at each occurrence are independently chosen from H, Ci- ⁇ -alkyl, and Q- ⁇ -haloalkyl. More preferably, R 60 and R 61 at each occurrence are independently chosen from H and Ci ⁇ -alkyl. More preferably, R 60 and R 61 at each occurrence are H.
  • R 70 at each occurrence is independently chosen from H, Ci-6-alkyl, and Ci- ⁇ - haloalkyl. More preferably, R 70 at each occurrence is independently chosen from H and Ci - 6 - alkyl. More preferably, R 70 at each occurrence is H.
  • R 7 is an optionally mono- or polysubstituted group chosen from Ci-6-alkyl, aryl, C 3 -io-cycloalkyl, heterocycloalkyl, and heteroaryl. More preferably, R 7 is an optionally mono- or polysubstituted group chosen from Ci-6-alkyl, aryl, heterocycloalkyl, and heteroaryl. More preferably, R 7 is an optionally mono- or polysubstituted group chosen from aryl, C 3- io- cycloalkyl, heterocycloalkyl, and heteroaryl. More preferably, R 7 is an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl.
  • R 7 is an optionally mono- or polysubstituted group chosen from pyridinyl, phenyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, isopentyl, hexyl, piperazinyl, pyrrolidinyl, morpholinyl, pyrimidinyl, dihydropyridinyl, tetrahydropyridinyl, propynyl, pyrazolyl, pyrrolyl, piperidinyl, l,3-dihydro-2-carbonylbenzoimidazolyl, 4-carbonyl-l,3,8-triazaspiro[4.5]decanyl, thieno[3,2-d]pyrimidinyl, furo[3,2-c]pyridinyl, benzo[d]isoxazolyl, thienyl, quinoliny
  • R 7 is an optionally mono- or polysubstituted group chosen from pyridin-3-yl, piperazin-1-yl, phenyl, pyrrolidin-1-yl, morpholin-4-yl, methyl, ethyl, propyl, butyl, pentyl, hexyl, piperidin-1-yl, pyridin-4-yl, isoxazol-4-yl, pyrimidin-5-yl, propyn-1-yl, l,l-dioxo-l ⁇ 6 -thiomo ⁇ holin-4-yl, pyrazol-4-yl, pyrrol-3-yl, pyrimidin-2-yl, isopropyl, isobutyl, isopentyl, tert-butyl, l,3-dihydro-2-carbonylbenzoimidazol-l-yl, 4-carbonyl- 1,3,8- triazaspiro[
  • G 1 and R 7 is an optionally mono- or polysubstituted group chosen from aryl, C ⁇ io-cycloalkyl, heterocycloalkyl, and heteroaryl.
  • each R 7 substituent is independently chosen from halogen, -OR 80 , -C(O)R 80 , -C(O)OR 80 , - C(O)NR 80 R 81 , -NR 80 R 81 , d- 6 -alkyl, d- ⁇ -haloalkyl, aryl, heteroaryl, C 3- io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(O) n R 80 , -S(O) 2 NR 80 R 81 , -OCF 3 , and -SiR 80 R 81 R 82 .
  • each R 7 substituent is independently chosen from methyl, carboxy, N,N- dimethylamino, acetyl, methanesulfonyl, aminocarbonyl, ethylaminocarbonyl, cyano, ethoxycarbonyl, methoxycarbonyl, pyrrolidin-1-yl, chloro, mo ⁇ holin-4-yl, fluoro, methoxy, tert-butoxycarbonyl, pyrrolidin-1-yl, tert-butoxycarbonylamino, amino, 1,1-dioxo-l ⁇ 6 - thiomorpholin-4-yl, isopentyl, triisopropylsilyl, phenyl, pyrimidin-2-yl, l,3-dihydro-2- carbonylbenzoimidazol-1-yl, trifluoromethyl, thieno[3,2-d]pyrimidin-4-yl, furo[3,2-c]pyri
  • R 80 , R 81 , and R 82 at each occurrence are independently chosen from H, Ci -6 - alkyl, and C ⁇ - 6 -haloalkyl. More preferably, R 80 , R 81 , and R 82 at each occurrence are independently chosen from H and Ci ⁇ -alkyl. More preferably, R 80 , R 81 , and R 82 at each occurrence are H. Preferably, R 80 at each occurrence is independently chosen from H, Ci- 6 -alkyl, Ci -6 - haloalkyl, aryl, heteroaryl, and heterocycloalkyl.
  • R 80 at each occurrence is independently chosen from H, Ci-6-alkyl, Ci-6-haloalkyl, aryl, and heteroaryl. More preferably, R 80 at each occurrence is independently chosen from H, Ci- ⁇ -alkyl, Q-6-haloalkyl, and aryl.
  • R 7 is Ci- ⁇ -alkyl, at least one of L 2 , G 1 , L 3 , G 2 , or L 4 is not a bond.
  • R 7 is chosen from pyridin-3-yl, 4-methylpiperazin-l-yl, 4-carboxyphenyl, pyrrolidin-1-yl, morpholi ⁇ -4-yl, N,N-dimethylaminom ethyl, N,N-dimethylaminoethyl, N 5 N- dimethylaminopropyl, N,N-dimethylaminobutyl, N,N-dimethylaminopentyl, N 5 N- dimethylaininohexyl, 4-acetylphenyl, methyl, ethyl, 4-methanesulfonylphenyl, benzamidyl, N- ethylbenzamidyl, 2-cyanopyridin-5-yl, 2-ethoxycarbonylpyridin-5-yl 5 4-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 3-carboxyphenyl, 3-methoxycarbon
  • the compounds of Formula I(d) are useful as intermediates for the preparation of other compounds of Formula I (e.g., compounds of Formula I(c)).
  • n is 0 or 2. More preferably, n is 0. More preferably, n is 2.
  • the present invention provides a compound of Formula I in which A, L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , G 1 , L 3 , G 2 , L 4 , R 7 , R 8 , R 10 , R 20 , R 21 , R 30 , R 40 , R 41 , R 50 , R 60 , R 61 , R 70 , R 80 , R 81 , R 82 , and n are independently chosen as set forth in any of the above-recited definitions.
  • the present invention includes a compound of Formula I having A, L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , G 1 , L 3 , G 2 , L 4 , R 7 , R 8 , R 10 , R 20 , R 21 , R 30 , R 40 , R 41 , R 50 , R 60 , R 61 , R 70 , R 80 , R 81 , R 82 , and n defined by any combination of the broader and narrower definitions of these substituents as set forth above.
  • R 10 , R 20 , R 21 , R 30 , R 40 , R 41 , R 50 , R 51 , R 60 , R 61 , R 70 , R 80 , R 81 , and R 82 at each occurrence are independently chosen from H and d ⁇ -alkyl.
  • R 10 , R 20 , R 21 , R 30 , R 40 , R 41 , R 50 , R 51 , R 60 , R 61 , R 70 , R 80 , R 81 , and R 82 at each occurrence are H.
  • G 1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, and each G 1 substituent is independently chosen from halogen and -OR 40 .
  • G 2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, and each G 2 substituent is independently chosen from halogen and -OR 60 .
  • R 2 and R 3 are independently chosen from H, OH, and Ci- ⁇ -alkyl, or R 2 and R 3 together form a carbonyl group;
  • R 4 and R 5 are independently chosen from H and Ci- 6 -alkyl, or R 4 and R 5 together form a carbonyl group, or one of R 4 and R 5 forms a double bond with R 6 ;
  • R 6 is chosen from H and Ci- ⁇ -alkyl, or R 6 forms a double bond with R 4 or R 5 ; X iS -L 2 G 1 L 3 G 2 L 4 R 7 ;
  • G 1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C 3- io- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -OR 40 , and Ci -3 -haloalkyl;
  • G 2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C 3- io- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -OR 60 , and Ci -3 -haloalkyl;
  • R 10 , R 20 , R 21 , R 30 , R 40 , R 50 , R 60 , R 70 , and R 81 at each occurrence are independently chosen from H, Ci- 6 -alkyl, and C ⁇ -haloalkyl;
  • R 80 at each occurrence is independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ -haloalkyl, aryl, and heteroaryl; and n is O or 2.
  • R 80 at each occurrence is independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ -haloalkyl, aryl, and heteroaryl; and n is O or 2.
  • R 80 at each occurrence is independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ -haloalkyl, aryl, and heteroaryl; and n is O or 2.
  • R 80 at each occurrence is independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ -haloalkyl, aryl, and heteroaryl; and n is O or 2.
  • A is N;
  • R 2 and R 3 are independently chosen from H and Ci ⁇ -alky], or R 2 and R 3 together form a carbonyl group;
  • R 4 and R 5 are H, or one of R 4 and R 5 forms a double bond with R 6 ;
  • R 6 is H, or R 6 forms a double bond with R 4 or R 5 ;
  • X is -L 2 G 1 L 3 G 2 L 4 R 7 ;
  • G 1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and -OR 40 ;
  • G 2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and —OR 60 .
  • R 20 , R 30 , R 40 , R 50 , R 60 , R 70 , R 80 , R 81 , and R 82 at each occurrence are independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ -haloalkyl; and n is 2.
  • R 20 , R 30 , R 40 , R 50 , R 60 , R 70 , R 80 , R 81 , and R 82 at each occurrence are independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ -haloalkyl; and n is 2.
  • R 20 , R 30 , R 40 , R 50 , R 60 , R 70 , R 80 , R 81 , and R 82 at each occurrence are independently chosen from H, Ci- 6 -alkyl, and Ci- ⁇ -haloalkyl; and n is 2.
  • A is CH
  • L 1 is -Coo-alkyl-O-Coo-alkyl-, or-C ⁇ -alkyl-;
  • R 2 and R 3 are independently chosen from H and Ci- 6 -alkyl, or R 2 and R 3 together form a carbonyl group;
  • R 4 and R 5 are H, or one of R 4 and R 5 forms a double bond with R 6 ;
  • R 6 is H, or R 6 forms a double bond with R 4 or R 5 ;
  • G 1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and -OR 40 ;
  • G 2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and -OR 60 .
  • R 20 , R 30 , R 40 , R 50 , R 60 , R 70 , R 80 , R 81 , and R 82 at each occurrence are independently chosen from H, Ci- ⁇ -alkyl, and Ci- ⁇ -haloalkyl; and n is 2.
  • the present invention provides a compound of Formula I(c) chosen from: l-(2-Chloro-3,6- ⁇ 4fluoroberizyl)-7-pyridin-3-yl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; 4-[l -(2-Chloro-3,6-difluorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester;
  • 1 -yl-ethyl)benzamide 1 -(2,5-Difluorobenzyl)-7-[4-(4-methylpiperazine- 1 -carbonyl)phenyl]-3,4-dihydro- 1 H- pyrido[2,3-b]pyrazin-2-one; l-(2,5-Difluorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-3,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one;
  • the present invention provides a compound of Formula I(d) chosen from: l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
  • the present invention provides pharmaceutically acceptable salts of compounds of Formula I.
  • Pharmaceutically acceptable acid addition salts of basic compounds of Formula I include, but are not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, and phosphorus, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids.
  • Such salts thus include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate.
  • salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., "Pharmaceutical Salts,” J. of Pharmaceutical Science, 1977;66:1-19.
  • the acid addition salts of basic compounds of Formula I may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms can differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but it is expected that the salts are generally similar to their respective free bases for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts of acidic compounds of Formula I are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines.
  • metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium.
  • suitable amines include, but are not limited to, N 5 N 1 - dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane- 1,2-diamine), N-methylglucamine, and procaine; see, for example, Berge et al., supra., 1977.
  • the base addition salts of acidic compounds of Formula I may be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms can differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but it is expected that the salts are generally similar to their respective free acids for purposes of the present invention.
  • Geometric isomers include compounds of the present invention that have alkenyl groups, which may exist as Chrysler or sixteen conformations, in which case all geometric forms thereof, both Cincinnati and sixteen, cis and trans, and mixtures thereof, are within the scope of the present invention.
  • Some compounds of the present invention have cycloalkyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures thereof, are within the scope of the present invention.
  • the compounds to be used in the present invention can exist in unsolvated crystalline forms as well as solvated crystalline forms, including hydrated crystalline forms.
  • the solvated forms, including hydrated forms are similar to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the present invention further provides pharmaceutical compositions comprising a compound of the present invention (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof), together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable styrene, a pharmaceutically acceptable styrene, a pharmaceutically acceptable styrene, a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains a therapeutically effective amount of a compound of the present invention.
  • these compositions are useful in the treatment of an ALK- or c-Met-mediated disorder or condition.
  • the compounds of the invention can also be combined in a pharmaceutical composition that also comprises compounds that are useful for the treatment of cancer or another ALK- or c- Met-mediated disorder.
  • a compound of the present invention can be formulated as a pharmaceutical composition in the form of a syrup, an elixir, a suspension, a powder, a granule, a tablet, a capsule, a lozenge, a troche, an aqueous solution, a cream, an ointment, a lotion, a gel, an emulsion, etc.
  • a compound of the present invention will cause a decrease in symptoms or a disease indicia associated with an ALK- or c-Met-mediated disorder as measured quantitatively or qualitatively.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component (i.e., compound of the present invention).
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets contain from 1% to 95% (w/w) of the active compound (i.e., compound of the present invention). In certain embodiments, the active compound ranges from 5% to 70% (w/w).
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • compositions of the present invention are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams and Wilkdns, 2000).
  • a compound of the present invention can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation.
  • Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally.
  • the formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials.
  • Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the dose administered to a subject should be sufficient to effect a beneficial therapeutic response in the subject over time.
  • the dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular subject.
  • the physician can evaluate factors such as the circulating plasma levels of the compound, compound toxicities, and/or the progression of the disease, etc.
  • the dose equivalent of a compound is from about 1 ⁇ g/kg to 10 mg/kg for a typical subject. Many different administration methods are known to those of skill in the art.
  • compounds of the present invention can be administered at a rate determined by factors that can include, but are not limited to, the LD 5O of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the compound at various concentrations, as applied to the mass and overall health of the subject. Administration can be accomplished via single or divided doses. IV. Methods of Treatment
  • the present invention provides a use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ALK- or c-Met-mediated disorder or condition.
  • the compound of Formula I or a pharmaceutically acceptable salt form thereof is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • the ALK- or c-Met-mediated condition or disorder is cancer.
  • the ALK- or c-Met-mediated condition is selected from anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, glioblastoma, and other solid tumors.
  • the ALK- or c-Met-mediated condition is selected from colon cancer, breast cancer, renal cancer, lung cancer, hemangioma, squamous cell myeloid leukemia, melanoma, glioblastoma, and astrocytoma.
  • the ALK- or c-Met-mediated disorder or condition can be treated prophylactically, acutely, and chronically using compounds of the present invention, depending on the nature of the disorder or condition.
  • the host or subject in each of these methods is human, although other mammals can also benefit from the administration of a compound of the present invention.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. Ih certain embodiments, the compounds of the present invention are delivered orally. The compounds can also be delivered rectally, bucally or by insufflation.
  • the compounds utilized in the pharmaceutical method of the invention can be administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily.
  • the daily dose range is from about 0.1 mg/kg to about 10 mg/kg.
  • the dosages may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. V.
  • the target column temperature was 45°C, with a run time of two (2) minutes, a flow rate of 0.600 mL/min, and a solvent mixture of 5% (0.1% formic acid/water):95% (acetonitrile/0.1% formic acid).
  • the mass spectrometry data was acquired on a Micromass LC-ZQ 2000 quadrupole mass spectrometer.
  • the overall synthesis for compounds of Formula I in which A is nitrogen is generically set forth in Scheme 1.
  • Step 1 2-amino-5-iodo-3-nitropyridine (A) is converted into its corresponding diazonium salt (NaNO 2 ZHCl) in the presence of cuprous chloride to form 2-chloro-5-iodo-3- nitropyridine (B).
  • A is converted into its corresponding diazonium salt
  • B is formed in the presence of cuprous chloride to form 2-chloro-5-iodo-3- nitropyridine
  • 2-amino-5-iodo-3- nitropyridine is commercially available from Sigma-Aldrich Corp. (St. Louis, MO).
  • 2-amino- 5-iodo-3-nitropyridine may be prepared by reacting 2-amino-3-mtropyridine with iodine and hydroiodic acid (See Carroll et al.).
  • Step 2 the 2-chloropyridine B obtained in Step 1 is reacted with an alpha-amino ester C containing suitable R 4 and R 5 groups to form the 2-aminopyridine D.
  • Step 3 compound D is reduced (SnCl 2 ) and cyclized to form compound E, which contains the bicyclic pyrido[2,3-->]pyrazinone core.
  • Step 4 an R 1 -L 1 group is introduced at the amido nitrogen of compound E by displacement of the leaving group (LG) from compound F.
  • the product is compound G.
  • R 1 is aryl or heteroaryl, and L 1 is a bond
  • a Buchwald-Hartwig coupling may be used to prepare compound G.
  • the carbonyl group of compound G is optionally reduced.
  • a reduction reaction useful in Step (5) is described in General Procedure 3 (below).
  • an X group is introduced.
  • Transition metal mediated coupling reactions useful in Step 6 are described in General Procedures 4-6 (below).
  • Reactions useful for modifying the introduced X side chain are described in General Procedures 7-10 (below).
  • General Procedure 3 Reduction
  • Suitable boronic acids or boronate esters include, but are not limited to, those in which the X group of the X-B(OR) 2 reagent is linked to the boron atom of the X-B(OR) 2 reagent via an alkyl, aryl, heteroaryl, or alkenyl C-B bond.
  • Alternative reaction conditions include, but are not limited to, the following: (a) Reaction of a heteroaryl boronic acid with compound H in dioxane/water (2: 1 ) at
  • the product may be converted to the corresponding alkenyl and alkyl compounds of Formula I(a) by reduction of the triple bond (e.g., catalytic hydrogenation or Na/NH 3 ).
  • General Procedure 6 Rosenmund-von Braun Coupling
  • the iodo starting material H is dissolved in anhydrous N,N-dimethylformamide.
  • CuCN 2.0 eq
  • the reaction mixture is heated to 120 0 C in a microwave oven for 15 minutes.
  • the reaction mixture is concentrated, diluted with CH2CI 2 , and washed with H 2 O/NH 4 OH (10:1, v/v) to remove copper.
  • the mixture is then filtered.
  • the organic phase is dried over MgSC> 4 , filtered, and concentrated.
  • the product is purified by silica gel chromatography.
  • a suitable aryl carboxylic acid starting material is combined with N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.0 eq), 1-hydroxybenzotriazole (1.7 eq), and triethylamine (1.4 eq) in anhydrous N,N-dimethylformamide.
  • the resulting mixture is stirred at room temperature for 30 minutes, a suitable amine is added, and the mixture is stirred for 3-16 hours.
  • the reaction mixture is then concentrated, diluted with CH 2 Cl 2 , washed with H 2 O, and dried over MgSO 4 .
  • the product amide is purified via silica gel chromatography or reversed-phase preparative HPLC.
  • the amidation reaction of General Procedure 8 may also be used to prepare amide boronates for use in the Suzuki coupling reaction (General Procedure 4).
  • Scheme 4 shows the amidation of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid, which is commercially available from Sigma- Aldrich Corp. (St. Louis, MO), by reaction with 4-(pyrrolidin-l-yl)piperidine using the reaction conditions of General Procedure 8.
  • a suitable cyano starting material is suspended in a mixture of NaOH (10 N), H 2 O, and ethanol (1 :1 :1, v/v/v) and heated to 80 0 C for 16 hours.
  • the reaction mixture is diluted with H 2 O and neutralized with HCl.
  • the resulting carboxylic is isolated (e.g., by filtration).
  • Step 1 2-amino-5-bromopyridine (M) is converted to 3-(6-bromo-pyridin-2- ylamino)propionic acid (O) by reaction with ethyl acrylate (N).
  • ethyl acrylate This process is described in Settimo, D.A. et al., Il Farmaco - Ed. Sc, 1978, 33(10), 770-80, which is incorporated herein by reference in its entirety.
  • 2-amino-5-bromopyridine is commercially available from Sigma- Aldrich Corp. (St. Louis, MO).
  • Step 2 the aryl carboxylic acid O is treated with Eaton's reagent to afford 7-bromo-
  • Step 3 compound P is reduced (NaBHU), debrominated (n-BuLi), and rebrominated (N-bromosuccinimide) to form compound Q.
  • the carbonyl group of compound P can be converted to an enolate and then substituted with R 2 ZR 3 groups prior to the reduction reaction.
  • compound P can be transformed into the corresponding ⁇ ,/3-unsaturated ketone (e.g., by conversion to an ⁇ -selenoxide or ⁇ -sulfoxide intermediate followed by elimination) and then substituted at the ⁇ - position with R 4 ZR 5 groups (e.g., via a Michael addition reaction) prior to the reduction reaction.
  • an R 6 group can be introduced (e.g., by N-alkylation) prior to the reduction reaction.
  • Compound Q may be converted to a compound of Formula I(b) by steps 4 and 5 or 4 1 and 5 1 .
  • Step 4 compound Q is converted to compound R by introduction of an R'-L 1 group.
  • the conversion may be accomplished by a variety of methods known to those of ordinary skill in the art.
  • the benzylic hydroxyl group of compound Q may be activated by conversion to the corresponding tosylate, mesylate, triflate, or halide intermediate and then displaced with a nucleophilic R 1 -L 1 group or a nucleophilic derivative of a R 1 -L 1 group, such as an organolithium or organometallic derivative (e.g., Grignard, lithium, lithium dialkylcopper, aluminum, or boron derivatives) (See March, J., "Advanced Organic Chemistry," 3d ed., John Wiley & Sons, Inc., 1985, pp.
  • organolithium or organometallic derivative e.g., Grignard, lithium, lithium dialkylcopper, aluminum, or boron derivatives
  • Step 4 may be performed by coupling the hydroxyl group of compound Q to a suitable carbonyl chloride reagent.
  • Step 4' A coupling reaction useful in Step 4' is described in General Procedurel3 (below).
  • the coupling reactions in General Procedures 4, 5, and 6 (above) are also useful for preparing the corresponding compounds of Formula IQo).
  • Steps 4' and 5 1 are the same as Steps 5 and 4, respectively.
  • compound Q is reacted with/7-toluenesulfonyl chloride (tosyl chloride) to form the activated tosylate XX.
  • activating groups that can be used instead of tosylate include, but are not limited to, mesylate, triflate, and halide.
  • compound XX is reacted with a suitable Grignard reagent (R 1 L 1 - MgBr) or another suitable organometallic reagent to form compound R.
  • suitable organometallic reagents include, but are not limited to, R'-L 1 — Li, R'-L 1 — MgBr, and (R 1 - L ⁇ 2 CuLi, wherein R ⁇ L 1 - is -Ci.
  • Step 1 compound P (Scheme 5) is converted to compound T by means of a Takai reaction.
  • the carbonyl group of compound P can be converted to an enolate and then substituted with R 2 ZR 3 groups prior to the Takai reaction.
  • compound P can be transformed into the corresponding ogS-unsaturated ketone (e.g., by conversion to an ct- selenoxide or ot-sulfoxide intermediate followed by elimination) and then substituted at the ⁇ - position with R 4 /R s groups (e.g., via a Michael addition reaction) prior to the Takai reaction.
  • an R 6 group can be introduced (e.g., by N-alkylation) prior to the Takai reaction.
  • Step 2 compound T is converted to compound U via a transition metal catalyzed coupling reaction (e.g., a Suzuki reaction).
  • Step 3 compound U is hydrogenated and debrominated by hydrogenolysis to form compound V.
  • Step 4 compound V is brominated to form compound W.
  • Step 5 compound W is converted to compound I(e) via a transition metal catalyzed coupling reaction (See General Procedures 4-6 and 13).
  • Step 1 compound P (Scheme 5) is converted to an imine or iminium of Formula AA by means of a condensation reaction with an amine of formula Z-NH-R 10 .
  • the carbonyl group of compound P can be converted to an ⁇ -enolate and then substituted at the Ct- position with R 2 /R 3 groups prior to the condensation reaction.
  • compound P can be transformed into the corresponding ⁇ ,/3-unsaturated ketone (e.g., by conversion to an ⁇ - selenoxide or ⁇ -sulfoxide intermediate followed by elimination) and then substituted at the ⁇ - position with R 4 ZR 5 groups (e.g., via a Michael addition reaction) prior to the condensation reaction.
  • an R 6 group can be introduced (e.g., by N-alkylation) prior to the condensation reaction.
  • Step 2 compound AA is converted to compound BB by means of a reduction.
  • Steps 1 and 2 maybe combined into a single step (i.e. a reductive amination).
  • Step 3 compound BB is converted to compound CC by means of debromination/rebromination (e.g., as in Scheme 5, Step 3).
  • the — NHR 10 group of compound BB may be coupled to a suitable carbonyl or sulfonyl chloride reagent to form additional compounds of Formula CC.
  • Step 4 compound CC is converted to compound I(f) (e.g., as in Scheme 5, Step 5).
  • compound CC may be prepared from compound Q by activation of compound Q (e.g., by transformation to the corresponding benzylic halide, alkyl sulfonate or aryl sulfonate as in Scheme 5, Step 4) prior to treatment with an amine of formula Z-NH-R 10 .
  • Step 1 compound P (Scheme 5) is converted to compound DD by means of a Homer-Emmons reaction.
  • R 2 , R 3 , R 4 , R 5 and/or R 6 groups may be introduced prior to the Horner-Emmons reaction as in Scheme 8.
  • Step 2 compound DD is converted to compound EE by means of hydrogenation of the double bond and debromination by hydrogenolysis or metallation/protonation (Scheme 5, Step 3).
  • Step 3 compound EE is brominated and hydrolyzed to form compound FF.
  • compound FF may be alkylated ⁇ to the carbonyl group prior to the coupling step with one or two methyl groups or an ethyl group (e.g., by treatment with base and then methyl bromide).
  • Step 4 compound FF is coupled with an amine of formula Z-NH-R 10 to form compound GG.
  • Step 5 compound GG is converted to compound I(g) (e.g., as in Scheme 5, Step 5).
  • Step 1 compound FF (Scheme 9) is esterified with Z-OH to form compound HH.
  • Step 2 compound HH is converted to compound I(h) (e.g., as in Scheme 5, Step 5).
  • compound FF or HH may be alkylated a to the carbonyl group prior to Steps 1 or 2 with one or two methyl groups or an ethyl group (e.g., by treatment with base and then methyl bromide).
  • Step 1 compound Q (Scheme 5) is activated by means of transformation to the benzylic halide, alkyl sulfonate or aryl sulfonate prior to treatment with a thiol of formula Z- SH to form compound JJ.
  • activated compound Q may be treated with a sulfonic acid of formula Z-SO 2 H to form the sulfone analog of compound JJ.
  • Step 2 the bromide group of compound JJ is converted to the X group of compound I(i) (e.g., as in Scheme 5, Step 5).
  • Step 1 compound EE (Scheme 9) is converted to compound KK by reaction with an organometallic reagent such as a Grignard or organolithium reagent (e.g., Z-MgBr or Z-Li).
  • organometallic reagent such as a Grignard or organolithium reagent (e.g., Z-MgBr or Z-Li).
  • Step 2 compound KK is converted to compound I(j) (e.g., as in Scheme 5, Step 5).
  • compound EE or KK may be alkylated a to the carbonyl group prior to Steps 1 or 2 with one or two methyl groups or an ethyl group (e.g., by treatment with base and then methyl bromide).
  • General Procedure 12 Mitsunobu Reaction
  • the starting bromide (Q or R) (1.0 eq) is combined with a suitable boronic acid or boronic ester (1.4 eq) and Pd(PPIvO 4 (0.05 eq) in a mixture of toluene and ethanol (1-5:1, v/v).
  • ALK Kinase Assay Example compounds were tested for their ability to inhibit the kinase activity of baculovirus-expressed ALK using a modification of the ELISA protocol reported for trkA in Angeles, T. S. et al., Anal. Biochem. 1996, 236, 49-55, which is incorporated herein by reference in its entirety. Phosphorylation of the substrate, phospholipase C-gamma (PLC- ⁇ ) generated as a fusion protein with glutathione S-transferase (GST) as reported in Rotin, D. et al., EMBOJ.
  • PLC- ⁇ phospholipase C-gamma
  • each 96-well plate was coated with 100 ⁇ L/well of 10 ⁇ g/mL substrate (phospholipase C- ⁇ ) in Tris-buffered saline (TBS).
  • TRF time- resolved fluorescence
  • total volume 100 ⁇ L/well
  • the assay mixture consisting of 20 mM HEPES (pH 7.2), 1 ⁇ M ATP (K m level), 5 mM MnCl 2 , 0.1% BSA, 2.5% DMSO, and various concentrations of test compound was then added to the assay plate.
  • the reaction was initiated by adding enzyme (30 ng/ml ALK) and was allowed to proceed at 37°C for 15 minutes. Detection of the phosphorylated product was performed by adding 100 ⁇ l/well of Eu-Nl labeled PT66 antibody (Perkin Elmer # AD0041). Incubation at 37°C then proceeded for one (1) hour, followed by addition of 100 ⁇ L enhancement solution (Wallac #1244-105). The plate was gently agitated and after thirty minutes, the fluorescence of the resulting solution was measured using the En Vision 2100 (or 2102) multilabel plate reader (Perkin Elmer).
  • IC 50 values were calculated by plotting percent inhibition versus logio of the concentration of compound and fitting to the nonlinear regression sigmoidal dose-response (variable slope) equation in XLFit (IDBS, Guilford, UK).
  • c-Met Kinase Assay The kinase activity of c-Met was evaluated using the same methods as for ALK, with the following modifications: Plates were coated with 20 ⁇ g/mL phospholipase C- ⁇ and the assay mixture consisted of 50 mM HEPES (pH 7.2), 50 mM NaCl, 3 ⁇ M ATP (K n , level), 4 mM MnCl 2 , 0.01% TritonX-100, 0.02% BSA, 2.5% DMSO. Reactions were initiated with 30 ng/mL c-Met (cytoplasmic domain, Invitrogen Corporation #PV3143). ALK Cellular Assay
  • the lysates were cleared by centrifugation, mixed with sample buffer and subjected to SDS-PAGE.
  • the membranes were blotted with either rabbit phospho-NPM-ALK(Y664) (Cat* 3341) or ALK antibody (Cat* 3342) from Cell Signaling Technology (Beverly, MA), and then the HRP-conjugated goat anti-rabbit antibodies (Santa Cruz, CA) after washed in TBS/0.2% Tween-20.
  • the protein bands were visualized with ECL Western Blotting detection reagents (RPN2106, Amersham Biosciences, Buckinghamshire, UK) and quantitated with gel- pro analyzer 3.1 software.
  • fluoronunc plates (Cat* 437796, Nalge Nunc, Rochester, NY) were pre-coated with goat anti-mouse IgG, and incubated with the capture mouse ALK antibody (Cat* 35-4300, Zymed, Seattle, WA) diluted 1:1000 in Superblock (Pierce, Rockford, IL). Following blocking, cell lysates were added to plates and incubated overnight at 4°C.
  • c-Met Cellular Assay HT29 and GTL-16 cells were serum starved for one hour in media containing 0.05% BSA and varying concentrations of Example compounds (1-10 ⁇ M).
  • A549 cells were serum starved overnight in media containing 0.05% BSA then treated for one hour with Example compounds followed by a 15 minute stimulation with 50 ng/mL HGF (Peprotech, Rocky Hill, NJ), respectively. Samples were resolved by electrophoresis on a 3-8% Tris-Acetate gel (40 ma/gel) and then transferred to a nitrocellulose membrane. Membranes were blocked for one hour at room temperature in Odyssey Blocking Buffer (Licor # 927-40000) diluted 1:1 with IX TBS.
  • Odyssey Blocking Buffer Lior # 927-40000
  • Membranes were then co-incubated overnight at 4°C with primary antibodies [total Met (Cell Signaling, #3127) and Phospho-Met (Biosource, #44-888G) 1:1000 each in Odyssey Blocking Buffer diluted 1:1 with IX TBS-T 0.05%]. The next day, membranes were washed and co-incubated with secondary antibodies [Goat anti mouse IRDye800 (Rockland, #610-132- 121) and Goat anti rabbit Alexa fluor 700 (Molecular Probes, #A21038) 1:10,000] in Odyssey Blocking Buffer diluted 1 : 1 with IX TBS-T 0.05% for one hour at room temperature protected from light. Blots were then washed then read on the Odyssey Infrared Imager. Total c-Met signal was visualized at 800nm detection and phospho-c-Met signal was visualized at 700nm detection.
  • the compounds of the present invention exhibit an IC 50 in the ALK kinase assay of 100 ⁇ M - 10 ⁇ M. More preferably, the compounds of the present invention exhibit an IC 50 in the ALK kinase assay of 10 ⁇ M - 1 ⁇ M. More preferably, the compounds of the present invention exhibit an IC 50 in the ALK kinase assay of 1 ⁇ M — 0.1 ⁇ M. More preferably, the compounds of the present invention exhibit an IC 50 in the ALK kinase assay of ⁇ 0.1 ⁇ M. Preferably, the compounds of the present invention exhibit an IC 50 in the c-Met kinase assay of 100 ⁇ M - 10 ⁇ M.
  • the compounds of the present invention exhibit an IC 50 in the c-Met kinase assay of 10 ⁇ M - 1 ⁇ M. More preferably, the compounds of the present invention exhibit an IC 50 in the c-Met kinase assay of 1 ⁇ M — 0.1 ⁇ M. More preferably, the compounds of the present invention exhibit an IC 50 in the c-Met kinase assay of ⁇ 0.1 ⁇ M.
  • the compounds of the present invention exhibit an inhibition score in the c- Met Cellular Assay of 26-50%. More preferably, the compounds of the present invention exhibit an inhibition score in the c-Met Cellular Assay of 51-75%. More preferably, the compounds of the present invention exhibit an inhibition score in the c-Met Cellular Assay of 76-100%.
  • the compounds of the present invention exhibit an inhibition score in the ALK Cellular Assay of 26-50%. More preferably, the compounds of the present invention exhibit an inhibition score in the ALK Cellular Assay of 51-75%. More preferably, the compounds of the present invention exhibit an inhibition score in the ALK Cellular Assay of 76-100%.
  • Example 20 1 -Benzyl-7-[3-(pyrrolidine- 1 -carbonyl)phenyl]-3 ,4-dihydro- 1 H- ⁇ yrido[2,3- b]pyrazin-2-one
  • Example 24 1 -Benzyl-7-(4-methanesulfonyl-phenyl)-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one
  • Example 25 l-Benzyl-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4-dihydro-lH- pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
  • Example 26 1 -Benzyl-7-[4-(4-(pyrrolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl] -3 ,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
  • Example 49 2-[Ethyl-((S)-l-pyrrolidin-l-ylmethyl-propyl)-amino]-ethanesulfonic acid ⁇ 4-[l- (2,5-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl ⁇ -amide
  • Example 52 4-( 1 -Benzoyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino- ethyl)benzamide
  • Example 54 ⁇ 7-[4-(4-Methylpiperazine-l-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3- b]p yrazin- 1 -yl ⁇ phenylmethanone
  • Example 55 4-[ l-(2,5-Difluorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]benzoic acid ethyl ester
  • Example 60 l-(2,5-Difluorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]- 3 ,4-dihydro- 1 H-pyrido[2 ,3 -b]pyrazin-2-one
  • Example 64 4-[ 1 -(2 S 5-Difluorobenzyl)-1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid
  • Example 65 ⁇ 4-[ 1 -(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl ⁇ - ((S)-2-((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone
  • Example 68 ⁇ 4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl ⁇ - morpholin-4-yl-methanone
  • Example 70 l-(2,5-Difluorobenzyl)-7-(6-mo ⁇ holin-4-yl-pyridin-3-yl)- 1,2,3,4- tetrahydropyrido[2,3-b]pyrazine
  • Example 75 l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester
  • Example 76 ⁇ 5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin- 2-yl ⁇ morpholin-4-yl-methanone
  • Example 80 1 -(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [2(4-methylpiperazin- 1 -yl)ethyl] amide
  • Example 85 7-[4-(4-Methylpiperazine-l-carbonyl)phenyl]-l-(2,4,5-trifluorobenzyl)-3,4- dihydro- 1 H-pyrido[2,3 -b]pyrazin-2-one
  • Example 92 1 -(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro- lH-pyrido[2,3- b]pyrazin-2-one
  • Example 93 1 -(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazine
  • Example 95 1 -(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-(4-methylpiperazine-l - carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
  • Example 96 ⁇ 4-[l-(2,5-Difluorobenzyl)-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 7-yl]phenyl ⁇ -((S)-2-((pyrrolidin-l -yl)methyl)pyrrolidin- 1 -yl)methanone
  • Example 99 ⁇ 4-[l-(2-Chloro-3,6-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl ⁇ -(4-(pyrrolidin-l-yl)piperidin-l -yl)methanone
  • Example 100 ⁇ 4-[l-(2-Chloro-3,6-difluorobenzyl)-l,2,3 J 4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl ⁇ -((S)-2-((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone

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Abstract

The present invention provides a compound of Formula I: or a pharmaceutically acceptable salt form thereof, wherein A, L1, R1, R2, R3, R4, R5, R6, and X are as defined herein. The compounds of Formula I have ALK and/or c-Met inhibitory activity, and may be used to treat ALK- or c-Met-mediated disorders or conditions.

Description

PYRIDOPYRAZINES AND DERIVATIVES THEREOF AS ALK AND C-
MET INHIBITORS
BACKGROUND OF THE INVENTION Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning receptor tyrosine kinase, which belongs to the insulin receptor subfamily. The most abundant expression of ALK occurs in the neonatal brain, suggesting a possible role for ALK in brain development (Duyster, J. et al., Oncogene, 2001, 20, 5623-5637).
ALK is also implicated in the progression of certain tumors. For example, approximately sixty percent of anaplastic large cell lymphomas (ALCL) are associated with a chromosome mutation that generates a fusion protein consisting of nucleophosmin (NMP) and the intracellular domain of ALK. (Armitage, J.O. et al., Cancer: Principle and Practice of Oncology, 6th edition, 2001, 2256-2316; Kutok J.L. & Aster J.C., J. CHn. Oncol, 2002, 20, 3691-3702). This mutant protein, NMP-ALK, possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic property through activation of downstream effectors. (Falini, B. et al., Blood, 1999, 94, 3509-3515; Morris, S.W. et al., Brit. J. Haematol, 2001, 113, 275-295; Duyster et al.; Kutok & Aster). Experimental data have demonstrated that the aberrant expression of constitutively active ALK is directly implicated in the pathogenesis of ALCL and that inhibition of ALK can markedly impair the growth of ALK+ lymphoma cells (Kuefer, Mu et al. Blood, 1997, 90, 2901-2910; Bai, R. Y. et al., MoI Cell Biol, 1998, 18, 6951-6961; Bai, R. Y. et al., Blood, 2000, 96, 4319-4327; Ergin, M. et al., Exp. Hematol, 2001, 29, 1082-1090; Slupianek, A. et al., Cancer Res., 2001, 61, 2194-2199; Turturro, F. et al., Clin. Cancer Res., 2002, 8, 240-245). The constitutively activated chimeric ALK has also been demonstrated in about 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growing sarcoma that mainly affects children and young adults. (Lawrence, B. et al., Am. J. Pathol, 2000, 157, 377-384; Duyster et al.).
In addition, ALK and its putative ligand, pleiotrophin, are overexpressed in human glioblastomas (Stoica, G. et al., J. Biol. Chem., 2001, 276, 16772-16779). In mouse studies, depletion of ALK reduced glioblastoma tumor growth and prolonged animal survival (Powers, C. et al., J. Biol Chem., 2002, 277, 14153-14158; Mentlein, R. et al, J. Neurochem., 2002, 83, 747-753).
It is possible that an ALK inhibitor would either permit durable cures when combined with current chemotherapy for ALCL, IMT, or glioblastoma, or be used as a single therapeutic agent in a maintenance role to prevent cancer recurrence in those patients. Various ALK inhibitors have been reported, including indazoloisoquinolines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894). c-Met is a member of the tyrosine kinase growth factor receptor family. c-Met expression occurs in endothelial, epithelial, and mesenchymal cells. c-Met binding to the endogenous ligand, hepatocyte growth factor (HGF), promotes cell migration, proliferation, and invasion. c-Met is implicated in the progression of certain tumors. c-Met overexpression has been shown in numerous tumor types including colon, breast, renal, lung, hemangiomas, squamous cell myeloid leukemia, melanomas, glioblastomas, and astrocytomas. (Maulik et al., Cytokine & Growth Factor Reviews, 2002, 13, 41-59 ; Funakoshi et al., Clinica Chimica Acta, 2003, 1-23; Longati et al., Curr. Drug Targets, 2001, 2, 41-55). Activation of tumor cell c-Met receptors enhances tumor cell proliferation, invasion/metastasis, and resistance to apoptosis and cytotoxic therapies.
It is possible that a c-Met inhibitor would have potent anti-tumor effects in many cancers. Various c-Met inhibitors have been reported, including aminoheteroaryl compounds (WO 2004/076412; WO 2005/082411; US 2005/0009840), 5-6 bicyclic heterocycles (WO 2005/028475), monocyclic heterocycles (US 2005/0245530), bicyclic heterocycles (US 2005/0239820), triazolotriazine compounds (WO 2005/010005; US 2005/0075340), triarylimidazoles (US 2005/0085473), indolinone hydrazides (WO 2005/005378), tetracyclic compounds (WO 2005/004808), imidazole derivatives (WO 2005/040154), quinolines and quinazolines (WO 2005/030140), and quinolinoxynaphthalenes (WO 2005/070891). (See also Sattler, M., et al., Cancer Res., 2003, 63, 5462-5469; Christensen, J.G., et al., Cancer Res., 2003, 63, 7345-7355).
A need exists for ALK and c-Met inhibitors for use as pharmaceutical agents.
SUMMARY OF THE INVENTION
The present invention provides a compound of Formula I
Figure imgf000004_0001
I or a pharmaceutically acceptable salt form thereof, wherein A, L1, R1, R2, R3, R4, R5, R6, and X are as defined herein. The compounds of Formula I have ALK and/or c-Met inhibitory activity, and may be used to treat ALK- or c-Met-mediated disorders or conditions.
The present invention further provides a pharmaceutical composition comprising at least one compound of the present invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient therefor. In another aspect, the present invention provides a method of treating a subject suffering from an ALK- or c-Met-mediated disorder or condition comprising: administering to the subject the pharmaceutical composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION I. Definitions
As used herein, the following terms have the meanings ascribed to them unless specified otherwise.
"Alkyl" or "alkyl group" includes both straight and branched chain aliphatic hydrocarbon groups. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.
Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, tert-butyl, isobutyl, etc.
The term "Cx-y" indicates the number of carbon atoms in a group. For example, a "Ci-β- alkyl" is an alkyl group having from one (1) to six (6) carbon atoms. In some instances, x = 0, i.e., "Co-y". The term "Co-y" indicates that the group may be absent or present, and if present, defines the number of carbon atoms in the group. For example, "Co-6-alkyl" indicates that an alkyl group may be absent (x = 0) or present (x = 1-6), and if present contains from one (1) to six (6) carbon atoms. For example, "-C0-6-alkyl-C(=0)-Co-6-alkyl-" includes -C(=O)-, -Ci-β- alkyl-C(=O)-, and -Ci-6-alkyl-C(=O)-Ci-6-alkyl-. Examples of-C0-6-alkyl-C(=0)-Co-6-alkyl- include, but are not limited to, -C(=O)-, -CH2CH2-C(=O)-, and -CH(CH3)CH2CH2-CC=O)- CH2-.
"Alkenyl" or "alkenyl group" includes straight and branched chain unsaturated alkyl groups which have two (2) or more carbon atoms and at least one double bond. Examples include, but are not limited to, ethenyl, 3-buten-l-yl, 2-ethenylbutyl, and 3-hexen-l-yl.
"Alkynyl" or "alkynyl group" includes straight and branched chain unsaturated alkyl groups which have two (2) or more carbon atoms and at least one triple bond. Examples include, but are not limited to, ethynyl, 3-butyn-l-yl, propynyl, 2-butyn-l-yl, and 3-pentyn-l- yi. "Haloalkyl" or "haloalkyl group" refers to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups, such as for example -CF3, -CHF2, -CH2F, -CF2CF3, — CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -CI=CH2, -C ≡C-CF3, -CHFCH2CH3 and -CHFCH2CF3. "Halogen" includes fluorine, chlorine, bromine and iodine atoms.
'Tseudohalogen" refers to -OCN, -SCN, -CF3, and -CN.
"Cycloalkyl" or "cycloalkyl group" includes monocyclic, bicyclic, and tricyclic non- aromatic carbocyclic rings, which may be saturated or unsaturated. Examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, and norbornenyl.
A cycloalkyl group can also include ring systems substituted on ring carbons with one or more -OH functional groups (which may further tautomerize to give a ring C=O group).
"Heterocycloalkyl" or "heterocycloalkyl group" includes 3-15 membered monocyclic, bicyclic, and tricyclic non-aromatic rings, which may be saturated or unsaturated, and which contain, in addition to carbon atoms, at least one heteroatom, such as nitrogen, oxygen or sulfur. Examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S- dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofliryl, dihydropyranyl, tetrahydrothienyl-5- oxide, tetrahydrothienyl-S,S-dioxide, homothiomoφholinyl-5-oxide, 2-oxa-5- azabicyclo[2.2. ljheptane, 8-oxa-3-aza-bicyclo[3.2.1 ]octane, 3,8-diaza-bicyclo[3.2.1 ]octane, 2,5-diaza-bicyclo[2.2.1 ]heptane, 3,8-diaza-bicyclo[3.2.1 ]octane, 3,9-diaza- bicyclo[4.2.1]nonane and 2,6-diaza-bicyclo[3.2.2]nonane.
Unless otherwise indicated, the foregoing heterocycloalkyl groups can be C- attached or N-attached where such is possible and results in the creation of a stable structure. For example, piperidinyl can be piperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).
A heterocycloalkyl group can also include ring systems substituted on ring carbons with one or more -OH functional groups (which may further tautomerize to give a ring C=O group) and/or substituted on a ring sulfur atom by one (1) or two (2) oxygen atoms to give S=O or SO2 groups, respectively.
"Aryl" or "aryl group" includes phenyl and 9-15 membered bicyclic or tricyclic hydrocarbon ring systems in which at least one of the rings is aromatic. Examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, and 6,7,8,9-tetrahydro- 5H-benzocycloheptenyl. An aryl group can also include ring systems substituted on ring carbons with one or more -OH functional groups (which may further tautomerize to give a ring C=O group).
"Heteroaryl" or "heteroaryl group" includes (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 8-15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atoms, at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. Examples include, but are not limited to, 2,3- dihydrobenzofuranyl, 1 ,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, A-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3- thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-l-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, and isoquinolinyl. A heteroaryl group can also include ring systems substituted on ring carbons with one or more -OH functional groups (which may further tautomerize to give a ring C=O group) and/or substituted on a ring sulfur atom by one (1) or two (2) oxygen atoms to give S=O or SO2 groups, respectively. "Linker" or "linker group" refers to a bond, atom, or group of atoms that connects other atoms or groups of atoms within a molecule. For example, L1 is a linker group that connects the groups A and R1 in a compound of Formula I (A-L1 -R1). Linker groups are identified herein as an atom or group of atoms between two dashed lines (— ). For example, an oxygen atom linker is identified herein as -O— . As used herein, no directionality is intended in the representation of asymmetrical linkers. Therefore, "-Ci-6-alkyl-C(=O)-" is equivalent to "— CtOVQ-s-alkyl-" and "-Cl.6-alkyl-C(=O)O-" is equivalent to "-OC(=O)-Ci-6-alkyl-." For example, the A and R1 groups may be connected by the asymmetrical linker, -C^-alkyl- C(=O)-, in either of the following manners: A-Ci^-alkyl-C(=O)-Rl or A-C(=O)-Ci-6-alkyl-R1. "Chemically stable" or "stable" refers to a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture, and then incorporated into a pharmaceutical composition. The present invention is directed only to stable compounds.
"Pharmaceutical composition" refers to a composition suitable for administration in medical or veterinary use.
When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, those of ordinary skill in the art will appreciate that if G1 is a bond, then L2 and L3 should not both be -O— , since peroxides are not chemically stable. "Pharmaceutically acceptable" refers to physiologically tolerable materials, which do not typically produce an allergic or other untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal.
"Therapeutically effective amount" refers to an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit, halt, or cause an improvement in a disorder or condition being treated in a particular subject or subject population. For example in a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.
It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts, and is described below.
"Subject" refers to a member of the class Mammalia. Examples of mammals include, without limitation, humans, primates, chimpanzees, rodents, mice, rats, rabbits, horses, livestock, dogs, cats, sheep, and cows.
'Treatment" refers to the acute or prophylactic diminishment or alleviation of at least one symptom or characteristic associated or caused by a disorder being treated. For example, treatment can include diminishment of several symptoms of a disorder or complete eradication of a disorder.
"Administering" refers to the method of contacting a compound with a subject. Modes of "administering" include, but are not limited to, methods that involve contacting the compound intravenously, intraperitoneally, intranasally, transdeπnally, topically, via implantation, subcutaneously, parentally, intramuscularly, orally, systemically, and via adsorption. II. Compounds
In one embodiment, the present invention provides a compound of Formula I
Figure imgf000008_0001
I or a pharmaceutically acceptable salt form thereof, wherein:
A is chosen from N and CH; X is chosen from -L2G1L3G2L4R7 and R8;
L1 is a bond, -C0-3-alkyl-C(=0)-Co.3-alkyl-, -Co-3-alkyl-S(=0)n-Co-3-alkyl-, -Cc3- alkyl-C(=0)NR10-Co-3-alkyl- -C0-3-alkyl-S(=0)2NR10-Co-3-alkyl- -Co-3-alkyl- C(=O)O-C0-3-alkyl-, -Co-3-alkyl-OC(=0)NR10-Co-3-alkyl-, -CO-3-alkyl-NRlo-Co-3- alkyl-, -Co^-alkyl-O-Co-s-alkyl-, -Ci-6-alkyl-, -C2-6-alkenyl-, or -C2-6-alkynyl-; R1 is an optionally mono- or polysubstituted group chosen from aryl, Ca-io-cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, -OR20, -C(O)R20, -C(=O)OR20, -C(K))NR20R21, -NR20R21, Ci-3-alkyl, Ci-3-haloalkyl, aryl, heteroaryl, C3-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(O)nR20, -S(O)2NR20R21, -OCH2F, -OCHF2, -OCF3, - NHOH, -OC(O)R20, -OC(O)NR20R21, -NR20C(O)R21, -NR20C(O)OR21, and -SCF3;
R2 and R3 are independently chosen from H, OH, and Ci-6-alkyl, or R2 and R3 together form a carbonyl group;
R4 and R5 are independently chosen from H and Ci-6-alkyl, or R4 and R5 together form a carbonyl group, or one of R4 and R5 forms a double bond with R6; R6 is chosen from H and Ci-6-alkyl, or R6 forms a double bond with R4 or Rs; L2 is a bond, -Co-3-alkyl-C(0)-Co-3-alkyl-, -Co-3-alkyl-S(=0)n-Co-3-alkyl-, -C0-3- alkyl-C(0)NR30-Co-3-alkyl-, -Co-3-alkyl-S(0)2NR30-Co-3-alkyl-, -C0-3-alkyl-
C(0)0-Co-3-alkyl- -Co-3-alkyl-OC(=0)NR30-Co-3-alkyl-, -C0-3-alkyl-NR30-Co-3- alkyl-, -CtKralkyl-O-Coo-alkyl-, -Cio-alkyl-, -C2-3-alkenyl-, or -C2-3-alkynyl-; G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C3-10- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, -OR40, -C(O)R40, -C(O)OR40, -C(O)NR40R41, -NR40R41, Q-3-alkyl, Q-3-haloalkyl, aryl, heteroaryl, C3-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(O)nR40, -S(O)2NR40R41, -OCH2F, -OCHF2, -OCF3, - NHOH, -OC(O)R40, -OC(O)NR40R41, -NR40C(O)R41, -NR40C(O)OR41, and -SCF3;
L3 is a bond, -Co-3-alkyl-C(0)-Co-3-alkyl-, -Co-3-alkyl-S(=0)n-Co-3-alkyl-, -Qw- alkyl-C(0)NR50-Co-3-alkyl-, -Co-3-alkyl-S(0)2NR50-Co_3-alkyl-, -Co-3-alkyl- C(0)0-Co-3-alkyl- -Co-3-alkyl-OC(0)NR50-Co-3-alkyl-, -Co-3-alkyl-NR50-Co-3- alkyl-, -Coo-alkyl-O-Qw-alkyl-, -Ci-3-alkyl-, -C2-3-alkenyl-, or -C2.3-alkynyl-; G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C3-10- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, -OR60, -C(O)R60, -C(O)OR60, -C(O)NR60R61, -NR60R61, Ci-3-alkyl, Ci-3-haloalkyl, aryl, heteroaryl, Cs-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -SC=O)nR60, -S(=O)2NR60R61, -OCH2F, -OCHF2, -OCF3, - NHOH, -OCC=O)R60, -OCC=O)NR60R61, -NR60CC=O)R61, -NR60CC=O)OR61, and -SCF3; L4 is a bond, -C0-3-alkyl-CC=0)-Co.3-alkyl-, -Co-3-alkyl-S(=0)n-C0-3-alkyl-, -C0-3- alkyl-CC=O)NR70-C0-3-alkyl- -C0-3-alkyl-SC=0)2NR70-Co,3-alkyl-, -Co-3-alkyl-
Figure imgf000010_0001
-Co-3-alkyl-OCC=0)NR70-Co-3-alkyl- -Co-3-alkyl-NR70-Co-3- alkyl-, -Qw-alkyl-O-Co-ralkyl-, -C1-3-alkyl-, -C2.3-alkenyl-, or -C2.3-alkynyl-; R7 is an optionally mono- or polysubstituted group chosen from Ci-6-alkyl, C2-6- alkenyl, C2-6-alkynyl, aryl, Cs-io-cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, -OR80, -CC=O)R80, -CC=O)OR80, -CC=O)NR80R81, -NR80R81, Ci-6-alkyl, Ci^-haloalkyl, aryl, heteroaryl, Cs-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -SC=O)nR80, -SC=O)2NR80R81, -OCH2F, -OCHF2, -OCF3, - NHOH, -OCC=O)R80, -OCC=O)NR80R81, -NR80CC=O)R81, -NR80CC=O)OR81, -
SiR80R81R82 and -SCF3;
R8 is chosen from H, halogen, CN, and C(=O)OH; R10, R20, R21, R30, R40, R41, R50, R60, R61, R70, R80, R81, and R82 at each occurrence are independently chosen from H, Ci-6-alkyl, Ci-6-haloalkyl, aryl, heteroaryl, C3-1O- cycloalkyl, and heterocycloalkyl; and n is O, 1, or 2; provided that when L1 is -CC=O)- and R1 is phenyl, R8 is not H or Br. In certain embodiments, A is N, i.e., a compound of Formula ICa):
Figure imgf000010_0002
ICa)
Preferably, when A is N, L1 is -C0-3-alkyl-C(=0)-Co.3-alkyl-, -Co-3-alkyl-SC=0)n-Co-3- alkyl- -C0-3-alkyl-C(=0)NR10-Co.3-alkyl- -Co-3-alkyl-SC=0)2NR10-Co-3-alkyl- -C0-3-alkyl- CC=0)0-Co-3-alkyl-, or -Q^-alkyl-. More preferably, when A is N, L1 is -CC=O)-C0-3-alkyl-, -SC=0)2-Co.3-alkyl-, -CC=0)NR10-Co.3-alkyl-, -SC=O)2NR1 °-Co-3-alkyl-, -CC=0)0-Co-3-alkyl- , or -Ci-6-alkyl-. More preferably, when A is N, L1 is -Co-3-alkyl-C(=0)-Co-3-alkyl-, -C0-3- alkyl-S(=0)2-Co.3-alkyl-, or-Cl-6-alkyl-. More preferably, when A is N, L1 is -C(=O)-C0-3- alkyl-, -S(=O)2-C0-3-aIkyl-, or -C1-6-alkyl-. More preferably, when A is N, L1 is -CC=O)-C0- 3-alkyl- -S(O)2-, or-Ci-6-alkyl-. More preferably, when A is N, L1 is -CC=O)-, - CC=O)CH2-, -SC=O)2-, or -Ci-6-alkyl-. More preferably, when A is N, L1 is -CC=O)-, -
CC=O)CH2-, -SC=O)2-, -CH2-, or -CHCCH3)-. More preferably, when A is N, L1 is -CC=O)-, -CC=O)CH2-, -SC=O)2-, or -CH2-.
In certain embodiments, A is CH, i.e., a compound of Formula ICb):
Figure imgf000011_0001
ICb)
Preferably, when A is CH, L1 is -Co-3-alkyl-CC=0)-C0-3-alkyl-, -C0-3-alkyl-SC=0)n-Co- 3-alkyl-, -C0-3-alkyl-CC=O)NR10-C0-3-alkyl-, -C0-3-alkyl-SC=O)2NR10-C0-3-alkyl-, -C0-3-alkyl- CC=0)0-Co-3-alkyl-, -Coo-alkyl-NR^-Coo-alkyl-, -Coj-alkyl-O-Co-s-alkyl-, or-Ci-β-alkyl-. More preferably, when A is CH, L1 is -Ci.3-alkyl-CC=O)-C0-3-alkyl-, -SC=0)n-Co.3-alkyl-, -CN 3-alkyl-CC=O)NR10-Co-3-alkyl-, -Ci.3-alkyl-CC=O)O-C0-3-alkyl-, -Co-3-alkyl-NRlo-Co-3-alkyl-, -Co-s-alkyl-O-Co-s-alkyl-, or -Ci-6-alkyl-. More preferably, when A is CH, L1 is -CH2- CC=O)-C0-3-alkyl-, -SC=O)n-C0-3-alkyl-, -CH2-CC=O)NR10-C0-3-alkyl-, -CH2-CC=O)O-C0-3- alkyl-, -C0-3-alkyl-NR10-C0-3-alkyl-, -QKj-alkyl-O-Coo-alkyl-, or -Ci-6-alkyl-. More preferably, when A is CH, L1 is -CH2-CC=0)-Co-3-alkyl-, -SC=0)n-Co-3-alkyl-, -CH2- CC=O)NRl0-C0-3-alkyl-, -CH2-CC=O)O-C0-3-alkyl- -C0-3-alkyl-NRl0-C0-3-alkyl-, -C0-3-alkyl- O-Co-3-alkyl-, Or-CH2-. More preferably, when A is CH, L1 is -Co-3-alkyl-NRIO-Co-3-alkyl-, -Qw-alkyl-O-Coo-alkyl-, or -Ci^-alkyl-. More" preferably, when A is CH, L1 is -NR10-Co-3- alkyl-, -O-Co-3-alkyl-, or -CH2-. More preferably, when A is CH, L1 is -NR10-, -0-C0-3- alkyl-, or -CH2-. More preferably, when A is CH, L1 is -Co-3-alkyl-O-Co-s-alkyl- or -Ci-6- alkyl-. More preferably, when A is CH, L1 is -Coo-alkyl-O-Co-s-alkyl- or -CH2-. More preferably, when A is CH, L1 is -O-Co-3-alkyl— , or -CH2-. More preferably, when A is CH, L1 is -O- or -CH2-.
Preferably, when A is CH, iΛR1 is -Ci.3-alkyl-CC=O)-C0-3-alkyl-R1, -Co-3-alkyl- SC=0)n-Co-3-alkyl-^ -C,-3-alkyl-CC=0)m10^ alkyl-, -C0-3-alkyl-S(=0)2NR10-Co-3-alkyl-R1, R1-Co-3-alkyl-S(=0)2NRlo-Co-3-alkyl-) -Cu3- alkyl-C(=0)0-Co-3-alkyl-R1, R1-Co.3-alkyl-C(=0)0-C0-3-alkyl- -Co-3-alkyl-OC(=0)NR10-C0-3- alkyl-R1, R1-C0-3-alkyl-OC(=O)NRl0-C0-3-alkyl- -Co^-alkyl-NR^-Qw-alkyl-R1, -Qw-alkyl- O-Co-3-alkyl-R1, -Ci-β-alkyl-R1, -C2-6-alkenyl-R1, or -Cz-δ-alkynyl-R1. More preferably, when A is CH, L1 -R1 is -C1-3-alkyl-C(=0)-Co-3-alkyl-R1, -C0-3-alkyl-S(=O)n-C0-3-alkyl-R1, -C1.3- alkyl-C(=0)NR1°-Co-3-alkyl-R1, R1-Co-3-alkyl-C(=0)NR10-Co-3-alkyl-, -C0-3-alkyl- S(=0)2NR10-Co-3-alkyl-R1, R1-C0-3-alkyl-S(=O)2NR -Qw-alkyl-, -C1.3-alkyl-C(=0)0-Co.3- alkyl-R1, R^Coo-alkyl-CCK^O-Co-s-alkyl-, -C0-3-OUCyI-OCC=O)NR10-Q«-alkyl-Rl, R'-COO- alkyl-OC(=0)NR10-Co-3-alkyl-, -Co^-alkyl-NR^-Coo-alkyl-R1, -Co-s-alkyl-O-Co-s-alkyl-R1, or -C-β-alkyl-R1.
Preferably, R10 at each occurrence is independently chosen from H, Ci-6-alkyl, and Ci-β- haloalkyl. More preferably, R10 at each occurrence is independently chosen from H and Ci-β- alkyl. More preferably, R10 at each occurrence is H.
Preferably, L1 is -Co-3-alkyl-C(=0)-C0-3-alkyl-, -Co-3-alkyl-S(=0)n-Co-3-alkyl-, -C0-3- alkyl-C(=0)NR10-Co-3-alkyl-, -C0-3-alkyl-S(=0)2NR10-Co-3-alkyl-, -C0.3-alkyl-C(=0)0-Co-3- alkyl-, -Co-3-alkyl-OC(=0)NR10-C0.3-alkyl-, -Co.3-alkyl-NR10-C0-3-alkyl- -C0.3-alkyl-O-C0.3- alkyl-, -Ci-6-alkyl-, -C2-6-alkenyl-, or -Cz-β-alkynyl-.
Preferably, R1 is an optionally mono- or polysubstituted group chosen from aryl and heteroaryl. More preferably, R1 is an optionally mono- or polysubstituted aryl group. More preferably, R1 is an optionally mono- or polysubstituted group chosen from phenyl, pyridinyl, and furanyl. More preferably, R1 is an optionally mono- or polysubstituted group chosen from phenyl, pyridin-3-yI, and furan-2-yl.
Preferably, each R1 substituent is independently chosen from halogen, -NO2, -OR20, — C(=O)OR20, -NR20R21, Ci.3-alkyl, Ci.3-haloalkyl, aryl, heteroaryl,
Figure imgf000012_0001
heterocycloalkyl, pseudohalogen, -S(O)nR20, -S(=O)2NR20R21, -OCH2F, -OCHF2, -OCF3, - NHOH, -OC(=O)R20, -OCC=O)NR20R21, -NR20CC=O)R21, and -SCF3. More preferably, each R1 substituent is independently chosen from halogen, -OR20, -CC=O)R20, -C(=O)OR20, - CC=O)NR20R21, -NR20R21, C,.3-alkyl, C1-3-haloalkyl, pseudohalogen, -SC=O)nR20, - SC=O)2NR20R21, -OCH2F, -OCHF2, -OCF3, -NHOH, -OCC=O)R20, -OCC=O)NR20R21, - NR20CC=O)R21, -NR20CC=O)OR21 , and -SCF3. More preferably, each R1 substituent is independently chosen from halogen, -OR20, -C(=O)R20, -CC=O)OR20, -CC=O)NR20R21, - NR20R21, Cio-alkyl, Ci-3-haloalkyl, pseudohalogen, -OCF3, -OCC=O)R20, -OCC=O)NR20R21, - NR20CC=O)R21, -NR20CC=O)OR21, and -SCF3. More preferably, each R1 substituent is independently chosen from halogen, -OR20, -C(=O)R20, -C(=O)OR20, -C(=O)NR20R21, - NR20R21, d-3-alkyl, C1-3-haloalkyl, pseudohalogen, -OCF3, -NR20C(=O)R21, and - NR20C(=O)OR21. More preferably, each R1 substituent is independentlychosen from halogen, -OR20, -C(=O)R20, -C(=O)OR20, -C(=O)NR20R21, -NR20R21, Ci-3-haloalkyl, -CN, and - OCF3. More preferably, each R1 substituent is independentlychosen from halogen, -C(=O)R20, Ci-3-haloalkyl, pseudohalogen, and -OCF3. More preferably, each R1 substituent is independently chosen from halogen, -C(=O)R20, Cι.3-haloalkyl, -CN, and -OCF3. More preferably, each R1 substituent is independently chosen from halogen, -C(=O)-Ci-6-alkyl, C1-3- haloalkyl, pseudohalogen, and -OCF3. More preferably, each R1 substituent is independently chosen from halogen, -C(=O)-Ci-6-alkyl, Ci-3-haloalkyl, -CN, and -OCF3. More preferably, each R1 substituent is independently chosen from chloro, fluoro, -CF3, -C(=O)CH3, -CN, and -OCF3.
Preferably, R1 is chosen from 2-chloro-3,6-difluorophenyl, phenyl, 2,5-difluorophenyl, 2,4,5-trifluorophenyl, 5-chloro-2-(trifluoromethyl)phenyl, 2-chloro-5 -(trifluoromethyl)phenyl, 2-chlorophenyl, 2,5-dichlorophenyl, 5-fluoro-2-(trifluoromethyl)phenyl, 2,6-dichlorophenyl, 3- fluoro-2-(trifluoromethyl)phenyl, 3-chlorophenyl, 3,5-dichlorophenyl, pyridin-3-yl, 2-acetyl-5- fluorophenyl, 2-cyano-3,6-difluorophenyl, 5-(trifluoromethyl)furan-2-yl, 2- (trifluoromethoxy)phenyl, and 2-chloropyridin-3-yl.
Preferably, R20 and R21 at each occurrence are independently chosen from H, Ci-6-alkyl, and Ci-6-haloalkyl. More preferably, R20 and R21 at each occurrence are independently chosen from H and Ci-β-alkyl. More preferably, R20 and R21 at each occurrence are H.
Preferably, R2 and R3 are independently chosen from H and Ci-β-alkyl, or R2 and R3 together form a carbonyl group. More preferably, R2 and R3 are H, or R2 and R3 together form a carbonyl group. More preferably, R2 and R3 together form a carbonyl group. More preferably, R2 and R3 are H.
Preferably, R2 and R3 together form a carbonyl group, and R4 and R5 are independently chosen from H and Ci-β-alkyl, or one of R4 and R5 forms a double bond with R6.
Preferably, R4 and R5 are H, or one of R4 and R5 forms a double bond with R6. More preferably, R4 and R5 are H. Preferably, R6 is H, or R6 forms a double bond with R4 or R5. More preferably, R6 is H.
In certain embodiments, X is -L2G1L3G2L4R7, i.e., a compound of Formula I(c):
Figure imgf000014_0001
I(c)
Preferably, L2 is a bond, -C0-3-alkyl-C(=0)-Co-3-alkyl-, -S(=0)π-Co-3-alkyl-, - C(=0)NR30-Co-3-alkyl-, -S(=O)2NR30-C0-3-alkyl-, -C(=0)0-Co-3-alkyl-, -CH2-OCC=O)NR30- Co-3-alkyl-, -C0.3-alkyl-OC(=O)NR30-CH2-) -CH2-NR3O-Co-3-alkyl- -CH^O-Qw-alkyl-, - CH2-OC(=0)-Co-3alkyl-, -CH2-NR10C(=O)-C0-3-alkyl- -CH2-NRIOS(=0)2-Co-3-alkyl-, -C1-3- alkyl-, -C2-3-alkenyl— , or — C2-3-alkynyl— . More preferably, L2 is a bond, -Cα-3-alkyl-C(=O)- Co-3-alkyl-, -S(=O)n-C0-3-alkyl-, -C(=O)NR30-C0-3-alkyl-, -S(=0)2NR30-Co-3-alkyl-, - C(=O)O-C0-3-alkyl- -CH2-OC(=O)NR30-C0-3-alkyl-, -C0-3-alkyl-OC(=O)NR30-CH2-, -CH2- NR30-Co-3-alkyl-, -CH2-O-C0-3 -alkyl-, -C1-3-BDCyI-, -C2-3-alkenyl-, or -C2-3-alkynyl-. More preferably, L2 is a bond, -C0-3-alkyl-C(=O)-C0-3-alkyl-, -S(=O)n-C0-3-alkyl-, -C(=0)NR30-Co- 3-alkyl- -S(=0)2NR30-Co-3-alkyl-, -C(=0)0-Co-3-alkyl- -CH2-OC(=0)NR30-Co-3-alkyl-, - Co-3-alkyl-OC(=0)NR30-CH2-, -CH2-NR30-C0-3-alkyl-, -CH∑-O-Coo-alkyl-, or -C2-3-alkynyl- . More preferably, L2 is a bond, -Co.3-alkyl-C(=0)-Co-3-alkyl-,
Figure imgf000014_0002
alkyl—, -Co-3-alkyl-C(=0)0-Co-3-alkyl-, or -C2-3-alkynyl— . More preferably, L2 is a bond, -Co- 3-alkyl-C(=O)-C0-3-alkyl- -C(=0)NR30-Co-3-alkyl-, -C(=0)0-Co-3-alkyl-, or -C2-3-alkynyl-. More preferably, L2 is a bond, -C(=0)-Co-3-alkyl-, -C(=0)NR30-Co-3-alkyl-, -C(=O)O-C0-3- alkyl-, or -C2.3-alkynyl-. More preferably, L2 is a bond, -C(=O)-, -C(=O)O-, -CC=O)O-C1-3- alkyl-, -C(=0)NR30-Co-3-alkyl-, or -C2-3-alkynyl-. More preferably, L2 is a bond, -C(=O)-, - C(=O)NR30-, or -C2-3-alkynyl-. More preferably, L2 is a bond, -CC=OK -CC=O)O-, -
CC=O)O-CH2-, -CC=O)NH-CCH2)3-, -CC=O)NH-CCH2)2-, -CC=O)NH-CH2-, -CC=O)NH-, - C ≡C- or -C ^C-CH2-.
Preferably, R30 at each occurrence is independently chosen from H, Ci-6-alkyl, and Ci .6- haloalkyl. More preferably R30 at each occurrence is independently chosen from H and Ci -6- alkyl. More preferably, R30 at each occurrence is H.
Preferably, G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl. More preferably, G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl and heteroaryl. More preferably, G1 is a bond or an optionally mono- or polysubstituted aryl group. More preferably, G1 is a bond, or an optionally mono- or polysubstituted group chosen from phenyl, pyridinyl, piperazinyl, pyrimidinyl, tetrahydropyridinyl, pyrazolyl, pyrrolyl, piperidinyl, 4-carbonyl- 1,3,8- triazaspiro[4.5]decanyl, pyrrolidinyl, and thiazolyl.
" Preferably, each G1 substituent is independently chosen from halogen, — NO2, -OR40, — C(=O)R40, -C(=O)OR40, -C(=O)NR40R41, -NR40R41, C1-3-alkyl, Ci.3-haloalkyl, pseudohalogen, SQ=O)nR40, -SC=O)2NR40R41, -OCH2F, -OCHF2, -OCF3, -NHOH, - OCC=O)R40, -OCC=O)NR40R41, -NR40CC=O)R^ -NR40CC=O)OR41, and -SCF3. More preferably, each G1 substituent is independently chosen from halogen, -OR40, -CC=O)R40, — CC=O)OR40, -CC=O)NR40R41, -NR40R41, C,.3-alkyl, Ci-3-haloalkyl, -CN, -SC=O)nR40, - SC=O)2NR40R41 , -OCF3, -OCC=O)R40, -NR40CC=O)R41 , and -SCF3. More preferably, each G1 substituent is independently chosen from halogen, -OR40, -CC=O)R40, -CC=O)OR40, - CC=O)NR40R41, -NR40R41, Cu-alkyl, Ci-3-haloalkyl, -CN, and -OCF3. More preferably, each G1 substituent is independently chosen from halogen, —OR40, Ci-3-alkyl, and Ci-3-haloalkyl. More preferably, each G1 substituent is independently chosen from halogen, -OR40, and C1-3- haloalkyl. More preferably, each G1 substituent is independently chosen from halogen and — OR40. More preferably, each G1 substituent is independently chosen from halogen and hydroxyl. More preferably, each G1 substituent is independently chosen from chloro, fluoro, and hydroxyl. More preferably, G1 is unsubstituted.
Preferably, R40 and R41 at each occurrence are independently chosen from H, Ci-6-alkyl, and Ci-6-haloalkyl. More preferably, R40 and R41 at each occurrence are independently chosen from H and Ci-6-alkyl. More preferably, R40 and R41 at each occurrence are H.
Preferably, L3 is a bond, -C0-3-alkyl-CC=0)-Co-3-alkyl-, -Co-3-alkyl-S(=0)n-Co-3-alkyl-, ^o-3-alkyl-CC=0)NR50-Co-3-alkyl-, -Co-3-alkyl-SC=0)2NR50-Co-3-alkyl-, -Co-3-alkyl-CC=0)0- Co-3-alkyl-, -Co-3-alkyl-NR5O-Co-3-alkyl- -Coo-alkyl-O-Qw-alkyl-, -C1-3-alkyl- -C2-3- alkenyl-, or -C2.3-alkynyl-. More preferably, L3 is a bond, -Co-3-alkyl-CC=0)-Co-3-alkyl-, - Co-3-alkyl-SC=0)n-Co-3-alkyl-, -Co-3-alkyl-CC=0)NR50-(^3-alkyl-, -Co-3-alkyl-SC=0)2NR50-Co_ 3-alkyl-, -Co-3-alkyl-CC=0)0-Co-3-alkyl-, -C0-3-alkyl-OCC=0)NR50-Co-3-alkyl- -Co-3-alkyl- NR5O-Co-3-alkyl-, -Co-a-alkyl-O-Co-ralkyl-, or -Cio-alkyl-. More preferably, L3 is a bond, - Co-3-alkyl-CC=0)-Co-3-alkyl-, -C0-3-alkyl-SC=0)n-Co-3-alkyl-, -Co-3-alkyl-CC=0)NR50-Co-3- alkyl-, -C0-3-alkyl-SC=0)2NR50-Co-3-alkyl-, -C0-3-alkyl-CC=O)0-C0-3-alkyl- -Co-3-alkyl-
NR5O-Co-3-alkyl-, -Co-s-alkyl-O-Qw-alkyl- or -d-3-alkyl-. More preferably, L3 is a bond, - CC=O)-C0-3-alkyl-, -SC=0)2-Co.3-alkyl- -Co-3-alkyl-CC=0)NR50-C0.3-alkyl-, -C0-3-alkyl- SC=O)2NR50-, -CC=0)0-Co-3-alkyl-, -OCC=0)NR50-Co-3-alkyl-, -NR5O-Co_3-alkyl-, -O-C0.3- alkyl-, or -Ci-3-alkyl-. More preferably, L3 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl-, -Co-3- alkyl-C(=0)NR50-Co-3-alkyl-, -Co-3-alkyl-S(=0)2NR50-Co-3-alkyl-, -Co-3-alkyl-C(=0)0-Co-3- alkyl- -<V3-alkyl-OC(=0)NR50-Q,-3-alkyl- -Co-3-alkyl-NR50-Co-3-alkyl- -Co-3-alkyl-0-Co-3- alkyl-, or -Cio-alkyl-. More preferably, L3 is a bond, -C(=0)-Co-3-alkyl-, -Co-3-alkyl- C(=0)NR50-Co-3-alkyl-, -C0-3-alkyl-S(=O)2NR50-, -C(=O)O-C0-3-alkyl-, -OC(=O)NR50-C0-3- alkyl-, -NR50-Co-3-alkyl-, -O-Co-3-alkyl-, or -C1-3-alkyl-. More preferably, L3 is a bond, - CC=O)-, -C(=0)0-Co-3-alkyl- -C(=0)NR50-Co-3-alkyl- -Co-s-alkyl-SC^∑NR50-, -0-C0-3- alkyl- -C,.3-alkyl- -NR5O-Co-3-alkyl-, -OC(=0)NR50-Co_3 -alkyl-, or-Ci.3-alkyl- C(=O)NR50-. More preferably, L3 is a bond, -C(=O)-C0-3-alkyl-, -SC=O)2-, -C(=O)NR50-, or -S(=O)2NR50-. More preferably, L3 is a bond, -CC=OK -CC=0)0-Co.3-alkyl-, -CC=O)NCCi. 3-alkyl)-Co-3-alkyl-, -C(=O)NH-C0-3-alkyl-, -Co-3-alkyl-SC=0)2NH- -O-Co-3-alkyl- -C1-3- alkyl-, -NH-Co-3-alkyl-, -OCC=O)NH-C0-3-alkyl-, or -Ci.3-alkyl-CC=O)NH-. More preferably, L3 is a bond, -CC=O)-, -CC=O)O-, -CC=O)O-CH2-,
Figure imgf000016_0001
- CC=O)NH-CCHz)3- -CC=O)NH-CCH2)2- -CC=O)NH-CH2-, -CC=O)NH-, -CC=O)NCCH3)- CH2-, -CC=O)NCCH3)-, -CCHz)2-SC=O)2NH-, -CH2-SC=O)2NH-, -SC=O)2NH-, -0-(CH2)T-, - O-CHz- -O-, -CCH2)z-,-CH2-, -NH-CCHz)2-, -NH-CH2-, -NH-, -OCC=O)NH-CH2-, - OCC=O)NH-, Or-CH2-CC=O)NH-.
Preferably, R50 at each occurrence is independently chosen from H, Ci-^-alkyl, and Ci-6- haloalkyl. More preferably, R50 at each occurrence is independently chosen from H and Q -6- alkyl. More preferably, R50 at each occurrence is H.
Preferably, G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl. More preferably, G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl and heteroaryl. More preferably, G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl and heterocycloalkyl. More preferably, G2 is a bond or an optionally mono- or polysubstituted aryl group. More preferably, G2 is a bond or an optionally mono- or polysubstituted heterocycloalkyl group. More preferably, G2 is a bond or an optionally mono- or polysubstituted heteroaryl group. More preferably, G2 is a bond, or an optionally mono- or polysubstituted group chosen from piperazinyl, pyrrolidinyl, piperidinyl, phenyl, 4-carbonyl-l,3,8-triazaspiro[4.5]decanyl, and thiazolyl.
Preferably, each G2 substituent is independently chosen from halogen, -NOz, -OR60, - CC=O)R60, -CC=O)OR60, -CC=O)NR60R61, -NR60R61, C,.3-alkyl, Ct-3-haloalkyl, pseudohalogen, -SC=O)nR60, -SC=O)2NR60R61, -OCH2F, -OCHF2, -OCF3, -NHOH, - OC(=O)R60, -OC(=O)NR60R61, -NR60CC=O)R61, -NR60CC=O)OR61, and -SCF3. More preferably, each G2 substituent is independently chosen from halogen, -OR60, -CC=O)R60, - C(O)OR60, -CC=O)NR60R61, -NR60R61, Ci-3-alkyl, C1-3-haloalkyl, -CN, -SC=O)nR60, - SC=O)2NR60R61, -OCF3, -OCC=O)R60, -NR60CC=O)R61, and -SCF3. More preferably, each G2 substituent is independently chosen from halogen, -OR60, -CQO)R60, -CC=O)OR60, -
CC=O)NR60R61, -NR60R61, Ci-3-alkyl, Ci-3-haloalkyl, -CN, and -OCF3. More preferably, each G2 substituent is independently chosen from halogen, -OR60, Ci-3-alkyl, and Ci-3-haloalkyl. More preferably, each G2 substituent is independently chosen from halogen, -OR60, and C1.3- haloalkyl. More preferably, each G2 substituent is independently chosen from halogen and - OR60. More preferably, each G2 substituent is independently chosen from halogen and hydroxyl. More preferably, each G2 substituent is independently chosen from chloro, fluoro, and hydroxyl. More preferably, each G2 substituent is hydroxyl. More preferably, G2 is unsubstituted.
Preferably, R60 and R61 at each occurrence are independently chosen from H, Ci-β-alkyl, and Q-β-haloalkyl. More preferably, R60 and R61 at each occurrence are independently chosen from H and Ci^-alkyl. More preferably, R60 and R61 at each occurrence are H.
Preferably, L4 is a bond, -C0-3-alkyl-CC=O)-C0-3-alkyl-, -Coo-alkyl-SCOVCoo-alkyl-, -C0-3-alkyl-CC=O)NR70-C0-3-alkyl-, -Q-3-al^ Co-3-alkyl- -CO-3-alkyl-NR7O-Co-3-alkyl- -Co-÷j-alkyl-O-Co-s-alkyl-, -Ci-3-alkyl- -C2.3- alkenyl-, or -C2-3-alkynyl— . More preferably, L4 is a bond, -Co-3-alkyl-CC=0)-Co-3-alkyl— , — C0-3-alkyl-SC=0)n-Co-3-alkyl-, ^o-3-alkyl-CC=0)NR70-C^3-alkyl-, -Co-3-alkyl-SC=0)2NR70-Co- 3-alkyl-, -C0-3-alkyl-CC=O)O-C0-3-alkyl-, -C0-3-alkyl-NR70-C0-3-alkyl-, -C0.3-alkyl-O-C0.5- alkyl-, or -Ci.3-alkyl-. More preferably, L4 is a bond, -Co-3-alkyl-CC=0)-Co-3-alkyl-, - SC=0)n-Co-3-alkyl-, -Co-3-alkyl-CC=0)NR70-Co-3-alkyl-, -SC=O)2NR70-C0-3-alkyl- -Co-3-alkyl- CC=O)O-C0-3-alkyl-, -NR70-C0-3-alkyl-, -O-Co-3-alkyl-, or -Ci-3-alkyl-. More preferably, L4 is a bond, -CC=0)-Co-3-alkyl- -SC=O)n-C0-3-alkyl-, -Co-3-alkyl-CC=0)NR70-, -SC=O)2NR70-, -CC=O)O-C0-3-alkyl-, -NR70-Co-3-alkyl-, -O-Co-3-alkyl-, or -Ci-3-alkyl- More preferably, L4 is a bond, -CC=O)-C0-3-alkyl- -SC=0)2-Co-3-alkyl- -C0-3-alkyl-CC=O)NR70-, -SC=O)2NR70-, -CC=O)O-C0-3-alkyl-, -NR70-, or -Ci.3-alkyl-. More preferably, L4 is a bond, -Co-3-alkyl- CC=0)-Co-3-alkyl-, -Co-3-alkyl-CC=0)NR70-C0-3-alkyl-, -C0-3-alkyl-CC=O)O-C0-3-alkyl-, or - Ci-3-alkyl- More preferably, L4 is a bond, -CC=O)-C0-3-alkyl-, -C0-3-alkyl-CC=O)NR70-, - CC=0)0-Co-3-alkyl-, or -Ci^-alkyl-. More preferably, L4 is a bond, -CC=O)-, -Ci-3-alkyl-, - C(=O)O-C0-3-alkyl-, or -Ci.3-alkyl-C(=O)NH-. More preferably, L4 is a bond, -C(=O>-, - (CH2)r-, -CH2-, -C(K))O-, -C(K))O-CH2-, or -CH2-C(K))NH.
Preferably, R70 at each occurrence is independently chosen from H, Ci-6-alkyl, and Ci-β- haloalkyl. More preferably, R70 at each occurrence is independently chosen from H and Ci -6- alkyl. More preferably, R70 at each occurrence is H.
Preferably, R7 is an optionally mono- or polysubstituted group chosen from Ci-6-alkyl, aryl, C3-io-cycloalkyl, heterocycloalkyl, and heteroaryl. More preferably, R7 is an optionally mono- or polysubstituted group chosen from Ci-6-alkyl, aryl, heterocycloalkyl, and heteroaryl. More preferably, R7 is an optionally mono- or polysubstituted group chosen from aryl, C3-io- cycloalkyl, heterocycloalkyl, and heteroaryl. More preferably, R7 is an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl. More preferably, R7 is an optionally mono- or polysubstituted group chosen from pyridinyl, phenyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, isopentyl, hexyl, piperazinyl, pyrrolidinyl, morpholinyl, pyrimidinyl, dihydropyridinyl, tetrahydropyridinyl, propynyl, pyrazolyl, pyrrolyl, piperidinyl, l,3-dihydro-2-carbonylbenzoimidazolyl, 4-carbonyl-l,3,8-triazaspiro[4.5]decanyl, thieno[3,2-d]pyrimidinyl, furo[3,2-c]pyridinyl, benzo[d]isoxazolyl, thienyl, quinolinyl, pyrazinyl, thiazolyl, naphthalenyl, indanyl, cyclohexyl, tetrahydrofuranyl, indolyl, and isoindolyl. More preferably, R7 is an optionally mono- or polysubstituted group chosen from pyridin-3-yl, piperazin-1-yl, phenyl, pyrrolidin-1-yl, morpholin-4-yl, methyl, ethyl, propyl, butyl, pentyl, hexyl, piperidin-1-yl, pyridin-4-yl, isoxazol-4-yl, pyrimidin-5-yl, propyn-1-yl, l,l-dioxo-lλ6-thiomoφholin-4-yl, pyrazol-4-yl, pyrrol-3-yl, pyrimidin-2-yl, isopropyl, isobutyl, isopentyl, tert-butyl, l,3-dihydro-2-carbonylbenzoimidazol-l-yl, 4-carbonyl- 1,3,8- triazaspiro[4.5]decan-8-yl, thieno[3,2-d]pyrimidin-4-yl, furo[3,2-c]pyridin-4-yl, benzo[d]isoxazol-3-yl, pyridin-2-yl, piperidin-4-yl, thien-2-yl, quinolin-4-yl, pyrazin-2-yl, thiazol-4-yl, naphthalen-1-yl, indan-1-yl, cyclohexyl, 4-biphenyl, tetrahydrofuran-2-yl, indan- 2-yl, thiazol-2-yl, indol-3-yl, and isoindol-2-yl.
Preferably, at least one of G1 and R7 is an optionally mono- or polysubstituted group chosen from aryl, C^io-cycloalkyl, heterocycloalkyl, and heteroaryl.
Preferably, each R7 substituent is independently chosen from halogen, -OR80, — C(=O)R80, -C(=O)OR80, -C(=O)NR80R81, -NR80R81, Ci-6-haloalkyl, aryl, heteroaryl, C3-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(=O)nR80, -S(=O)2NR80R81, - OCH2F, -OCHF2, -OCF3, -NHOH, -OC(=O)R80, -OC(K))NR80R81, -NR80C(K))R81, - NR80C(K))OR81, -SiR80R81R82 and -SCF3. More preferably, each R7 substituent is independently chosen from halogen, -OR80, -C(O)R80, -C(=O)OR80, -C(O)NR80R81, - NR80R81, Ci-6-alkyl, Ci-e-haloalkyl, aryl, heteroaryl, C^o-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(=O)nR80, -S(O)2NR80R81, -OCF3, OC(O)R80, -NR80C(O)R81, - SiR80R81R82 and -SCF3. More preferably, each R7 substituent is independently chosen from halogen, OR80, -C(O)R80, -C(O)OR80, -C(O)NR80R81, -NR80R81, C1-6-alkyl, Ci-6- haloalkyl, aryl, heteroaryl, C3-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(=O)nR80, - S(O)2NR80R81, -OCF3, -OC(O)R80, and -NR80C(O)R81. More preferably, each R7 substituent is independently chosen from halogen, -OR80, -C(O)R80, -C(O)OR80, - C(O)NR80R81, -NR80R81, d-6-alkyl, d-β-haloalkyl, aryl, heteroaryl, C3-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(O)nR80, -S(O)2NR80R81, -OCF3, and -SiR80R81R82.
More preferably, each R7 substituent is independently chosen from halogen,— OR80, -C(=O)R80, -C(O)OR80, -C(O)NR80R81, -NR80R81, Ci-e-alkyl, Cl-6-haloalkyl, aryl, heteroaryl, C3-10- cycloalkyl, heterocycloalkyl, cyano, -S(O)2R80, -S(O)2NR80R81, -OCF3, and -SiR80R81R82. More preferably, each R7 substituent is independently chosen from methyl, carboxy, N,N- dimethylamino, acetyl, methanesulfonyl, aminocarbonyl, ethylaminocarbonyl, cyano, ethoxycarbonyl, methoxycarbonyl, pyrrolidin-1-yl, chloro, moφholin-4-yl, fluoro, methoxy, tert-butoxycarbonyl, pyrrolidin-1-yl, tert-butoxycarbonylamino, amino, 1,1-dioxo-lλ6- thiomorpholin-4-yl, isopentyl, triisopropylsilyl, phenyl, pyrimidin-2-yl, l,3-dihydro-2- carbonylbenzoimidazol-1-yl, trifluoromethyl, thieno[3,2-d]pyrimidin-4-yl, furo[3,2-c]pyridin- 4-yl, fluoro, pyridin-2-yl, trifluoromethoxy, thien-2-yl, pyridin-4-yl, pyridin-3-yl, pyrrolidin-1- yl, sulfamoyl, pyrazin-2-yl, naphthalen-1-yl, phenoxy, tetrahydrofuran-2-ylcarbonyl, tetrahydrofuran-2-yl, indan-2-ylaminocarbonyl, cyclohexyl, pyridin-3-yl, thiazol-2-yl, acetamido, indol-3-yl, benzoyl, isopropylaminocarbonyl, morpholin-4-ylcarbonyl, cyclohexylaminocarbonyl, indan-1-ylaminocarbonyl, indan-2-ylaminocarbonyl, and isoindol- 2-ylcarbonyl.
Preferably, R80, R81, and R82 at each occurrence are independently chosen from H, Ci-6- alkyl, and Cι-6-haloalkyl. More preferably, R80, R81, and R82 at each occurrence are independently chosen from H and Ci^-alkyl. More preferably, R80, R81, and R82 at each occurrence are H. Preferably, R80 at each occurrence is independently chosen from H, Ci-6-alkyl, Ci-6- haloalkyl, aryl, heteroaryl, and heterocycloalkyl. More preferably, R80 at each occurrence is independently chosen from H, Ci-6-alkyl, Ci-6-haloalkyl, aryl, and heteroaryl. More preferably, R80 at each occurrence is independently chosen from H, Ci-β-alkyl, Q-6-haloalkyl, and aryl. Preferably, when R7 is Ci-β-alkyl, at least one of L2, G1, L3, G2, or L4 is not a bond. Preferably, R7 is chosen from pyridin-3-yl, 4-methylpiperazin-l-yl, 4-carboxyphenyl, pyrrolidin-1-yl, morpholiπ-4-yl, N,N-dimethylaminom ethyl, N,N-dimethylaminoethyl, N5N- dimethylaminopropyl, N,N-dimethylaminobutyl, N,N-dimethylaminopentyl, N5N- dimethylaininohexyl, 4-acetylphenyl, methyl, ethyl, 4-methanesulfonylphenyl, benzamidyl, N- ethylbenzamidyl, 2-cyanopyridin-5-yl, 2-ethoxycarbonylpyridin-5-yl5 4-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 3-carboxyphenyl, 3-methoxycarbonylphenyl, 4-(l- pyrrolidinyl)piperidin-l-yl, 2-carboxypyridin-5-yl, S-ethoxycarbonylpyridin-S-yl, 3- carboxypyridin-5-yl, 3-chloro-2-morpholin-4-ylpyridin-4-yl, 3-fluoro-2-morpholin-4- ylpyridin-4-yl, 3,5-dimethylisoxazol-4-yl, 2-(4-morpholinyl)ρyrimidin-5-yl, 2- methoxypyrimidin-5-yl, 1 -tert-butoxycarbonyl-S.ό-dihydro^H-pyridin^-yl, 1 ,2,3 ,6- tetrahydropyridin-4-yl, 2-chloropyridin-5-yl, 2-(l-pyrrolidinyl)pyridin-5-yl, 2-chloropyridin-4- yl, 3-tert-butoxycarbonylaminopropyn-l-yl, 3-aminopropyn-l-yl, 3-dimethylaminopropyn-l- yl, 3-(l5l-dioxo-lλ6-thiomorpholin-4-yl)propyn-l-yl5 l5l-dioxo-lλ6-thiomoφholin-4-yl, 2- aminopyridin-5-yl, 2-(l-pyrrolidinyl)pyridin-4-yl5 2-(4-moφholinyl)pyridin-4-yl, 3-(4- morpholinyl)phenyl, l-isopentylpyrazol-4-yl, 2-(l-piperazinyl)pyridin-4-yl54-acetylpiperazin- 1-yl, pyrazol-4-yl, pyτrol-3-yl, l-(triisopropylsilyl)pyrrol-3-yl, l-methylpyrazol-4-yl, piperidin- 1-yl, 4-methoxypiperidin-l-yl, 4-phenylpiperazin-l-yl, pyrimidin-2-yl, phenyl, methyl, ethyl, isopropyl, isobutyl, isopentyl, tert-butyl, piperazin-1-yl, 4-(2-pyrimidinyl)piperazin-l-yl, 4- chlorophenyl, l.S-dihydro^-carbonylbenzoimidazol-l-yl, 4-(l,3-dihydro-2- carbonylbenzoimidazol-l-yl)piperidin-l-yl, 2-methoxyphenyl, 3-(trifluoromethyl)phenyl, 4- phenylpiperidin-1-yl, 3,4-dichlorophenyl, benzhydryl, benzyl, 4-carbonyl- 1 -phenyl- 1,3,8- triazaspiro[4.5]decan-8-yl, 4-carbonyl-l53,8-triazaspiro[4.5]decan-8-yl, thieno[3,2- d]pyrimidin-4-yl, 4-thieno[352-d]pyrimidin-4-ylpiperazin-l-yl, 4-methoxyphenyl, furo[3,2- c]pyridin-4-yl, 4-furo[3,2-c]pyridin-4-ylpiperazin-l-yl, 6-fluorobenzo[d]isoxazol-3-yl, 3- chlorophenyl, pyridin-2-yl, 2-pyridinylmethyl, 2-(2-pyridinyl)ethyl, 1- ethoxycarbonylpiperidin-4-yl, 4-(trifluoromethoxy)phenyl, 4-(4-morpholinyl)piperidin- 1 -yl, thien-2-yl, 2-thienylmethyl, 2-(2-thienyl)ethyl, pyridin-4-yl, 4-pyridinylmethyl, 3- pyridinylmethyl, quinolin-4-yl, 2-methylquinolin-4-yl, 1-pyrrolidinylmethyl, 3,5- bis(trifluoromethyl)phenyl, 4-sulfamoylphenyl, pyrazin-2-yl, 4-(2-pyrazinyl)piperazin-l-yl, thiazol-4-yl, 2-phenylthiazol-4-yl, naphthalene- 1-yl, 1-naphthalenyhnethyl, indan-1-yl, cyclohexyl, 4-biphenyl, 2-phenoxyethyl, phenoxymethyl, tetrahydrofuran-2-yl, 4-(2- tetrahydrofuranylcarbonyl)piperazin-l-yl, phenethyl, 2-tetrahydrofuranylmethyl, 2- chlorophenyl, 2-(trifluoromethyl)phenyl, indan-2-yl, 3-(2-indanylaminocarbonyl)phenyl, cyclohexylmethyl, 2-(3-pyridinyl)pyrrolidin-l-yl, 4-(4-morpholinyl)phenyl, thiazol-2-yl, 4-(2- thiazolyl)piperazin-l-yl, 2-(4-morpholinyl)pyridin-5-yl, 4-acetamidophenyl, indol-3-yl, 4-(3- indolyl)piperidin-l-yl, 4-benzoylpiperazin-l-yl, l-methylpiperidin-4-yl, isopropylaminocarbonylmethyl, 3-(4-morpholinylcarbonyl)phenyl, 3-methoxyphenyl, 3- (cyclohexylaminocarbonyl)phenyl, 4-(trifluoromethyl)phenyl, methoxymethyl, methoxyethyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(l -indanylaminocarbonyl)phenyl, 4-(2- indanylaminocarbonyl)phenyl, isoindol-2-yl, and 4-(2-isoindolylcarbonyl)phenyl. In certain embodiments, X is R8, i.e., a compound of Formula I(d):
Figure imgf000021_0001
I(d)
Preferably, R8 is H, Br, I, CN, or C(=O)OH. More preferably, R8 is Br, I, CN, or C(=O)OH. More preferably, R8 is I, CN, or C(=O)OH. More preferably, R8 is I.
In addition to having ALK and c-Met inhibitory activity, the compounds of Formula I(d) are useful as intermediates for the preparation of other compounds of Formula I (e.g., compounds of Formula I(c)).
Preferably, n is 0 or 2. More preferably, n is 0. More preferably, n is 2. The present invention provides a compound of Formula I in which A, L1, R1, R2, R3, R4, R5, R6, L2, G1, L3, G2, L4, R7, R8, R10, R20, R21, R30, R40, R41, R50, R60, R61, R70, R80, R81, R82, and n are independently chosen as set forth in any of the above-recited definitions. Thus, the present invention includes a compound of Formula I having A, L1, R1, R2, R3, R4, R5, R6, L2, G1, L3, G2, L4, R7, R8, R10, R20, R21, R30, R40, R41, R50, R60, R61, R70, R80, R81, R82, and n defined by any combination of the broader and narrower definitions of these substituents as set forth above. For example, included within the scope of the present invention are compounds of Formula I in which R10, R20, R21, R30, R40, R41, R50, R51, R60, R61, R70, R80, R81, and R82 at each occurrence are independently chosen from H and d^-alkyl. As another example, also included within the scope of the present invention are compounds of Formula I in which R10, R20, R21, R30, R40, R41, R50, R51, R60, R61, R70, R80, R81, and R82 at each occurrence are H. As another example, also included within the scope of the present invention are compounds of Formula I in which G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, and each G1 substituent is independently chosen from halogen and -OR40. As another example, also included within the scope of the present invention are compounds of Formula I in which G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, and each G2 substituent is independently chosen from halogen and -OR60. As another example, also included within the scope of the present invention are compounds of Formula I in which R7 is an optionally mono- or polysubstituted group chosen from Ci-β-alkyl, aryl, C3-io-cycloalkyl, heterocycloalkyl, and heteroaryl, and each R7 substituent is independently chosen from halogen, -OR80, -C(=O)R80, -C(=O)OR80, -C(O)NR80R81, -NR80R81, Ce-alkyl, Ci-6- haloalkyl, aryl, heteroaryl, C3-io-cycloalkyl, heterocycloalkyl, cyano, -SC=O)nR80, - SC=O)2NR80R81, -OCF3, and -SiR80R81R82. As another example, also included within the scope of the present invention are compounds of Formula I in which at least one of G1 and R7 is an optionally mono- or polysubstituted group chosen from aryl, C3-io-cycloalkyl, heterocycloalkyl, and heteroaryl, each G1 substituent is independently chosen from halogen and -OR40, and each R7 substituent is independently chosen from halogen, —OR80, -CC=O)K-80? -C(=O)OR80, -CC=O)NR80R81, -NR80R81, Ci-6-alkyl, Cl-6-haloalkyl, aryl, heteroaryl, C3-10- cycloalkyl, heterocycloalkyl, cyano, -SC=O)nR80, -SC=O)2NR80R81, -OCF3, and -SiR80R81R82. As another example, also included within the scope of the present invention are compounds of Formula I in which A is N;
L1 is -Co-3-alkyl-CC=0)-Co-3-alkyl-, -Co-3-alkyl-SC=0)n-Co-3-alkyl-, -Co-3-alkyl- CCK))NR10-C^3-alkyl-, -Coo-alkyl-SC=0)2NR10-C^.3-alkyl-, -Co-3-alkyl-CC=0)0-Co-3-alkyl-, or -Ci-6-alkyl-; R1 is an optionally mono- or polysubstituted group chosen from aryl, C3.ιo-cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be the same or different and are chosen from halogen, -OR20, -CC=O)R20, -CC=O)OR20, -CC=O)NR20R21, -NR20R21, CJ-3- haloalkyl, -CN, and -OCF3;
R2 and R3 are independently chosen from H, OH, and Ci-β-alkyl, or R2 and R3 together form a carbonyl group;
R4 and R5 are independently chosen from H and Ci-6-alkyl, or R4 and R5 together form a carbonyl group, or one of R4 and R5 forms a double bond with R6;
R6 is chosen from H and Ci-β-alkyl, or R6 forms a double bond with R4 or R5; X iS -L2G1L3G2L4R7;
L2 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl-, -S(=0)n-Co-3-alkyl- -C(=0)NR30-Co-3- alkyl- -S(=0)2NR30-Co-3-alkyl-, -C(=O)O-C0-3-alkyl- -CH2-OC(=0)NR30-Co-3-alkyl-, -C0- 3-alkyl-OC(=O)NR30-CH2-, -CH2-NR3O-Co.3-alkyl-,
Figure imgf000023_0001
-Cio-alkyl- -C2-3- alkenyl— , or — C2-3-alkynyl— ;
G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C3-io- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -OR40, and Ci-3-haloalkyl;
L3 is a bond, -C(=0)-Co-3-alkyl-, -S(=0)2-Co-3-alkyl-, -Co-3-alkyl-C(=0)NR50-C0-3- alkyl-, -Qw-alkyl-SCO^NR50-, -C(=0)0-Co-3-alkyl-, -OC(=0)NR50-Co-3-alkyl-, -NR5O-Co- 3-alkyl- -O-Co-3-alkyl-, or -C 1 -3-alkyl-;
G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C3-io- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -OR60, and Ci-3-haloalkyl; L4 is a bond, -C(=0)-Co-3-alkyl-, -S(=0)2-Co-3-alkyl-, -Co-3-alkyl-C(=0)NR70-, -
S(=O)2NR70-, -C(=0)0-Co.3-alkyl-, -NR70-, or -C,-3-alkyl-;
R7 is an optionally mono- or polysubstituted group chosen from Ci-6-alkyl, aryl, C3-io- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -OR80, -C(=O)R80, -C(O)OR80, -C(=O)NR80R81 , - NR80R81, Ci-6-alkyl, Ci-6-haloalkyl, aryl, heteroaryl, C3-j0-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(=O)nR80, -S(=O)2NR80R81, -OCF3, -OC(=O)R80, and -NR80C(=O)R81;
R10, R20, R21 , R30, R40, R50, R60, R70, and R81 at each occurrence are independently chosen from H, Ci-6-alkyl, and C^-haloalkyl;
R80 at each occurrence is independently chosen from H, Ci-6-alkyl, and Ci-β-haloalkyl, aryl, and heteroaryl; and n is O or 2. As another example, also included within the scope of the present invention are compounds of Formula I in which
A is N;
L1 is -Co-3-alkyl-C(=0)-C0-3-alkyl-, -Co-3-alkyl-S(=0)2-C0-3-alkyl- or -C1-6-alkyl-; R1 is an optionally mono- or polysubstituted group chosen from aryl and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, — C(=O)R20, Ci-3-haloalkyl, -CN, and -OCF3; R2 and R3 are independently chosen from H and Ci^-alky], or R2 and R3 together form a carbonyl group;
R4 and R5 are H, or one of R4 and R5 forms a double bond with R6;
R6 is H, or R6 forms a double bond with R4 or R5; X is -L2G1L3G2L4R7;
L2 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl-, -Co-3-alkyl-C(=0)NR30-Co-3-alkyl-, -C0-3- alkyl-C(=O)O-C0-3-alkyl-, or -C2-3-alkynyl-;
G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and -OR40;
L3 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl-, -Co-3-aUcyl-C(=0)NR50-Co.3-alkyl- -C0-3- alkyl-SC^M^-Qo-alkyl-. -C^s-^ alkyl-, -Co-3-alkyl-NR50-Co.3-alkyl- -Co-s-alkyl-O-Qw-alkyl- or-Ci.3-alkyl-;
G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and —OR60.
L4 is a bond, -C0-3-alkyl-C(=0)-Co-3-alkyl-, -C0-3-alkyl-C(=0)NR70-Co-3-alkyl-, -C0-3- alkyl-C(=0)0-Co-3-alkyl-, or -Ci-3-alkyl-;
R7 is an optionally mono- or polysubstituted group chosen from Ci-β-alkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -OR80, -C(=O)R80, -C(=O)OR80, -C(=O)NR80R81, -NR80R81, C,.6-alkyl, Ci-6-haloalkyl, aryl, heteroaryl, C3.i0-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(=O)nR80, -S(=O)2NR80R81, -OCF3, and -SiR80R81R82;
R20, R30, R40, R50, R60, R70, R80, R81, and R82 at each occurrence are independently chosen from H, Ci-6-alkyl, and Ci-β-haloalkyl; and n is 2. As another example, also included within the scope of the present invention are compounds of Formula I in which
A is CH;
L1 is -Coo-alkyl-O-Coo-alkyl-, or-C^-alkyl-; R1 is an optionally mono- or polysubstituted group chosen from aryl and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, — C(=O)R20, Cio-haloalkyl, -CN, and -OCF3; R2 and R3 are independently chosen from H and Ci-6-alkyl, or R2 and R3 together form a carbonyl group;
R4 and R5 are H, or one of R4 and R5 forms a double bond with R6; R6 is H, or R6 forms a double bond with R4 or R5;
Figure imgf000025_0001
L2 is a bond, -C0-3-alkyl-C(=O)-C0-3-alkyl-> -C0-3-alkyl-C(=0)NR30-Co-3-alkyl-, -C0-3- alkyl-C(=0)0-Co-3-alkyl-, or -C2-3-alkynyl-;
G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and -OR40;
L3 is a bond, -C0-3-alkyl-C(=O)-Co-3-alkyl-, -C0-3-alkyl-C(=O)NR50-C0-3-alkyl-, -C0-3- alkyl-S(=0)2NR50-Co.3-alkyl- -Co-3-alkyl-C(=0)0-C0-3-alkyl- -C0-3-alkyl-OC(=O)NR50-C0-3- alkyl-, -Co-3-alkyl-NR50-C0-3-alkyI-, -Coo-alkyl-O-Co-s-alkyl-, or -Ci-3-alkyl-;
G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen and -OR60.
L4 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl- -Co-3-alkyl-C(=0)NR70-C0-3-alkyl-, -C0-3- alkyl-C(=0)0-Co-3-alkyl-, or -Cu-alkyl-;
R7 is an optionally mono- or polysubstituted group chosen from Ci-6-alkyl, aryl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen,-OR80, -C(=O)R80, -C(=O)OR80, -C(=O)NR80R81, -NR80R81, Ci-β-alkyl, Ci-6-haloalkyl, aryl, heteroaryl, C3-io-cycloalkyl, heterocycloalkyl, pseudohalogen, — S(=O)nR80, -S(^O)2NR80R81, -OCF3, and -SiR80R81R82;
R20, R30, R40, R50, R60, R70, R80, R81, and R82 at each occurrence are independently chosen from H, Ci-β-alkyl, and Ci-β-haloalkyl; and n is 2.
In one embodiment, the present invention provides a compound of Formula I(c) chosen from: l-(2-Chloro-3,6-ά4fluoroberizyl)-7-pyridin-3-yl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; 4-[l -(2-Chloro-3,6-difluorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester;
4-[l-(2-Chloro-3,6-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid; 1 -(2-Chloro-3 ,6-difluorobenzyl)-7-[4-(4-methylpiperazine- 1 -carbonyl)phenyl] -3 ,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one;
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester;
4-(l-Benzyl-2-oxo-l,2,3»4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid; l-Benzyl-7-pyridin-3-yl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
4-(l -Benzyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-pyrrolidin- 1 -yl- ethyl)benzamide; jS'-l-Benzyl-7-[4-(2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carbonyl)phenyl]-3,4-dihydro-lH- pyrido[2,3-b]pyrazin-2-one; 4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-morpholin-4-yl- propyl)benzamide;
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(4- dimethylaminobutyl)benzamide;
4-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(6- dimethylaminohexyl)benzamide; l-Benzyl-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-lH-pyrido[2,3-b]pyrazin-2- one;
S-I -Benzyl-7-[3-(2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 -carbonyl)phenyl]-3,4-dihydro- 1 H- pyrido[2,3-b]pyrazin-2-one; 3-(l-Benzyl-2-oxo-lJ2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino- ethyl)benzamide; l-Benzyl-7-[3-(pyrrolidine-l-carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
7-(4-Acetylphenyl)- 1 -benzyl-3 ,4-dihydro- 1 H-pyrido [2,3-b]pyrazin-2-one;
3-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide; 4-( 1 -Benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzamide; l-Benzyl-7-(4-methanesulfonyl-phenyl)-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-Benzyl-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-
2-one;
1 -Benzyl-7-[4-(4-(pyrrolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl]-3,4-dihydro- 1 H-pyrido[2,3- b]pyτazin-2-one;
4-(l-Benzyl-2-oxo-l,2s3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide;
5-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile; 5-( 1 -Benzyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carboxylic acid ethyl ester;
3-(l-Benzyl-2-oxo-l,2,3,4-tetrahydxopyrido[2,3-b]pyrazin-7-yl)benzoic acid methyl ester;
3-( 1 -Benzyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid; 1 -Benzyl^-pyridin-S-yl- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazine;
4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester;
4-( 1 -B enzyl- 1 ,2,3 ,4-tetrahydropyrido [2,3-b]pyrazin-7-yl)benzoic acid;
[4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-methylpiperazin-l- yl)methanone; [4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-((S)-2- pyrrolidinyknethylpyrrolidin- 1 -yl)methanone;
[4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-(pyrrolidin-l- yl)piperidin-l-yl)methanone;
Phenyl-(7-pyridin-3-yl-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)methanone; 4-(l -Benzoyl- 1 ,2,3 ,4-tetrahydropyrido[2,3-bJpyrazin-7-yl)benzoic acid ethyl ester;
2-Pyrrolidin-l-yl-ethanesulfonic acid [4-(l -benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl)phenyl] amide;
2-Pyrrolidin-l-yl-ethanesulfonic acid [4-(l -benzoyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl)phenyl] amide; 2-(4-Methylpiperazin- 1 -yl)-ethanesulfonic acid [4-( 1 -benzoyl-1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl)phenyl]amide;
2-Pyrrolidin- 1 -yl-ethanesulfonic acid {4-[ 1 -(2,5-difluorobenzyl)-2-oxo- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;
2-[Ethyl-((S)- 1 -pyrrolidin- 1 -ylmethyl-propyl)-amino]-ethanesulfonic acid {4-[ 1 -(2,5- difluorobenzyl)-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -amide;
2-Morpholin-4-yl-ethanesulfonic acid {4-[ 1 -(2,5-difluorobenzyl)-2-oxo- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;
2-Pyrrolidin- 1 -yl-ethanesulfonic acid {4-[ l-(2,5-difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]phenyl} -amide; 4-(l-Benzoyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino- ethyl)benzamide;
4-(l-Benzoyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-dimethylamino- propyl)benzamide; {7-[4-(4-Methylpiperazine- 1 -carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3 -bjpyrazin- 1 - yl } phenylmethanone;
4-[l-(2,5-Difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester; 4-[l-(2,5-Difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]ben2oic acid;
1 -(2,5-Difluorobenzyl)-7-[4-((S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 -carbonyl)phenyl]-
3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
4-[l-(2,5-Difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin-
1 -yl-ethyl)benzamide; 1 -(2,5-Difluorobenzyl)-7-[4-(4-methylpiperazine- 1 -carbonyl)phenyl]-3,4-dihydro- 1 H- pyrido[2,3-b]pyrazin-2-one; l-(2,5-Difluorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-3,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one;
(S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxylic acid {4-[l-(2,5-difluorobenzyl)-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -amide;
4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester;
4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid;
{4-[l-(2)5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2-
((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone; {4-[l-(2-5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-
(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone;
{4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4- methylpiperazin- 1 -yl)methanone;
{4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-moφholin-4- yl-methanone; l-(2,5-Difluorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2,5-Difluorobenzyl)-7-(6-moφholin-4-yl-pyridin-3-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine; 5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2- carbonitrile;
5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyraziπ-7-yl]-pyridine-2-carboxylic acid; 5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic acid ethyl ester;
5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic acid; l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester; {5-[l-(2,5-Difluorobenzyl)-l,2,3.4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2- yl } morpholin-4-yl-methanone;
[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-methylpiperazin-l- yl)methanone; l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [2(4- methylpiperazin-l-yl)ethyl] amide;
7-[4-((S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carbonyl)phenyl]-l-(2,4,5-trifluorobenzyl)-
3,4-dihydro- 1 H-pyrido [2,3 -b]pyrazin-2-one;
((S)-2-((pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)-{4-[l-(2,4,5-trifluorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone; 7-[4-(4-Methylpiperazine-l-carbonyl)phenyl]-l-(2,4,5-trifluorobenzyl)-3,4-dihydro-lH- pyrido [2,3 -b]pyrazin-2-one;
(4-Methylpiperazin-l-yl)-{4-[l-(2,4,5-trifluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-
7-yl]phenyl} -methanone;
(2,5-Difluoropheπyl)-{7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4-dihydro-2H- pyrido[2,3 -b] pyrazin- 1 -yl } -methanone;
(2,5-Difluorophenyl)-{7-[4-((S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carbonyl)phenyl]-
3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl}-methanone;
1 -(2,5-Difluorobenzyl)-3 ,3-dimethyl-7-[4-((S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 - carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4- dihydro- 1 H-pyrido[2,3-t>]pyrazin-2-one;
{4-[ 1 -(2,5-Difluorobenzyl)-3 ,3-dimethyl- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -
((S)-2-((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone;
{4-[l-(2,5-Difluorobenzyl)-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}- (4-methylpiperazin-l-yl)methanone;
{4-[ 1 -(2-Chloro-3,6-difluorobenzyl)-l ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-
(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone; {4-[ 1 -(2-Chloro-3,6-difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -((S)-
2-((pyrrolidin- 1 -yl)methyl)pyrτolidin- 1 -yl)methanone; l-(2-Chloro-3,6-difluorobenzyl)-7-(3-chloro-2-morpholin-4-yl-pyridin-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-(3-fluoro-2-moφholin-4-yl-pyridin-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-(3,5-dimethyl-isoxazol-4-yl)-l,2,3,4-tetrahydropyrido[2,3- b]ρyrazine;
{4-[l-(2-Chloro-3,6-di£luorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4- methylpiperazin-l-yl)methanone; l-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-l-yl)-pyrimidin-5-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyriinidin-5-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
1 -(2-Chloro-3>6-difluorobenzyl)-7-(4-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazine;
7-[6-(4-Methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; 2-Phenyl-l-{7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-3,4-dihydro-2H- pyrido[2,3-b]pyrazin-l -yl}-ethanone;
2-(2,5-Difluorophenyl)-l-{7-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]-3,4-dihydro-2H- pyrido [2,3-b]pyrazin- 1 -yl } ethanone;
2-(2,5-Difluorophenyl)-l-{7-[4-(4-(pyrrolidin-l-yl)piperidine-l-caibonyl)phenyl]-3,4-dihydro- 2H-pyrido[2,3-b]pyrazin-l-yl}ethanone;
{4-[l-(5-Chloro-2-trifluoromethylbenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -(4-(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone; l-(5-Chloro-2-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-5-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-l -yl)pyridin-3-yl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
1 -(2,5-Difluorobenzenesulfonyl)-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-Benzenesulfonyl-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3>4-tetrahydropyrido[2,3- b]pyrazine;
1 -(2-Chlorobenzenesulfonyl)-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3 ,4 tetrahydropyrido[2,3-b]pyrazine; 1 -(2,5-Dichlorobenzyl)-7-(2-methoxypyτimidin-5-yl)- 1 ,2,3,4-tetτahydropyrido[2,3-b]pyrazine;
4-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H- . pyridine- 1-carboxylic acid tert-butyl ester; l-(2,5-Dichlorobenzyl)-7-(l,2,3,6-tetrahydropyridin-4-yl)-lJ2,3,4-tetrahydropyrido[2,3- b]pyrazine; {4-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4- methylpiperazin- 1 -yl)methanone;
1 -(2,6-Dichlorobenzyl)-7-pyridin-3-yl-3 ,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one; l-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
4-[ 1 -(2,6-Dichlorobenzyl)-2-oxo- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester;
4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid;
5-l-(2,6-Dichlorobenzyl)-7-[4-((2-pyrrolidin-l-yl)methylpyrrolidine-l-carbonyl)phenyl]-3,4- dihydro- 1 H-pyrido [2,3-b]pyrazin-2-one;
4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2-pyrrolidin- l-yl-ethyl)benzamide;
4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(6- dimethylaminohexyl)benzamide;
4-[l-(2,6-Dichlorobeπzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(4- dimethylaminobutyl)benzamide; 7-[4-(4-Methylpiperazine-l-carbonyl)phenyl]-l-[l-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-
1 H-pyrido [2,3-b]pyrazin-2-one;
S- {2-[(pyrrolidin- 1 -yl)methyl]pyrrolidiπ- 1 -yl} -(4- { 1 -[ 1 -(2,4,5-trifluorophenyl)ethyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyraziπ-7-yl}phenyl)methanone;
(4-Methylpiperaziπ- 1 -yl)-(4- { 1 -[ 1 -(2,4,5-trifluorophenyl)ethyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)methanone;
5-(4- { l-[ 1 -(2,5-Difluorophenyl)ethyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-
{2- [(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl } methanone; 1 -[ 1 -(2,5-Difluorophenyl)ethyl]-7-[4-(4-methylpiperazine- 1 -carbonyl)phenyl]-3,4-dihydro- 1 H- pyrido[2,3-b]pyrazin-2-one;
-?-(4-{l-[l-(2,5-Difluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)-
{2-[(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl} methanone; l-(2,5-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-3,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one;
5-l-(2,5-Dichlorobenzyl)-7-[4-(2-[(pyτrolidin-l-yl)raethyl]pyrrolidine-l-carbonyl)phenyl]-3,4- dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
S- {4-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} - {2- [(pyirolidin- l-yl)methyl]pyrrolidin-l -yl}methanone;
{4-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl>-(4-
(pyrrolidin-l-yl)piperidin-l-yl)methanone; l-(2,6-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-3,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one; {4-[l-(2,6-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-
(pyiτolidin-l-yl)piperidin-l-yl)methanone;
{4-[ 1 -(2,6-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}- {2-
[(pyrrolidin-l-yl)methyl]pyrrolidin-l-yl}methanone;
7-(6-Chloropyridin-3-yl)- 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-Dichlorobenzyl)-7-(6-pyrrolidin-l-yl-pyridin-3-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine;
7-(2-Chloropyridin-4-yl)-l-(2,6-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
{3-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl} carbamic acid tert-butyl ester; 3-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine;
{3-[l-(2,6-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamic acid tert-butyl ester;
3-[l-(2,6-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine;
N-{3-[l-(2,6-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyraziπ-7-yl]prop-2-ynyl}-2- dimethylamino-acetamide;
{3-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl} - dimethylamine; l-(2,5-Dichlorobenzyl)-7-[3-(l,l-dioxo-lλ6-thiomorpholin-4-yl)prop-l-ynyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
1 -[l-(2-Chloro-3,6-difluorophenyl)ethyl]-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2,5-Dichlorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-(2-pyrrolidin-l-yl-pyridin-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
5-[l-(2-Chloro-3,6-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2- ylamine; l-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpipera2in-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
1 -(2-Chloro-3,6-difluorobenzyl)-7-(2-moφholin-4-yl-pyridin-4-yl)- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazine; l-(2,5-Dichlorobenzyl)-4-methyl-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyτazine;
1 -(2-Chloro-3,6-difluorobenzyl)-7-(3-moφholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazine;
1 -(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin- 1 -yl)pyridin-4-yl] - 1 ,2,3 ,4- tetrahydropyrido [2 ,3-b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-[l-(3-methylbutyl)-lH-pyrazol-4-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-3,6-difluorobenzyl)-7-(lH-pyrazol-4-yl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyra2in-7- yl}benzoic acid ethyl ester; 3-{ 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid ethyl ester;
4- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljbenzoic acid; 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid;
(2- {4-[ 1 -(2-Chloro-3,6-difluorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyrazol-
1 -yl} ethyl)dimethylamine; l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-l-yl-pyridin-4-yI)-l,2,3)4-tetrahydro- pyrido[2,3-b]ρyrazine; l-[4_(4-{l-[5-Chloro-2-(tri£luoromethyl)benzyl]-l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7- yl}pyridin-2-yl)piperazin- 1 -yljethanone; l-[5-Chloro-2-(tri£luoromethyl)benzyl]-7-(lH-pyrazol-4-yl)-l,2,3,4-tetrahydro-pyrido[2,3- b]pyrazine; l-[5-Chloro-2-(tri£luoromethyl)benzyl]-7-(l-triisopropylsilanyl-lH-py-τol-3-yl)-l,2>3,4- tetrahydropyrido [2,3 -b]pyrazine; l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(lH-pyrrol-3-yl)-l,2,3,4-tetrahydro-pyrido[2,3- b]pyrazine; l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(l-methyl-lH-pyrazol-4-yl)-l,2,3,4- tetrahydropyrido [2,3-b]pyrazine;
{ 1 -[(5-Chloro-2-trifluoromethyl)benzyl]-l ,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7- yl } piperidin- 1 -yl-methanone ;
{l-[(5-Chloro-2-trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-(4- methoxy-piperidin- 1 -yl)methanone;
[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperazm- 1 - yl)-methanone;
[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-pyrimidin-2-yl- piperazin- 1 -yl)-methanone; [4-(4-Chlorophenyl)-4-hydroxypiperidin-l -yl]-[l -(2,5-dichlorobenzyl)-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;
1 - { 1 -[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperidin-4- yl } - 1 ,3-dihydrobenzoimidazol-2-one;
[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2- methoxyphenyl)piperazin- 1 -yl]methanone;
[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- {4-[3-
(trifluoromethyl)phenyl]piperazin-l-yl}methanone; [ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-phenylpiperidin- 1 - yl)methanone;
[l-(2,5-Dichlorobenzyl)-l,2:i3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(3J4-dichlorophenyl)- piperazin- 1 -yljmethanone; (4-Benzhydrylpiperazin- 1 -yl)-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b jpyrazin-
7-yl]methanone;
(4-Benzylpiperidin- 1 -yl)-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]methanone;
8-[l-(2,5-Dichlorobenzyl)-l^,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]-l-phenyl- 1 ,3,8-triaza-spiro [4.5]decan-4-one;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-thieno[3,2- d]pyrimidin-4-yl-piperazin- 1 -yl)methanone ;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4- methoxyberazyl)piperazin-l-yl]rnethanone; (4-Benzoylpiperazin- 1 -yl)-[l -(2,5-dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido [2,3-b]pyrazin-7- yl]methanone;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-furo[3,2-c]pyridin-4- yl-piperazin-1 -yl)methanone;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(6- fluorobenzo[d]isoxazol-3-yl)piperidin-l-yl]methanone;
[4-(3-Chlorophenyl)piperazin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]methanone;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2-pyridin-
2-yl-ethyl)amide; 4- {[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]amino}piperidine-l-carboxylic acid ethyl ester; l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (l-benzyl- piperidin-4-yl)amide;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2,2- diphenylethyl)amide;
1 - {4-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin- 1 - yl}ethanone; l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 3- chlorobenzylamide;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]
-[4-(2-pyridin-2-yl-ethyl)piperazin- 1 -yl]methanone; l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4-
(trifluoromethoxy)benzylamide;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-morpholin-4-yl- piperidin- 1 -yl)methanone; l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2-thiophen- 2-yl-ethyl)amide; l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid benzhydrylamide;
1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (pyridin-4- ylmethyl)amide; 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (pyridin-3- ylmethyl)amide;
2- {4-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]piperazin- 1 - yl} -N-isopropylacetamide;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-methylquinolin-4- yl)piperazin- 1 -yl]methanone;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-((S)-2-pyrrolidin-l- ylmethyl-pyrrolidin- 1 -yl)methanone;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 3,5-bis-
(trifluoromethyl)benzylamide; 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [2-(4- sulfamoylphenyl)ethyl]amide;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2,3,5,6-tetrahydro-
[ 1 ,2']bipyrazinyl-4-yl)methanone;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2- phenylthiazol-4-yl-methyl)amide;
[l-(2J5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]morpholin-4-yl- methanone; 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2 ,3-b]pyrazine-7-carboxylic acid
(naphthalen- 1 -yl-methyl)amide;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid indan-1 - ylamide; l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid benzylamide;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4- methoxyphenyl)piperazin-l-yl]methanone; l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (biphenyl-4- ylmethyl)amide;
[4-(4-Chlorophenyl)piperazin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]methanone; 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2- phenoxyethyl)amide;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(tetrahydrofuran-2- carbonyl)piperazin- 1 -yl]methanone;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid phenethyl- amide; l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid
(tetrahydrofuran-2-yl-methyl)amide;
[4-(4-Chlorobenzyl)piperazin-l-yl]-[ 1 -(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3- b3pyrazin-7-yl]methanone; 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-caτboxylic acid 2-chloro- benzylamide;
[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2-
(trifluoromethyl)phenyl)piperazin- 1 -yl]methanone;
1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4- methoxybenzylamide; l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid indan-2- ylamide; [l-(2,5-Dichloroben2yl)-l,2,3,4-tetrahydropyrido[2>3-b]pyrazin-7-yl]-(4-phenethyl-piperazin-
1 -yl)methanone;
[4-(2-Chlorophenyl)piperazin-l -yl]-[ 1 -(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]methanone; [(4-Cyclohexylmethyl)piperazin- 1 -yl]-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]methanone; l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4- sulfamoyl-benzylamide;
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2-pyridin-3-yl- pyrrolidin-l-yl)methanone;
{4-[5-(2,5-Dichlorophenoxy)-5,6,7>8-tetrahydro-[l,8]naphthyridin-3-yl]phenyl}-4-methyl- piperazin- 1 -yl)methanone;
4-(2-Chloro-3,6-difluorophenoxy)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydro-[l,8]naphthyridine; {4-[5-(3-Chlorophenoxy)-5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-3-yl]-phenyl} -A- methylpiperazin- 1 -yl)methanone;
{4-[5-(3,5-Dichlorophenoxy)-5,6,7)8-tetrahydro-[l,8]naphthyridin-3-yl]phenyl}-4- methylpiperazin- 1 -yl)methanone ;
(4-Methylpiperazin- 1 -yl)- {4-[5-(pyridine-3-yloxy)-5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-3- yl]phenyl}methanone;
1 -(4-Fluoro-2- {6-[4-(4-methylpiperazine-l-carbonyl)phenyl]-l ,2,3,4-tetrahydro-
[l.SJnaphthyridin^-yloxylpheny^ethanone;
4-(3-Chlorophenoxy)-6-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]-l,2,3,4-tetrahydro-
[ 1 ,8]naphthyridme; 4-(3-Chlorophenoxy)-6-(3-moφholin-4-yl-phenyl)-l,2,3,4-tetrahydro-[l,8]naphthyridine;
4-(3-Chlorophenoxy)-6-(4-morpholin-4-yl-phenyl)-l ,2,3,4-tetrahydro-[ 1 ,8]naphthyridine;
4-(3-Chlorophenoxy)-6-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3,4-tetrahydro-
[ 1 ,8]naphthyridine;
4-(2,5-Difluorobenzyl)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4-tetrahydro- [l,8]naphthyridine;
(4-{l-[5-Chloro-2-(tτifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-morpholin-4-yl-piperidin-l-yl)methanone; (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-thiazol-2-yl-piperazin-l-yl)methanone;
3,6-Difluoro-2-[7-(6-moφholin-4-yl-pyridin-3-yl)-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l- ylmethyl]benzonitrile; 7-(6-Moφholin-4-yl-pyridin-3-yl)- 1 -[5-(trifluoromethyl)furan-2-ylmethyl] - 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazine;
7-[2-(4-Methylpiperazin-l-yl)pyridin-4-yl]-l-[5-(trifluoromethyl)furan-2-ylmethyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [4-(dimethylamino)butyl] amide;
4-{l-[2-(Trifluoromethoxy)benzyl]-l,2,3)4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid ethyl ester;
4- { 1 -[2-(Trifluoromethoxy)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid;
4-[l-(2-Chloropyridin-3-ylmethyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester;
4-[ 1 -(2-Chloropyridin-3-ylmethyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid;
{4-[ 1 -(2-Chloropyridin-3-ylmethyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl } -(4- pyrrolidin- 1 -yl-piperidin- 1 -yl)methanone;
N-(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)acetamide;
(4-Pyrrolidin- 1 -yl-piperidin- 1 -yl)-(4- { 1 - [2-(trifluoromethoxy)benzyl] - 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-(4-phenylpiperazin- 1 -yl)methanone; (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-pyrimidin-2-ylpiperazin- 1 -yl)methanone;
[4-(4-Chlorophenyl)-piperazin-l-yl]-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
[4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl]-(3-{l-[5-Chloro-2-(tri£luoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} phenyl)methanone;
1 -[ 1 -(3- { 1 -[S-Chloro^-CtrifluoromethyObenzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoyl)piperidin-4-yl]-l,3-dihydrobenzoimidazol-2-one; (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyra2in-7- yl}phenyl)-[4-(2-methoxyphenyl)piperazin-l-yl]methanone;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)- {4-[3-(trifluoromethyl)phenyl]piperazin-l -yl}methanone; (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-phenylpiperidin-l-yl)tnethanone;
(3- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-[4-( 1 H-indol-3-yl)piperidin- 1 -yljmethanone;
(4-Benzhydrylpiperazin-l-yl)-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4-Benzylpiperidin-l-yl)-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)πiethanone;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-(3 ,4-dichlorophenyl)piperazin- 1 -yl]methanone; 8-(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoyl)- 1 -phenyl- 1 ,3 ,8-triaza-spiro[4.5]decan-4-one;
(3- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-l-yl}inethanone;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-ylpiperazin-l -yl)methanone;
[4-(4-Chlorobenzyl)piperazin-l-yl]-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l52,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-[4-(4-methoxybenzyl)piperazin- 1 -yljmethanone; (4-Benzoylpiperazin-l-yl)-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(3-{l-[5-Chloro-2-(trifluororaethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-(4-furo[3 ,2-c]pyridin-4-ylpiperazin- 1 -yl)methanone;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-l-yl]methanone;
4-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l>2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoylamino)piperidine-l-carboxylic acid ethyl ester; N-(l-Benzylpiperidin-4-yl)-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]benzamide;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N- (2,2-diphenylethyl)benzamide; 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(l - methylpiperidin-4-yl)benzamide;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-[4-(2-pyridin-2-yl-ethyl)pip erazin- 1 -yl]methanone;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-[4- (trifluoromethoxy)benzyl]benzamide;
N-[3,5-Bis(trifluoromethyl)benzyl]-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
N-Benzhydryl-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzamide; 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N- pyridin-4-ylmethylbenzamide;
3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N- pyridin-3 -ylmethylbenzamide;
2-[4-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoyl)piperazin-l-yl]-N-isopropylacetamide;
(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-[4-(2-methylquinolin-4-yl)piperazin- 1 -yl]methanone;
3- {1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-[2-
(4-sulfamoylphenyl)ethyl]benzamide; (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2>3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-yl)niethanone;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(2- phenylthiazol-4-ylmethyl)benzamide;
(3- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)morpholin-4-ylmethanone;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- naphthalen-1 -ylmethylbenzamide; 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- indan- 1 -ylbenzamide;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-[4-(3-methoxyphenyl)piperazin- 1 -yl]methanone; (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-[4-(4-methoxyphenyl)piperazin- 1 -yl]methanone;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- cyclohexylbenzamide;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(4- methanesulfonylbenzyl)benzamide;
N-(2-Chlorobenzyl)-3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzamide;
N-(4-Cmorobenzyl)-3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzamide; N-(3-Chlorobenzyl)-3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzamide;
(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin- 1 -yl] methanone;
3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N- (tetrahydrofuran-2-ylmethyl)benzamide;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3 J4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(3- methoxybenzyl)benzamide;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(4- methoxybenzyl)benzamide; 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(2- phenoxyethyl)benzamide;
N-Benzyl-3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-
7-yl}benzamide;
[4-(3-Chlorophenyl)piperazin-l-yl]-(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- indan-2-ylbenzamide; (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-phenethylpiperazin- 1 -yl)methanone;
[4-(2-Chlorophenyl)piperazin- 1 -yl]-(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone; N-Cl-Benzylpyrrolidin-S-y^-S-ll-tS-chloro^-CtrifluoromethyObenzyl]-!^^^- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzainide;
(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(cyclohexylmethyl)piperazin-l-yl]methanone;
3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4- sulfamoylbenzyl)benzamide;
(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-morpholin-4-ylpiperidin-l-yl)methanone;
(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido [2,3-b]pyrazin-7- yl } phenyl)-((S)-2-pyrrolidin- 1 -ylmethylpyrrolidin- 1 -yl)methanone; (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyra2in-7- yl}phenyl)-(2-pyridin-3-ylpyrrolidin-l-yl)methanone;
3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2- methoxybenzyl)-N-methylbenzamide;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-phenylpiperazin- 1 -yl)methanone ;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-pyrimidin-2-ylpiperazin- 1 -yl)methanone;
[4-(4-Chlorophenyl)piperazin-l-yl]-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone; [4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl]-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone; l-tl-C^fl-tS-Chloro^-CtrifluoromethyObenzylj-l^^^-tetrahydropyrido^^-blpyrazin-?- yl } benzoyl)piperidin-4-yl]- 1 ,3-dihydrobenzoimidazol-2-one;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(2-methoxyphenyl)piperazin-l-yl]methanone;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}methanone; (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-(4-phenylpiperidin- 1 -yl)methanone;
(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(lH-indol-3-yl)piperidin-l-yl]methanone; (4-Benzhydrylpiperazin-l-yl)-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4-Benzylpiperidin- 1 -yl)-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-l-yl]niethanone;
8-(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoyl)- 1 -phenyl- 1 ,3,8-triaza-spiro[4.5]decan-4-one;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-l-yl}methanone; (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-l-yl)methanone;
[4-(4-Chlorobenzyl)piperazin- 1 -yl]-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-(4-methoxybenzyl)piperazin- 1 -yl] methanone;
(4-Benzoylpiperazin- 1 -yl)-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-furo [3 ,2-c]pyridin-4-ylpiperazin- 1 -yl)methanone; (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-(6-fluorobenzo [d] isoxazol-3 -yl)-piperidin- 1 -yl]methanone;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(2- pyridin-2-yl-ethyl)benzamide;
4-(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoylamino)piperidine-l-carboxylic acid ethyl ester;
N-( 1 -Benzylpiperidin-4-yl)-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide; 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N- (2,2-diphenylethyl)benzamide;
1 -[4-(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoyl)piperazin-l-yl]ethanone; 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(l- methylpiperidin-4-yl)benzamide;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-l-yl]methanone;
4- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-[4- (trifluoromethoxy)benzyl]benzamide;
4- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-[4- (trifluoromethyl)benzyl]benzamide;
N-[3,5-Bis(trifluoromethyl)benzyl]-4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide; 4- { 1 -[5-Chloro-2-(tri£luoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(2- thiophen-2-yl-ethyl)benzamide;
N-Benzhydryl-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } benzamide;
4- { 1 -[S-Chloro^-CtrifluoromethyObenzylH ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- pyridin-4-ylmethylbenzaniide;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2 ,3-b]pyrazin-7-yl} -N- pyridin-3-ylmethylbenzainide;
2-[4-(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoyl)piperazin-l-yl]-N-isopropylacetamide; (4-{ 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyraziπ-7- yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin- 1 -yl]methanone;
4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2- methoxyethyl)benzamide;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-[2- (4-sulfamoylphenyl)ethyl]benzamide;
(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(2,3,5,6-tetrahydro[l,2']bipyrazinyl-4-yl)methanone; 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2J3-b]pyrazin-7-yl}-N-(2- phenylthiazol-4-ylmethyl)benzamide;
(4-{l-[5-Chloro-2<trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- y 1 } phenyl)moφholin-4-y lmethanone ; 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl> -N- naphthalen- 1 -ylmethylbenzamide;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- indan- 1 -ylbenzamide;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-[4-(4-methoxyphenyl)piperazin- 1 -yl]methanone;
N-(2-Chlorobenzyl)-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzamide;
N-(4-Chlorobenzyl)-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzamide; N-(3-Chloro-benzyl)-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzamide;
(4- { 1 -[5 -Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin- 1 -yl]methanone;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- phenethylbenzamide;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-
(tetrahydrofuran-2-ylmethyl)benzamide;
4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(3- methoxybenzyl)benzamide; 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4- methoxybenzyl)benzamide;
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N-(2- phenoxyethyl)benzamide;
N-Benzyl-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzamide;
[4-(3-Chlorophenyl)piperazin-l-yl]-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone; 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl} -N- indan-2-ylbenzamide;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-phenethylpiperazin- 1 -yl)methanone; N-Biphenyl-4-ylmethyl-4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
[4-(2-Chlorophenyl)piperazin- 1 -yl]-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetτahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
N-( 1 -Benzylpyrrolidin-3-yl)-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljpheny^-^-Ccyclohexylmethy^piperazin-l-yljmethanone;
4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(4- sulfamoylbenzyl)benzamide; (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-((S)-2-pyrrolidin- 1 -ylmethylpyrrolidin- 1 -yl)methanone;
(4-{l-[5-Chloro-2-(tri£luoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazϊn-7- yl}phenyl)-(2-pyridin-3-yl-pyrrolidin-l-yl)methanone;
4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-N-(2- methoxybenzyl)-N-methylbenzamide;
(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(l,3-dihydroisoindol-2-yl)methanone;
{4-[l-(5-Chloro-2-trifluoromethyl-benzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- phenyl} -(spiro[isobenzofuran- 1 (3H),4'-piperidine]- 1 -yl)methanone; and l-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyτidin-3-yl]-l,4-dihydro-2H- pyrido[2,3-b]pyrazin-3-one; or a pharmaceutically acceptable salt form thereof.
In one embodiment, the present invention provides a compound of Formula I(d) chosen from: l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -Benzyl-7-iodo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; (3,4-Dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl)phenylmethanone;
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone;
1 -(2,5-Difluorobenzyl)-7-iodo- 1 ,2,3 ,4-tetrahydropyrido [2,3-b]pyrazine; l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile; l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid;
7-Iodo-l-(2,4,5-trifluorobenzyl)-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
7-Iodo-l-(2,4,5-trifluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)methanone;
1 -(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one; l-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -(2-Chloro-3 ,6-difluorobenzyl)-7-iodo- 1 >2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl)-2-phenylethanone;
2-(2,5-Difluorophenyl)-l-(7-iodo-3s4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)ethanone; l-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-Difluorobenzenesulfonyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-Benzenesulfonyl-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2-Chlorobenzenesulfonyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile; l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid; l-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-2-ol; l-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; 7-Iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
7-Iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-[l-(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-[l-(2,5-Difluorophenyl)ethyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyraziπ-2-one; 1 -(2,5-Dichlorobenzyl)-7-iodo- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,6-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-[l-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-[l-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; 1 -(2,5-Dichlorobenzyl)-7-iodo-4-methyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; 6-Bromo-4-(3-chlorophenoxy)-l ,2,3,4-tetrahydro-[l ,8]naphthyridine; 4-(2,5-Difluorobenzyl)- 1 ,2,3,4-tetrahydro-[ 1 ,8]naphthyridine;
6-Bromo-4-(2,5-difluorobenzyl)-l ,2,3 ,4-tetrahydro-[ 1 ,8]naphthyridine; 7-Iodo-l-[5-(trifluoromethyl)furan-2-ylmethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; 7-Iodo-l-[5-(trifluoromethyl)furan-2-ylmethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; 7-Iodo-l-[2-(trifluoromethoxy)benzyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; 7-Iodo-l-[2-(trifluoromethoxy)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2-Chloropyridin-3-ylmethyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; and l-(2-Chloropyridin-3-ylmethyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; or a pharmaceutically acceptable salt form thereof.
The present invention provides pharmaceutically acceptable salts of compounds of Formula I. Pharmaceutically acceptable acid addition salts of basic compounds of Formula I include, but are not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, and phosphorus, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts thus include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of basic compounds of Formula I may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms can differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but it is expected that the salts are generally similar to their respective free bases for purposes of the present invention.
Pharmaceutically acceptable base addition salts of acidic compounds of Formula I are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N5N1- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane- 1,2-diamine), N-methylglucamine, and procaine; see, for example, Berge et al., supra., 1977.
The base addition salts of acidic compounds of Formula I may be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms can differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but it is expected that the salts are generally similar to their respective free acids for purposes of the present invention.
Some of the compounds in the present invention may exist as stereoisomers, including enantiomers, diastereomers, and geometric isomers. Geometric isomers include compounds of the present invention that have alkenyl groups, which may exist as entgegen or zusammen conformations, in which case all geometric forms thereof, both entgegen and zusammen, cis and trans, and mixtures thereof, are within the scope of the present invention. Some compounds of the present invention have cycloalkyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures thereof, are within the scope of the present invention. All of these forms, including (R), (S), epimers, diastereomers, cis, trans, syn, anti, (E), (Z), tautomers, and mixtures thereof, are contemplated in the compounds of the present inventio°n.
The compounds to be used in the present invention can exist in unsolvated crystalline forms as well as solvated crystalline forms, including hydrated crystalline forms. In general, the solvated forms, including hydrated forms, are similar to unsolvated forms and are intended to be encompassed within the scope of the present invention. III. Pharmaceutical Compositions
The present invention further provides pharmaceutical compositions comprising a compound of the present invention (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof), together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. Preferably, the pharmaceutical composition contains a therapeutically effective amount of a compound of the present invention. In certain embodiments, these compositions are useful in the treatment of an ALK- or c-Met-mediated disorder or condition. The compounds of the invention can also be combined in a pharmaceutical composition that also comprises compounds that are useful for the treatment of cancer or another ALK- or c- Met-mediated disorder.
A compound of the present invention can be formulated as a pharmaceutical composition in the form of a syrup, an elixir, a suspension, a powder, a granule, a tablet, a capsule, a lozenge, a troche, an aqueous solution, a cream, an ointment, a lotion, a gel, an emulsion, etc. Preferably, a compound of the present invention will cause a decrease in symptoms or a disease indicia associated with an ALK- or c-Met-mediated disorder as measured quantitatively or qualitatively.
For preparing a pharmaceutical composition from a compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component (i.e., compound of the present invention). In tablets, .the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets contain from 1% to 95% (w/w) of the active compound (i.e., compound of the present invention). In certain embodiments, the active compound ranges from 5% to 70% (w/w). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams and Wilkdns, 2000).
A compound of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
Formulations suitable for parenteral administration, such as, for example, by intravenous, intramuscular, intradermal, and subcutaneous routes, include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
The dose administered to a subject, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the subject over time. The dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular subject. In determining the effective amount of the compound to be administered in the treatment or prophylaxis of the disorder being treated, the physician can evaluate factors such as the circulating plasma levels of the compound, compound toxicities, and/or the progression of the disease, etc. In general, the dose equivalent of a compound is from about 1 μg/kg to 10 mg/kg for a typical subject. Many different administration methods are known to those of skill in the art.
For administration, compounds of the present invention can be administered at a rate determined by factors that can include, but are not limited to, the LD5O of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the compound at various concentrations, as applied to the mass and overall health of the subject. Administration can be accomplished via single or divided doses. IV. Methods of Treatment
In another aspect, the present invention provides a use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ALK- or c-Met-mediated disorder or condition. Preferably, the compound of Formula I or a pharmaceutically acceptable salt form thereof is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In certain embodiments, the ALK- or c-Met-mediated condition or disorder is cancer. In certain embodiments, the ALK- or c-Met-mediated condition is selected from anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, glioblastoma, and other solid tumors. In certain embodiments, the ALK- or c-Met-mediated condition is selected from colon cancer, breast cancer, renal cancer, lung cancer, hemangioma, squamous cell myeloid leukemia, melanoma, glioblastoma, and astrocytoma. The ALK- or c-Met-mediated disorder or condition can be treated prophylactically, acutely, and chronically using compounds of the present invention, depending on the nature of the disorder or condition. Typically, the host or subject in each of these methods is human, although other mammals can also benefit from the administration of a compound of the present invention. In therapeutic applications, the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. Ih certain embodiments, the compounds of the present invention are delivered orally. The compounds can also be delivered rectally, bucally or by insufflation.
The compounds utilized in the pharmaceutical method of the invention can be administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. In certain embodiments, the daily dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. V. Chemistry All reagents and solvents were obtained from commercial sources and used as received. 1H NMRs were obtained on a Bruker Avance at 400 MHz in the solvent indicated with tetramethylsilane as an internal standard. Analytical HPLC was run using a Zorbax RX-C8, 5 x 150 mm column eluting with a mixture of acetonitrile and water containing 0.1% trifluoroacetic acid with a gradient of 10- 100%. LCMS results were obtained on either of two instruments. First, in Examples that indicate LCMS retention times, analysis was performed on a Waters Aquity Ultra Performance LC with a 2.1 mm x 50 mm Waters Aquity UPLC BEH Cl 8 1.7 μm column. The target column temperature was 45°C, with a run time of two (2) minutes, a flow rate of 0.600 mL/min, and a solvent mixture of 5% (0.1% formic acid/water):95% (acetonitrile/0.1% formic acid). The mass spectrometry data was acquired on a Micromass LC-ZQ 2000 quadrupole mass spectrometer. Second, in Examples that do not indicate LCMS retention times, analysis was performed on a Bruker Esquire 200 ion trap. Automated column chromatography was performed on a CombiFlash Companion (ISCO, Inc.). Melting points were taken on a Mel-Temp apparatus and are uncorrected. The overall synthesis for compounds of Formula I in which A is nitrogen (i.e., compounds of Formula I(a)) is generically set forth in Scheme 1.
Scheme 1. Overall Synthesis: A = Nitrogen
Figure imgf000055_0001
I(a) H G
In Step 1, 2-amino-5-iodo-3-nitropyridine (A) is converted into its corresponding diazonium salt (NaNO2ZHCl) in the presence of cuprous chloride to form 2-chloro-5-iodo-3- nitropyridine (B). This process is described in Carroll, F.I. et al., J. Med. Chem., 2002, 45, 4755-4761, which is incorporated herein by reference in its entirety. 2-amino-5-iodo-3- nitropyridine is commercially available from Sigma-Aldrich Corp. (St. Louis, MO). 2-amino- 5-iodo-3-nitropyridine may be prepared by reacting 2-amino-3-mtropyridine with iodine and hydroiodic acid (See Carroll et al.).
In Step 2, the 2-chloropyridine B obtained in Step 1 is reacted with an alpha-amino ester C containing suitable R4 and R5 groups to form the 2-aminopyridine D. An R6 group may be introduced in this step (e.g., R6 = H, Ci-β-alkyl) or in a subsequent step.
In Step 3, compound D is reduced (SnCl2) and cyclized to form compound E, which contains the bicyclic pyrido[2,3-->]pyrazinone core.
In Step 4, an R1 -L1 group is introduced at the amido nitrogen of compound E by displacement of the leaving group (LG) from compound F. The product is compound G. Alkylation and acylation reactions useful in Step 4 are described in General Procedures 1 and 2 (below). Examples 121, 123, and 124 describe suitable sulfonylation reactions for preparing compound G in which compound F (R'-L'-LG) is R1-Co-3-alkyl-S(=0)2-Cl. For compounds in which R1 is aryl or heteroaryl, and L1 is a bond, a Buchwald-Hartwig coupling may be used to prepare compound G. In Step 5, the carbonyl group of compound G is optionally reduced. A reduction reaction useful in Step (5) is described in General Procedure 3 (below). hi Step 6, an X group is introduced. Transition metal mediated coupling reactions useful in Step 6 are described in General Procedures 4-6 (below). Reactions useful for modifying the introduced X side chain are described in General Procedures 7-10 (below). Compounds of Formula I in which X is -Ci-3-C(=O)-C0-3-alkyl-G1L3G2L4R7 (i.e., L2 = -Ci-3- C(=0)-Co-3-alkyl— ) can be synthesized by reacting compound H with the appropriately substituted ketone and strong base. Compounds of Formula I in which X is -S(=0)n-Co-3- 8IkVl-G1L3G2L4R7 (i.e., L2 = -S(=0)n-Co-3-alkyl-) or -S(=O)2NR30-C0-3-alkyl-G1 L3G2L4R7 (i.e., L2 = -S(=O) 2NR30-Co-3-alkyl-) can be synthesized by reacting compound H with an appropriately substituted sulfinic acid. Alternatively, compounds of Formula I in which X is - S(=0)n-Co-3-alkyl-G1L3G2L4R7 or -S(=0)2NR30-Co-3-alkyl-G 1L3G2L4R7 can be synthesized by introducing a sulfonyl moiety at the outset of the synthesis, as shown in Scheme 2, optionally followed by reduction of the sulfonyl moiety to form the corresponding sulfoxide or sulfide. Scheme 2. Alternative Synthesis of L2 = -S(=O)n-C0-3-alkyl- or -S(=0)nNR30-Co.3-alkyl-
Figure imgf000057_0001
General Procedure 1 — Alkylation
Figure imgf000057_0002
E G
Compound E is suspended in anhydrous N,N-dimethylforrnamide. NaH (1 eq) is added, forming a solution. A suitable R1 -L1 -LG compound (1 eq) is added and the resulting reaction stirred at room temperature for 1-4 hours. The resulting product (G) is purified by silica gel chromatography. Alkylation selectivity is determined by 1H NMR Nuclear Overhauser Effect (NOE) analysis.
Suitable R1 -L1 -LG compounds for use in this reaction include, but are not limited to, RI-Co-3-alkyl-C(=0)-Ci-3-alkyl-Br, R1-C0-3-alkyl-S(=O)n-C1-3-alkyl-Br, R'-Co-a-alkyl-
C(K))NR10-C1-3-alkyl-Br, R1-Q-3-alkyl-S(=<))2NR10C1-3-alkyl-Br, R1-Co-3-alkyl-C(=0)0-Ci.3- alkyl-Br, R1-Ci-3-alkyl-OC(=O)NRI0-Ci-3-alkyl-Br, R^Qo-alkyl-NR^-C^-alkyl-Br, R'-QHJ- alkyl-O-Ci-3-alkyl-Br, R'-C^-alkyl-Br, Cs-io-cycloalkyl-Br, heterocycloalkyl-Br, and heteroaryl-Br. General Procedure 2 — Acylation
Figure imgf000057_0003
Compound E is dissolved in anhydrous tetrahydrofuran. Pyridine (1.0 eq) is added, and the solution is cooled to O 0C. A suitable R'-L'-LG compound (1.0 eq) is added dropwise, forming a white precipitate. The reaction is stirred at O0C for 15 minutes, allowed to warm to room temperature, and stirred at room temperature for 2-16 hours. The reaction is diluted with ethyl acetate, washed with NaHCC>3, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography to provide compound G.
Suitable R1 -L1 -LG compounds for use in this reaction include, but are not limited to, the following R1 -L1 -LG compounds: R1-C0-3-alkyl-C(=O)-Cl, R1-C0-3-alkyl-S(=O)2-Cl, R'-Q,- 3-alkyl-OC(=O)-Cl, R1-C0-3-alkyl-NR10-C(=O)-Cl, and R1-C0-3-alkyl-NR10-S(=O)2-Cl. General Procedure 3 — Reduction
Figure imgf000058_0001
Compound G is suspended in anhydrous CH2Cl2 and cooled to 00C. DIBAL (8.0 eq) is added and the resulting solution is allowed to warm to room temperature over 16 hours. The reaction mixture is quenched with methanol and a saturated solution of potassium sodium tartrate is added. The resulting mixture is stirred at room temperature until the phases separated (about two (2) hours). The organic phase is isolated, dried over MgSO4, filtered, and concentrated. The product (H; R2 ^R3 = H) is purified via silica gel chromatography. General Procedure 4 — Suzuki Coupling
Figure imgf000058_0002
H I(a)
A. The iodo starting material (H), a suitable boronic acid (R = H) or boronate ester (R = alkyl) (1.2-2.0 eq), Pd(PPh3)4 (0.02-0.05 eq), and 2 M Na2CO3 (2.5 eq) are combined in a mixture of toluene/ethanol (6:1, v/v). The reaction mixture is heated to 80°C for 1-16 hours. The reaction mixture is then diluted with CH2Cl2, dried over MgSO4, filtered, and concentrated. The product (I(a)) is then purified via silica gel chromatography; or
B. The iodo starting material (H), a suitable boronic acid or boronate ester (1.5 eq-2.0 eq), and PdCl2(PPh3)2 (0.1 eq) are dissolved in tetrahydrofuran (6 mL). Potassium carbonate powder (5.0 eq.) is dissolved in water (6 mL) in a separate flask. The potassium carbonate solution is added to the boronic acid solution, and the resulting mixture is purged with nitrogen and stirred at 700C for one (1) hour. The reaction mixture is concentrated, and methylene chloride and water are added. The organic phase is isolated, washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated. The product of Formula I(a) is then purified by normal phase column chromatography.
Suitable boronic acids or boronate esters include, but are not limited to, those in which the X group of the X-B(OR)2 reagent is linked to the boron atom of the X-B(OR)2 reagent via an alkyl, aryl, heteroaryl, or alkenyl C-B bond.
Alternative reaction conditions include, but are not limited to, the following: (a) Reaction of a heteroaryl boronic acid with compound H in dioxane/water (2: 1 ) at
1000C for 18 hours in the presence of Pd2(dibenzylideneacetone)3 (1 mol-%), P(cyclohexyl)3 (2.4 mol-%) and K3PO4 (1.7 eq). (See Kudo, N. et al., Angew. Chem. Int. Ed., 2006, 45, 1282-1284); and
(b) Reaction of a vinyl or alkenyl boronic acid with compound H in tert-amyl alcohol at room temperature for 24 hours in the presence of Pd(acetate)2 (5 mol-%),
P(tert-butyl)2CH3 or [HP(tert-butyl)2CH3]BF4 (0.1 eq) and KOtert-butyl (3 eq). (See Kirchhoff, J.H. et al., J. Am. Chem. Soc, 2002, 124, 13662-13663). General Procedure 5 - Sonogashira Coupling
Figure imgf000059_0001
H The iodo starting material (H), a suitable terminal alkyne (20 mg), tetrakis(triphenylphosphine) palladium (0.045 eq.), copper (I) iodide (9 mg), triethylamine (0.5 mL) and anhydrous tetrahydrofuran (1 mL) are combined in a Schlenk flask. The solution is purged with nitrogen, evacuated, stirred under nitrogen for 16 hours. The reaction mixture is concentrated, diluted with CH2Cl2, washed with H2O, dried with magnesium sulfate, filtered and concentrated. The product is then purified by normal phase column chromatography.
The product may be converted to the corresponding alkenyl and alkyl compounds of Formula I(a) by reduction of the triple bond (e.g., catalytic hydrogenation or Na/NH3). General Procedure 6 — Rosenmund-von Braun Coupling
Figure imgf000060_0001
The iodo starting material H is dissolved in anhydrous N,N-dimethylformamide. CuCN (2.0 eq) is added and the reaction mixture is heated to 1200C in a microwave oven for 15 minutes. The reaction mixture is concentrated, diluted with CH2CI2, and washed with H2O/NH4OH (10:1, v/v) to remove copper. The mixture is then filtered. The organic phase is dried over MgSC>4, filtered, and concentrated. The product is purified by silica gel chromatography.
As shown in Scheme 3, the -CN group of the product is a useful building block, which can be converted by standard chemical processes into a variety of linker groups (L2). Examples include, but are not limited to, -C(=O)-C0-3-alkyl-, -C(=0)NRIO-Co-3-alkyl- -
C(=O)O-C0-3-alkyl-, -CH2-OC(=0)NR10-Co-3alkyl- -CH2-NR10C(=0)0-Co-3-alkyl-, -CH2- NRlo-Co-3-alkyl- -CHz-O-Coo-alkyl-, -CH2-OC(=O)-C0.3alkyl- -CH2-NR10C(=O)-C0-3- alkyl-, and -CH2-NR10S(=0)2-Co-3-alkyl-. (See Fleming, F.F. et al., Tetrahedron, 2005, 61, 747). Scheme 3. Transformation of Cyano Group
Figure imgf000061_0001
Y = -Co_3-alkyl-G1L3G2L4R7
Conditions: a) basic hydrolysis (aqueous OH"1 heat), b) NaBH4, c) alkylation (Y-Br, base), d) DIBAL reduction, e) reductive amination (NaCNBH3, amine), f) reaction with Y-N=C=O, g) carbamate formation (YOC(=O)CI or YOC(=O)OC(=O)Y, base) h) ester formation (acid, Y-OH)1 i) amide coupling (e.g. EDCI, HOBT, TEA, DMF, Y-NHR10), j) Grignard reaction (Y-MgBr, CuI). General Procedure 7 - Saponification
Figure imgf000061_0002
A suitable aryl ester starting material is heated with LiOH Η2O (5 eq) in a mixture of tetrahydrofuran and H2O (1:1, v/v) at 700C for 2 to 16 hours. The resulting solution is concentrated and neutralized with 1 N HCl. The resulting precipitate is filtered to obtain the product aryl carboxylic acid. General Procedure 8 — Amidation
Figure imgf000062_0001
A suitable aryl carboxylic acid starting material is combined with N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.0 eq), 1-hydroxybenzotriazole (1.7 eq), and triethylamine (1.4 eq) in anhydrous N,N-dimethylformamide. The resulting mixture is stirred at room temperature for 30 minutes, a suitable amine is added, and the mixture is stirred for 3-16 hours. The reaction mixture is then concentrated, diluted with CH2Cl2, washed with H2O, and dried over MgSO4. The product amide is purified via silica gel chromatography or reversed-phase preparative HPLC.
The amidation reaction of General Procedure 8 may also be used to prepare amide boronates for use in the Suzuki coupling reaction (General Procedure 4). For example, Scheme 4 shows the amidation of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid, which is commercially available from Sigma- Aldrich Corp. (St. Louis, MO), by reaction with 4-(pyrrolidin-l-yl)piperidine using the reaction conditions of General Procedure 8.
Scheme 4. Synthesis of Amide Boronates
Figure imgf000062_0002
General Procedure 9 - Hydrolysis
Figure imgf000062_0003
A suitable cyano starting material is suspended in a mixture of NaOH (10 N), H2O, and ethanol (1 :1 :1, v/v/v) and heated to 800C for 16 hours. The reaction mixture is diluted with H2O and neutralized with HCl. The resulting carboxylic is isolated (e.g., by filtration). General Procedure 10 - Amidation
Figure imgf000063_0001
To a mixture of a suitable carboxylic acid starting material (1.3 eq) in anhydrous dimethylacetamide (DMA, 0.3 mL) is added polystyrene-supported dicyclohexylcarbodiimide (DCC, 6.0 eq) followed by a solution of N-hydroxybenzotriazole in DMA (300 mM, 1.5 eq). The reaction mixture is thoroughly mixed and allowed to stand at room temperature for 15 minutes. The reaction mixture is then treated with a 0.10 M solution of a suitable amine (1.0 eq) and heated with 250 W microwave pulses to 600C. The reaction mixture is then cooled to room temperature and treated with resin bound macroporous carbonate (acid scavenger) overnight. The reaction mixture is filtered, the solid is washed twice with DMA (200 μL) followed by acetonitrile (200 μL). The combined washes are evaporated under reduced pressure to afford the amide product. General Procedure 11 — Sulfonamide Boronate Synthesis
amine
Figure imgf000063_0002
Figure imgf000063_0003
4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenylamine (J) is dissolved in CH2Cl2 and N-methyl morpholine (3 eq) is added. The reaction mixture is cooled to 00C and 2- chloroethanesulfonyl chloride (1.1 eq) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for four (4) hours. The reaction mixture is then concentrated, diluted with ethyl acetate, washed with brine, dried over MgSO4, concentrated, and purified through silica gel chromatography. The resulting ethenesulfonic acid [4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl] amide (K) is dissolved in methanol and a suitable amine (2.5 eq) is added in methanol. The reaction mixture is stirred at room temperature for four (4) hours. Isocyanate resin is added to each vial to consume excess amine. After stirring overnight, the resin is filtered and the reaction solution concentrated to afford the desired sulfonamide boronate (L). The overall scheme used to prepare compounds of Formula I in which A is carbon (i.e., compounds of Formula I(b)) is generically set forth in Schemes 5-12.
Scheme 5. Overall Synthesis: A = Carbon
Figure imgf000064_0001
In Step 1, 2-amino-5-bromopyridine (M) is converted to 3-(6-bromo-pyridin-2- ylamino)propionic acid (O) by reaction with ethyl acrylate (N). This process is described in Settimo, D.A. et al., Il Farmaco - Ed. Sc, 1978, 33(10), 770-80, which is incorporated herein by reference in its entirety. 2-amino-5-bromopyridine is commercially available from Sigma- Aldrich Corp. (St. Louis, MO). In Step 2, the aryl carboxylic acid O is treated with Eaton's reagent to afford 7-bromo-
2,3-dihydro- 1 H-[ 1 ,8]naphthyridin-4-one (P).
In Step 3, compound P is reduced (NaBHU), debrominated (n-BuLi), and rebrominated (N-bromosuccinimide) to form compound Q. Optionally, the carbonyl group of compound P can be converted to an enolate and then substituted with R2ZR3 groups prior to the reduction reaction. Optionally, compound P can be transformed into the corresponding α,/3-unsaturated ketone (e.g., by conversion to an α-selenoxide or α-sulfoxide intermediate followed by elimination) and then substituted at the β- position with R4ZR5 groups (e.g., via a Michael addition reaction) prior to the reduction reaction. Optionally, an R6 group can be introduced (e.g., by N-alkylation) prior to the reduction reaction. Compound Q may be converted to a compound of Formula I(b) by steps 4 and 5 or 41 and 51. In Step 4, compound Q is converted to compound R by introduction of an R'-L1 group.
The conversion may be accomplished by a variety of methods known to those of ordinary skill in the art. For example, the benzylic hydroxyl group of compound Q may be activated by conversion to the corresponding tosylate, mesylate, triflate, or halide intermediate and then displaced with a nucleophilic R1 -L1 group or a nucleophilic derivative of a R1 -L1 group, such as an organolithium or organometallic derivative (e.g., Grignard, lithium, lithium dialkylcopper, aluminum, or boron derivatives) (See March, J., "Advanced Organic Chemistry," 3d ed., John Wiley & Sons, Inc., 1985, pp. 400-404, 407; Luh, T-Y et al., Chem. Rev., 2000, 100, 3187-3204) (See Scheme 6). A displacement reaction useful in Step 4 is described in General Procedure 12 (below). In addition, Step 4 may be performed by coupling the hydroxyl group of compound Q to a suitable carbonyl chloride reagent. Suitable carbonyl chloride reagents include, but are not limited to, Cl-C(=O)-C0-3-alkyl-R1 and Cl-C(=O)NR10-C0-3-alkyl-R1, which result in products of Formula R in which IΛR1 is -OC(=O)-C0-3-alkyl-R1 and -OC(=O)NR10-C0-3-alkyl-R1, respectively. In Step 5, compound R is converted to a compound of Formula I (A = carbon) by introduction of an X group. The conversion may be performed using a transition metal mediated coupling reaction (met = Pd, Cu, etc.). A coupling reaction useful in Step 4' is described in General Procedurel3 (below). The coupling reactions in General Procedures 4, 5, and 6 (above) are also useful for preparing the corresponding compounds of Formula IQo). Steps 4' and 51 are the same as Steps 5 and 4, respectively.
Scheme 6. Overall Synthesis: A = Carbon, R1L1 = Nucleophile
Figure imgf000065_0001
In the first step, compound Q is reacted with/7-toluenesulfonyl chloride (tosyl chloride) to form the activated tosylate XX. Other activating groups that can be used instead of tosylate include, but are not limited to, mesylate, triflate, and halide.
In the second step, compound XX is reacted with a suitable Grignard reagent (R1L1- MgBr) or another suitable organometallic reagent to form compound R. Suitable organometallic reagents include, but are not limited to, R'-L1— Li, R'-L1— MgBr, and (R1- L^2CuLi, wherein R^L1- is -Ci.3-alkyl-C(=O)-C0-3-alkyl-R1, -C1-3-alkyl-S(O)n-C0-3-alkyl- R1, -C1-3-alkyl-C(=0)NR10-Co-3-alkyl-R1, R1-C0-3-alkyl-C(=O)NR10-Ci.3-alkyl-, -C,-3-alkyl-
Figure imgf000066_0001
R1-Co-3-alkyl-S(=0)2NR10-Ci.3-alkyl-, -C1.3-alkyl-C(=0)0-Co-3- alkyl-R1, R1-C0.3-alkyl-C(-O)O-C,.3-alkyl-, -Ci-3-alkyl-OC(=0)NR10-Co-3-alkyl-R1, R'-QKJ- alkyl-OC(=O)NR10-Ci.3-alkyl-, -d^-alkyl-NR^-Co-s-alkyl-R1, -Cu-alkyl-O-Co-s-alkyl-R1, - Ci-6-alkyl-R1, -C2-6-alkenyl-R1, or-Ca-ό-alkynyl-R1.
Scheme 7. Overall Synthesis: A = Carbon, L1 = -CH2-
Figure imgf000066_0002
In Step 1, compound P (Scheme 5) is converted to compound T by means of a Takai reaction. Optionally, the carbonyl group of compound P can be converted to an enolate and then substituted with R2ZR3 groups prior to the Takai reaction. Optionally, compound P can be transformed into the corresponding ogS-unsaturated ketone (e.g., by conversion to an ct- selenoxide or ot-sulfoxide intermediate followed by elimination) and then substituted at the β- position with R4/Rs groups (e.g., via a Michael addition reaction) prior to the Takai reaction. Optionally, an R6 group can be introduced (e.g., by N-alkylation) prior to the Takai reaction.
In Step 2, compound T is converted to compound U via a transition metal catalyzed coupling reaction (e.g., a Suzuki reaction). In Step 3, compound U is hydrogenated and debrominated by hydrogenolysis to form compound V.
In Step 4, compound V is brominated to form compound W.
In Step 5, compound W is converted to compound I(e) via a transition metal catalyzed coupling reaction (See General Procedures 4-6 and 13).
Scheme 8. Overall Synthesis: A = Carbon, L1 = -NR^-CcM-alkyl-R1
Figure imgf000067_0001
Z = -C^-alkyl-R1 Step 3
Figure imgf000067_0002
In Step 1, compound P (Scheme 5) is converted to an imine or iminium of Formula AA by means of a condensation reaction with an amine of formula Z-NH-R10. Optionally, the carbonyl group of compound P can be converted to an α-enolate and then substituted at the Ct- position with R2/R3 groups prior to the condensation reaction. Optionally, compound P can be transformed into the corresponding α,/3-unsaturated ketone (e.g., by conversion to an α- selenoxide or α-sulfoxide intermediate followed by elimination) and then substituted at the β- position with R4ZR5 groups (e.g., via a Michael addition reaction) prior to the condensation reaction. Optionally, an R6 group can be introduced (e.g., by N-alkylation) prior to the condensation reaction.
In Step 2, compound AA is converted to compound BB by means of a reduction. Steps 1 and 2 maybe combined into a single step (i.e. a reductive amination).
In Step 3, compound BB is converted to compound CC by means of debromination/rebromination (e.g., as in Scheme 5, Step 3).
In addition, when Z = H the — NHR10 group of compound BB may be coupled to a suitable carbonyl or sulfonyl chloride reagent to form additional compounds of Formula CC. Suitable carbonyl or sulfonyl chloride reagents include, but are not limited to, R^-Coo-alkyl- C(O)-Cl, R1-Co-3-alkyl-S(=0)2-Cl, or R1-C0-3-alkyl-OC(=O)-Cl, which result in products of Formula CC in which iΛR1 is R1-C0-3-alkyl-C(=O)NR10- R1-Co-3-alkyl-S(=0)2NR10- or R1- C0-3-alkyl-OC(=O)NR10-, respectively.
In Step 4, compound CC is converted to compound I(f) (e.g., as in Scheme 5, Step 5). Alternatively, in Step 1 ', compound CC may be prepared from compound Q by activation of compound Q (e.g., by transformation to the corresponding benzylic halide, alkyl sulfonate or aryl sulfonate as in Scheme 5, Step 4) prior to treatment with an amine of formula Z-NH-R10.
Scheme 9. Overall Synthesis: A = Carbon, L1 = -Ci^-alkyl-CONR^-Co-a-alkyl-R1
Figure imgf000068_0001
Z = -C,,.3-alkyl-R1
In Step 1, compound P (Scheme 5) is converted to compound DD by means of a Homer-Emmons reaction. Optionally, R2, R3, R4, R5 and/or R6 groups may be introduced prior to the Horner-Emmons reaction as in Scheme 8.
In Step 2, compound DD is converted to compound EE by means of hydrogenation of the double bond and debromination by hydrogenolysis or metallation/protonation (Scheme 5, Step 3).
In Step 3, compound EE is brominated and hydrolyzed to form compound FF. Optionally, compound FF may be alkylated αto the carbonyl group prior to the coupling step with one or two methyl groups or an ethyl group (e.g., by treatment with base and then methyl bromide). In Step 4, compound FF is coupled with an amine of formula Z-NH-R10 to form compound GG.
In Step 5, compound GG is converted to compound I(g) (e.g., as in Scheme 5, Step 5). Scheme 10. Overall Synthesis: A = Carbon, L1 = -Ci-3-alkyl-C(=O)O-C0-3-alkyl-R1
Figure imgf000069_0001
Z = -C^-alkyl-R1
In Step 1, compound FF (Scheme 9) is esterified with Z-OH to form compound HH.
In Step 2, compound HH is converted to compound I(h) (e.g., as in Scheme 5, Step 5).
Optionally, compound FF or HH may be alkylated a to the carbonyl group prior to Steps 1 or 2 with one or two methyl groups or an ethyl group (e.g., by treatment with base and then methyl bromide).
Scheme 11. Overall Synthesis: A = Carbon, L1 = -S(=O)n-C0-3-alkyl-R1
Figure imgf000069_0002
Z = -C^-alkyl-R1
In Step 1, compound Q (Scheme 5) is activated by means of transformation to the benzylic halide, alkyl sulfonate or aryl sulfonate prior to treatment with a thiol of formula Z- SH to form compound JJ. Alternatively, activated compound Q may be treated with a sulfonic acid of formula Z-SO2H to form the sulfone analog of compound JJ.
In Step 2, the bromide group of compound JJ is converted to the X group of compound I(i) (e.g., as in Scheme 5, Step 5). Optionally, the sulfide group of compound JJ may be oxidized to the sulfoxide (n = 1) or sulfone (n = 2) before or after conversion of Br to X. Scheme 12. Overall Synthesis: A = Carbon, L1 = -Ci.3-alkyl-C(=O)-C0.3-alkyl-R1
Figure imgf000070_0001
Z = -C0_3-alky1-R1
In Step 1, compound EE (Scheme 9) is converted to compound KK by reaction with an organometallic reagent such as a Grignard or organolithium reagent (e.g., Z-MgBr or Z-Li).
In Step 2, compound KK is converted to compound I(j) (e.g., as in Scheme 5, Step 5).
Optionally, compound EE or KK may be alkylated a to the carbonyl group prior to Steps 1 or 2 with one or two methyl groups or an ethyl group (e.g., by treatment with base and then methyl bromide). General Procedure 12 — Mitsunobu Reaction
Figure imgf000070_0002
The starting benzyl alcohol (Q or S) (1 eq) is combined with a suitable nucleophile
(R L :) (1—3.0 eq) and triphenylphosphine (1—3.0 eq) in anhydrous tetrahydrofuran. Diisopropylazodicarboxylate (3.0 eq) is added and the reaction mixture stirred at room temperature for 15 minutes. The mixture is then concentrated under reduced pressure and purified by silica gel chromatography to afford the desired product (R or I(b)). General Procedure 13 — Suzuki Coupling
Figure imgf000070_0003
Q Y = OH S Y = OH R Y = ^1R1 I(b) Y = -L1R1
The starting bromide (Q or R) (1.0 eq) is combined with a suitable boronic acid or boronic ester (1.4 eq) and Pd(PPIvO4 (0.05 eq) in a mixture of toluene and ethanol (1-5:1, v/v).
Sodium carbonate Na2CO3 (2N, 4.0 eq) is added and the reaction mixture is heated at 80- 1000C for 0.5 to 24 hours. Two purification procedures may be followed. In the first procedure, the mixture is concentrated under reduced pressure, and the residue is taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel chromatography to afford the desired product (S or I(b)). In the second procedure, the crude reaction mixture is cooled, directly concentrated onto silica gel, and purified by silica gel chromatography to afford the desired product (S or I(b)). VI. Biology
ALK Kinase Assay Example compounds were tested for their ability to inhibit the kinase activity of baculovirus-expressed ALK using a modification of the ELISA protocol reported for trkA in Angeles, T. S. et al., Anal. Biochem. 1996, 236, 49-55, which is incorporated herein by reference in its entirety. Phosphorylation of the substrate, phospholipase C-gamma (PLC-γ) generated as a fusion protein with glutathione S-transferase (GST) as reported in Rotin, D. et al., EMBOJ. 1992, 11, 559-567, which is incorporated herein by reference in its entirety, was detected with a europium-labeled anti-phosphotyrosine antibody and measured by time- resolved fluorescence (TRF). Briefly, each 96-well plate was coated with 100 μL/well of 10 μg/mL substrate (phospholipase C-γ) in Tris-buffered saline (TBS). The assay mixture (total volume = 100 μL/well) consisting of 20 mM HEPES (pH 7.2), 1 μM ATP (Km level), 5 mM MnCl2, 0.1% BSA, 2.5% DMSO, and various concentrations of test compound was then added to the assay plate. The reaction was initiated by adding enzyme (30 ng/ml ALK) and was allowed to proceed at 37°C for 15 minutes. Detection of the phosphorylated product was performed by adding 100 μl/well of Eu-Nl labeled PT66 antibody (Perkin Elmer # AD0041). Incubation at 37°C then proceeded for one (1) hour, followed by addition of 100 μL enhancement solution (Wallac #1244-105). The plate was gently agitated and after thirty minutes, the fluorescence of the resulting solution was measured using the En Vision 2100 (or 2102) multilabel plate reader (Perkin Elmer).
Data analysis was performed using ActivityBase (IDBS, Guilford, UK). IC50 values were calculated by plotting percent inhibition versus logio of the concentration of compound and fitting to the nonlinear regression sigmoidal dose-response (variable slope) equation in XLFit (IDBS, Guilford, UK). c-Met Kinase Assay The kinase activity of c-Met was evaluated using the same methods as for ALK, with the following modifications: Plates were coated with 20 μg/mL phospholipase C-γ and the assay mixture consisted of 50 mM HEPES (pH 7.2), 50 mM NaCl, 3 μM ATP (Kn, level), 4 mM MnCl2, 0.01% TritonX-100, 0.02% BSA, 2.5% DMSO. Reactions were initiated with 30 ng/mL c-Met (cytoplasmic domain, Invitrogen Corporation #PV3143). ALK Cellular Assay
Immunoblotting of phospho-NPM-ALK and total NPM-ALK from cell lysates was carried out according to the protocols provided by the antibody suppliers. In brief, after treatment of Example compounds, cells were lysed in Frak lysis buffer [10 mM Tris, pH 7.5, 1% Triton X-100, 50 mM sodium chloride, 20 mM sodium fluoride, 2 mM sodium pyrophosphate, 0.1% BSA, plus freshly prepared 1 mM activated sodium vanadate, 1 mM dithiothreitol (#165680050, ARCOS Organics, Geel, Belgium), and 1 mM PMSF (#837091, Boehringer Mannheim Biochemicals, Indianapolis, IN), protease inhibitors cocktail III (#539134-1 Set, Calbiochem, 1:100 dilution)]. After brief sonication, the lysates were cleared by centrifugation, mixed with sample buffer and subjected to SDS-PAGE. Following transfer to membranes, the membranes were blotted with either rabbit phospho-NPM-ALK(Y664) (Cat* 3341) or ALK antibody (Cat* 3342) from Cell Signaling Technology (Beverly, MA), and then the HRP-conjugated goat anti-rabbit antibodies (Santa Cruz, CA) after washed in TBS/0.2% Tween-20. The protein bands were visualized with ECL Western Blotting detection reagents (RPN2106, Amersham Biosciences, Buckinghamshire, UK) and quantitated with gel- pro analyzer 3.1 software.
To measure ALK tyrosine phosphorylation in cells with an ELISA assay, fluoronunc plates (Cat* 437796, Nalge Nunc, Rochester, NY) were pre-coated with goat anti-mouse IgG, and incubated with the capture mouse ALK antibody (Cat* 35-4300, Zymed, Seattle, WA) diluted 1:1000 in Superblock (Pierce, Rockford, IL). Following blocking, cell lysates were added to plates and incubated overnight at 4°C. Plates were incubated with the detecting antibody, anti-phospho-ALK (Y664) (Cell Signaling Technology), diluted at 1 :2000, followed by incubation with goat anti-rabbit-IgG alkaline phosphatase to amplify the detection. Wells were exposed to the fluorogenic substrate 4 -MeUP (#3368-04-5, Calbiochem) and the signal quantified using a CytoFluor® (series 4000) Fluorescence Multi-Well Plate Reader (Applied Biosystems, Foster City, CA). c-Met Cellular Assay HT29 and GTL-16 cells were serum starved for one hour in media containing 0.05% BSA and varying concentrations of Example compounds (1-10 μM). A549 cells were serum starved overnight in media containing 0.05% BSA then treated for one hour with Example compounds followed by a 15 minute stimulation with 50 ng/mL HGF (Peprotech, Rocky Hill, NJ), respectively. Samples were resolved by electrophoresis on a 3-8% Tris-Acetate gel (40 ma/gel) and then transferred to a nitrocellulose membrane. Membranes were blocked for one hour at room temperature in Odyssey Blocking Buffer (Licor # 927-40000) diluted 1:1 with IX TBS. Membranes were then co-incubated overnight at 4°C with primary antibodies [total Met (Cell Signaling, #3127) and Phospho-Met (Biosource, #44-888G) 1:1000 each in Odyssey Blocking Buffer diluted 1:1 with IX TBS-T 0.05%]. The next day, membranes were washed and co-incubated with secondary antibodies [Goat anti mouse IRDye800 (Rockland, #610-132- 121) and Goat anti rabbit Alexa fluor 700 (Molecular Probes, #A21038) 1:10,000] in Odyssey Blocking Buffer diluted 1 : 1 with IX TBS-T 0.05% for one hour at room temperature protected from light. Blots were then washed then read on the Odyssey Infrared Imager. Total c-Met signal was visualized at 800nm detection and phospho-c-Met signal was visualized at 700nm detection.
Results
Biological data for the Example compounds is presented in the following Tables 1-3.
IC50 >100 μM -
ICso lOO μM - lO μM +
IC50 10 μM - 1 μM -H-
IC50 I μM - 0.1 μM 4-H-
IC50 < 0.1 μM I I I I
Not tested NT
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Preferably, the compounds of the present invention exhibit an IC50 in the ALK kinase assay of 100 μM - 10 μM. More preferably, the compounds of the present invention exhibit an IC50 in the ALK kinase assay of 10 μM - 1 μM. More preferably, the compounds of the present invention exhibit an IC50 in the ALK kinase assay of 1 μM — 0.1 μM. More preferably, the compounds of the present invention exhibit an IC50 in the ALK kinase assay of < 0.1 μM. Preferably, the compounds of the present invention exhibit an IC50 in the c-Met kinase assay of 100 μM - 10 μM. More preferably, the compounds of the present invention exhibit an IC50 in the c-Met kinase assay of 10 μM - 1 μM. More preferably, the compounds of the present invention exhibit an IC50 in the c-Met kinase assay of 1 μM — 0.1 μM. More preferably, the compounds of the present invention exhibit an IC50 in the c-Met kinase assay of < 0.1 μM.
Table 2. c-Met Cellular Activity / Autophosphorylation Assay*
Figure imgf000081_0001
Figure imgf000082_0001
*: Inhibition scores: 1, 0-25%; 2, 26-50%; 3, 51-75%; 4, 76-100%
Preferably, the compounds of the present invention exhibit an inhibition score in the c- Met Cellular Assay of 26-50%. More preferably, the compounds of the present invention exhibit an inhibition score in the c-Met Cellular Assay of 51-75%. More preferably, the compounds of the present invention exhibit an inhibition score in the c-Met Cellular Assay of 76-100%.
Table 3. ALK Cellular Activity
Figure imgf000082_0002
Figure imgf000083_0001
*: Inhibition scores: 1, 0-25%; 2, 26-50%; 3, 51-75%; 4, 76-100% **: IC50 >1000 nM
IC50 751 nM - 1000 nM +
IC50 501 nM - 750 nM ++
IC50 25 I nM - 50O nM
IC50 ≤250 nM
Preferably, the compounds of the present invention exhibit an inhibition score in the ALK Cellular Assay of 26-50%. More preferably, the compounds of the present invention exhibit an inhibition score in the ALK Cellular Assay of 51-75%. More preferably, the compounds of the present invention exhibit an inhibition score in the ALK Cellular Assay of 76-100%. EXAMPLES
Preparation 1. (S)-2-[(pyrrolidm-l-yl)methyl]pyiτolidme-l-carboxyl-[4-(4,4,5,5- tetramethyl[ 1 ,3,2]dioxaborolan-2-yl)phenyl]amide
Figure imgf000084_0001
X Y Z A solution of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenylamine (X) (15.12 g, 69 mmol) in CH2Cl2 (600 mL) was treated with pyridine (5.46 g, 69 mmol) and cooled in an ice bath. p-Nitrophenylchloroformate (14.0Og, 69.5 mmol) was added, the ice bath was removed, and the reaction was stirred overnight. The mixture was poured into a separatory funnel and successively washed with aqueous, saturated NaHCO3 solution (3X), H2O, aqueous, saturated CU2SO4, H2O, and brine. The organic phase was passed through a Buchner funnel containing Na2SO4, and the filtrate was evaporated to afford the carbamate product (Y) (24.84 g, 96% yield), which was used directly in the next step.
To a mixture of the carbamate (Y) (621 mg, 1.62 mmol) in dichloromethane (2 mL) was added triethylamine (227 μL, 1.63 mmol) and (S)-2-pyrrolidin-l-yl-methylpyrrolidine. After 1.5 hours, the reaction was extracted into ethyl acetate and washed with aqueous, saturated NaHCO3 solution (3X), H20, and brine. The organic phase was passed through a Buchner funnel containing MgSO4, and the filtrate was evaporated to afford a residue that was dissolved in CHCI3 and treated with macroporous-carbamate resin (to remove residual p- nitrophenol). After gentle agitation overnight, the mixture was filtered and the filtrate evaporated to give the title compound (Z).
Preparation 2. l-(l-Bromoethyl)-2,4,5-trifluorobenzene
Figure imgf000084_0002
Phosphorus tribromide (0.275 mL) and anhydrous methylene chloride (12 mL) were combined and the solution cooled over ice water for 15 minutes. The solution was added to a mixture of l-(2,4,5-trifluorophenyl)ethanol (0.506 g) and methylene chloride (8 mL), and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was then poured into H2O and extracted into methylene chloride. The organic phase was isolated, dried with magnesium sulfate, filtered and concentrated (without heat) to give the title compound. 1H-NMR (CD3OD, 400 MHz) δ 2.00 (3H, d, J= 7.1 Hz), 5.37 (IH, m), 6.92 (IH, m), 7.36 (IH, m). Preparation 3. 2-(l-Bromoethyl)-3-chloro-l,4-difluorobenzene
Figure imgf000085_0001
Phosphorus tribromide (1.3 mL) and anhydrous CH2CI2 (50 mL) were combined and then cooled over ice water for 20 minutes. The cooled solution was then added to a mixture of l-(2- chloro-3,6-difluorophenyl)ethanol (2.71 g) and methylene chloride (50 mL), and the resulting mixture was stirred at room temperature for two (2) hours. The mixture was then poured into H2O and extracted into CH2Cl2. The organic phase was isolated, dried with magnesium sulfate, filtered, and concentrated to give the title compound (78% yield). Example 1. (5-Iodo-3-nitro-pyridin-2-ylamino)-acetic acid ethyl ester
Figure imgf000085_0002
2-Chloro-5-iodo-3-m'tro-pyridine (13 g) was dissolved in ethanol. Glycine ethyl ester HCl was added (5.0 eq) followed by triethylamine (5.0 eq). The reaction mixture was heated to 8O0C for four (4) hours. The reaction mixture was concentrated to dryness and triturated with H2O to give the title compound as a white solid (82-94% yield). M.p. 2000C (dec), LCMS: m/z = 352.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.30 (t, J= 7.1 Hz, 3H), 4.25 (q, J= 7.1 Hz, 2H), 4.33 (d, J= 5.6 Hz, 2 H), 8.44 (bs, IH), 8.52 ( d, J= 2.0 Hz, IH), 8.69 ( d, J= 2.0 Hz, IH). Example 2. 7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000085_0003
(5-Iodo-3-nitro-pyridin-2-ylamino)-acetic acid ethyl ester (17 g) was dissolved in ethanol. SnCk 2H2O was added and the reaction mixture was heated to 800C for two (2) hours. The resulting precipitate was filtered and washed with ethanol to give the title compound as a rust colored solid (59-77% yield). M.p.81 0C, LCMS: m/z =275.91 (IVH-H+), 1H-NMR (DMSO-J6, 400 MHz) δ 3.94 (s, 2 H), 6.94 ( bs, IH), 7.12 ( d, J= 1.8 Hz, IH), 7.74 ( s, J= 1.8 Hz, IH), 10.40 (bs, IH).
Example 3. l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one
Figure imgf000086_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (300 mg) was reacted with 2-chloro-3,6- difluorobenzyl bromide as in General Procedure 1. The title compound was obtained as an off white solid (63% yield). M.p. 237 0C, LCMS: m/z = 436.17 (MH-H+), 1H-NMR (DMSO-J6, 400 MHz) δ 4.01 (s, 2H), 5.24 (s, 2H), 7.05 (d, J= 1.5 Hz, IH), 7.23-7.32 (m, IH), 7.41-7.48 (m, IH), 7.79 (d, J= 1.5 Hz, IH).
Example 4. l-(2-Chloro-3,6-difluorobenzyl)-7-pyridin-3-yl-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000086_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (21 mg)was reacted with pyridine 3-boronic acid as in General Procedure 4A, with the modification that the mixture was heated to 1300C in a microwave oven for 10 minutes. The reaction mixture was purified via reversed phase preparative HPLC to give the title compound as a pale yellow foam (48% yield). M.p.(foam), LCMS: m/z = 387.24(MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 4.53 (s, 2H), 5.51 (s, 2H), 7.13-7.19 (m, 2H), 7.34 (s, IH), 7.73 ( s, 2H), 7.98-8.02 (m, IH), 8.70-8.79 ( m, 2H), 10.9 (bs, IH). Example 5. 4-[ 1 -(2-Chloro-3,6-difluorobenzyl)-2 -oxo- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin- 7-yl]benzoic acid ethyl ester
Figure imgf000087_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (280 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A, with the modification that the mixture was heated to 1300C in a microwave oven for 5 minutes. The title compound was obtained as a white solid after silica gel chromatography (19% yield). M.p. 180-1820C, LCMS: m/z = 458.3701+H+), 1H-NMR (DMSCwZ6, 400 MHz) δ 1.34 (t, J= 7.1 Hz, 3H), 4.08 ( s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 5.39 (s, 2H), 7.18 ( bs, IH), 7.29-7.33 (m, IH), 7.39-7.47 (m, IH), 7.42 ( s, IH), 7.46 ( d, J=8.3 Hz, 2H), 7.66 (d, J= 8.3 Hz, 2H), 7.97 (s, IH).
Example 6. 4-[l-(2-Chloro-3,6-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 7-yl]benzoic acid
Figure imgf000087_0002
4-[ 1 -(2-Chloro-3,6-difluorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester (43 mg) was saponified as described in General Procedure 7 to give the title compound as a white solid (52% yield). M.p. >300°C, LCMS: m/z = 430.31 (M-HH+), 1H- NMR (DMSO-^6, 400 MHz) δ 4.15 (s, 2H), 5.41 (s, 2H), 7.28-7.33 (m, IH), 7.41-7.46 (m, IH), 7.59 (s, IH), 7.67 (d, J= 8.3 Hz, 2H), 7.98 (d, J= 8.3 Hz, 2H), 8.09 (s, IH). Example 7. 1 -(2-Chloro-3,6-difluorobenzyl)-7-[4-(4-methylpiperazine-l -carbonyl)phenyl]- 3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000088_0001
4-[ 1 -(2-Chloro-3 ,6-difluorobenzyl)-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (13 mg) was reacted with 1 -methyl piperazine as in General Procedure 8 to give the title compound as an off-white foam (45% yield). M.p. (foam), LCMS: m/z = 512.07 (M-J-H+), 1H- NMR (DMSO-flfc, 400 MHz) δ 2.30-2.43 (m, 2H), 2.83 (s, 3H), 3.06-3.18 (m, 2H), 3.21-3.33 (m, 2H), 3.40-3.48 (m, 2H), 4.08 (s, 2H), 5.39 (s, 2H), 7.28 (bs, IH), 7.22-7.32 (m, IH), 7.46 (s, IH), 7.50 (d, J = 8.3 Hz, 2H), 7.62 (d, J= 8.3 Hz, 2H), 8.05 (s, IH). Example 8. l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000088_0002
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.623 g) was reacted with benzyl bromide as in General Procedure 1 to give the title compound as a light yellow solid (38% yield). M.p.
225°C, LCMS: m/z =366.03 (M-I-H+), 1H-NMR (DMSO-^6, 400 MHz) δ 4.14 (s, 2H), 5.10 (s,
2H), 7.13 ( s, IH), 7.7.22-7.29 (m, 4H), 7.31-7.38 (m, 2H), 7.78 (s, IH).
Example 9. 4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester
Figure imgf000088_0003
1 -Benzyl- 7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (509 mg) was reacted with 4- ethoxycarbonyl phenyl boronic acid as in General Procedure 4B to give the title compound as a brown solid (72% yield). M.p. = 178°C, LCMS: m/z = 388.23 (M-J-H+), 1H-NMR (DMSO-^6, 400 MHz) δ 1.32 (3H, t, J= 7.1 Hz), 4.20 (2H, d, J= 1.5 Hz), 4.31 (2H, q, J= 7.1 Hz), 5.26 (2H, s), 7.23 (2H, m), 7.32 (2H, s), 7.34 (2H, m), 7.39 (IH, d, J= 1.8 Hz), 7.63 (2H,d, J= 8.6 Hz),
7.94 (2H,d, J= 8.3 Hz), 8.06 (lH,d, J= 2.0 Hz).
Example 10. 4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid
Figure imgf000089_0001
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester (390 mg) was saponified under the conditions of General Procedure 7 to give the title compound as a light brown solid (99% yield). M.p. >200°C, LCMS: m/z = 360.17 (MH-H+), 1H-NMR (DMSO-^6, 400 MHz) δ 4.19 (2H, s), 5.26 (2H, s), 7.23 (2H, s), 7.32 (4H, m), 7.39(lH,s), 7.60 (2H,d, J= 8.3 Hz), 7.92 (2H,d, J= 8.3 Hz), 8.05 (IH, s). Example 11. 1 -Benzyl^-pyridin-S-yl-θ^-dihydro- lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000089_0002
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (100 mg) was reacted with 3- pyridine boronic acid as in General Procedure 4A to give the title compound as a light yellow solid (60% yield). M.p. 58°C, LCMS: m/z = 317.16 (MH-H+), 1H-NMR (CD3OD, 400 MHz) δ 4.42 (s, 2H), 7.22-7.31 (m, 2H), 7.32-7.38 (m, 4 H), 7.50 ( s, IH), 7.85-7.92 ( m, IH), 8.02 (s, IH), 8.39 (d, J = 8.1 Hz, IH), 8.65-8.75 (m, IH), 8.75-8.90 (m, IH).
Example 12.4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-pyrrolidin- l-yl-ethyl)benzamide, trifluoroacetic acid salt
Figure imgf000089_0003
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (23 mg) was coupled to 2-pyrrolidin-l-yl-ethylamine as in General Procedure 8 to give the title compound as a brown solid after preparative reversed-phase HPLC purification (29% yield). M.p. = 107 0C, LCMS: m/z = 456.15 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) B 2.13 (4H, m), 3.40 (6H, m), 3.81 (4H, m), 4.54 (2H, s), 5.27 (2H, s), 7.38 (4H, m), 7.75 (IH, s), 7.92 (2H, d, J= 8.3 Hz). Example 13. 5-l-Benzyl-7-[4-(2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carbonyl)phenyl]-3,4- dihydro-lH-pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000090_0001
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (48 mg) was coupled to (S)-(+)-l-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a pink solid after preparative reversed-phase HPLC purification (43% yield). LCMS: m/z = 496.24 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.94 (3H, m), 2.13 (4H, bs), 2.29 (IH, m), 3.05 (IH, bs), 3.24 (2H, m), 3.38 (IH, m), 3.49 (IH, m), 3.64 (3H, m), 3.86 (1 H, bs), 4.05 (IH, bs), 4.57 (3H, s), 5.29 (2H, s), 7.35 (8H, m), 7.61 (2H, d, J= 8.1 Hz), 7.74 (IH, s).
Example 14. 4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3- morpholin-4-yl-propyl)benzamide, trifluoroacetic acid salt
Figure imgf000090_0002
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (43 mg) was coupled to 3-morpholin-4-yl-propylamine as in General Procedure 8 to give the title compound as an orange solid after preparative reversed-phase HPLC purification (12% yield). LCMS: m/z = 486.24 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.13 (3H, m), 3.18 (4H, m), 3.40 (IH, m), 3.53 (5H, m), 4.00 (6H, m), 4.57 (2H, s), 5.28 (2H, s), 7.36 (8H, m), 7.71 (IH, s), 7.93 (2H, d, J= 8.3 Hz)
Example 15. 4-(l -Benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(4- dimethylaminobutyl)benzamide, trifluoroacetic acid salt
Figure imgf000091_0001
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (40 mg) was coupled to 3-dimethylaminobutylarnine as in General Procedure 8 to give the title compound as a yellow solid after preparative reversed-phase EDPLC purification (17% yield). LCMS: m/z = 458.19 (IvH-H+), 1H-NMR (CD3OD, 400 MHz) δ 1.70 (2H, m), 1.79 (2H, m), 2.89 (6H, s), 3.19 (2H, t, J= 8.0 Hz), 3.45 (2H, t, J= 6.7 Hz), 4.50 (2H, s), 5.36 (2H, s), 7.30 (IH, m), 7.37 (4H, m), 7.49 (2H, d, J= 8.3 Hz), 7.54 (IH, d, J= 1.5 Hz), 7.88 (3H, m). Example 16. 4-(l -benzyl-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(6- dimethylaminohexyl)benzaniide
Figure imgf000091_0002
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (47 mg) was coupled to 3-dimethylaminohexylamine as in General Procedure 8 to give the title compound as a light brown solid (19% yield). M.p. > 2000C, LCMS: m/z = 486.19 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (9H, m), 3.47 (3H, m), 4.35 (2H, s), 4.96 (IH, bs), 5.21 (2H, s), 7.20 (2H, m), 7.35 (5H, m), 7.52 (IH, s), 7.77 (2H, A, J= 8.3 Hz), 7.99 (IH, d, J= 2.0 Hz). Example 17. l-Benzyl-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-lH-pyrido[2,3- b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000091_0003
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (22 mg) was coupled to 4-(l pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a tan solid after preparative reversed-phase HPLC purification (16 % yield). LCMS: m/z = 494.27 01+H+), 1H-NMR (CD3OD, 400 MHz) δ 1.67 (2H, bs), 2.10 (8H, m), 3.19 (3H, m), 3.45 (IH, m), 3.67 (2H, bs), 3.91 (IH, bs), 5.57 (2H, s), 7.28 (IH, m), 7.36 (4H, m), 7.51 (2H, d, J = 8.1 Hz), 7.61 (2H, d, J= 8.1 Hz), 7.78 (IH, ά, J= 1.5 Hz), 8.44 (IH, d, J= 1.0 Hz). Example 18. S- 1 -Benzyl-7-[3 -(2-[(pyrroIidin- 1 -yl)methyl]pyrrolidine- 1 -carbonyl)phenyl]-3,4- dihydro-lH-pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000092_0001
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (33 mg) was coupled to (S)-(+)-l-(2-pyrτolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a yellow solid after preparative reversed-phase HPLC purification (32 % yield). LCMS: m/z = 496.24 (TvM-H+), 1H-NMR (CD3OD, 400 MHz) δ 1.85 (2H, m), 2.00 (IH, m), 2.09 (2H, m), 2.23 (2H, m), 2.37 (IH, m), 3.21 (3H, m), 3.57 (5H, m), 3.76 (IH, m), 4.08 (IH, m), 4.38 (2H, s);4.59 (IH, m), 5.34 (2H, s), 7.30 (IH, m), 7.38 (4H, m), 7.42 (IH, d, J= 1.5 Hz), 7.55 (3H, s), 7.60 (IH, s), 7.92 (IH, s), 8.09 (IH, s).
Example 19. 3-(l -Benzyl-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2- dimethylamino-ethyl)benzamide, trifluoroacetic acid salt
Figure imgf000092_0002
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (33 mg) was coupled to 3-dimethylaminoethylamine as in General Procedure 8 to give the title compound as a yellow solid after preparative reversed-phase HPLC purification (34 % yield). LCMS: m/z = 430.22 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.92 (6H, s), 3.67 (3H, m), 3.82 (2H, t, J = 5.6 Hz), 4.00 (IH, s), 4.55 (2H, s), 5.30 (2H, s), 7.34 (7H, m), 7.49 (2H, m), 7.73 (IH, s), 7.87 (2H, m).
Example 20. 1 -Benzyl-7-[3-(pyrrolidine- 1 -carbonyl)phenyl]-3 ,4-dihydro- 1 H-ρyrido[2,3- b]pyrazin-2-one
Figure imgf000093_0001
3-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (31 mg) was coupled to pyrrolidine as in General Procedure 8 to give the title compound as a yellow solid (47% yield). LCMS: m/z = 413.30 (NH-H+), 1H-NMR (CD3OD, 400 MHz) δ 1.92 (2H, m), 2.02 (2H, m), 3.36 (IH, m), 3.40 (2H, t, J= 6.6 Hz), 3.62 (2H, t, J= 6.9 Hz), 4.49 (2H, s), 4.91 (IH, s), 5.36 (2H, s), 7.29 (IH, m), 7.37 (2H, d, J= 1.8 Hz), 7.39 (2H, s), 7.49 (IH, s), 7.52 (3H, s), 7.53 (IH, d, J= 1.5 Hz), 7.84 (IH7 d, J= 1.5 Hz). Example 21. 7-(4-Acetylphenyl)-l-benzyl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000093_0002
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (35 mg)was reacted with 4- acetylphenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid (20% yield). M.p. = 200° C, LCMS: m/z = 358.24 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.61 (3H, s), 4.36 (2H, s), 5.22 (2H, s), 7.21 (IH, d, J= 2.0 Hz), 7.28 (4H, m), 7.37 (4H, m),
7.96 (2H, d, J= 8.3 Hz), 8.01 (IH, d, J= 1.8 Hz).
Example 22. 3-(l-Benzyl-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl- benzamide
Figure imgf000093_0003
3-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (35 mg) was coupled with ethylamine as in General Procedure 8 to give the title compound as a yellow solid (3% yield). LCMS: m/z = 387.26 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.27 (3H, t, J= 7.2 Hz), 3.47 (2H, quartet, J= 7.2 Hz), 4.50 (2H, s), 5.28 (2H, s), 7.36 (8H, m), 7.48 (IH, t, J= 7.6
Hz), 7.79 (2H, m), 7.84 (IH, s).
Example 23. 4-(l -Benzyl-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzamide
Figure imgf000094_0001
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (50 mg) was reacted with 4- carbamoylphenyl boronic acid as in General Procedure 4B to give the title compound as a white solid (24% yield). M.p. > 200° C, LCMS: m/z = 359.22 (M+lT), 1H-NMR (DMSO-Cf6,
400 MHz) δ 4.22 (2H, s), 5.28 (2H, s), 7.24 (IH, m), 7.33 (5H, m), 7.41 (IH, s), 7.56 (2H, d, J
= 8.6 Hz), 7.88 (2H, d, J= 8.3 Hz), 7.96 (IH, bs), 8.04 (IH, d, J= 1.8 Hz).
Example 24. 1 -Benzyl-7-(4-methanesulfonyl-phenyl)-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one
Figure imgf000094_0002
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (46 mg) was reacted with 4- (methanesulfonyl)phenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid (43% yield). LCMS: m/z = 394.22 (M-HH+), 1H-NMR (CDCl3, 400 MHz) δ 3.08 (3H, s), 4.54 (2H, s), 5.28 (2H, s), 7.30 (3H, m), 7.39 (3H, m), 7.45 (2H, d, J= 8.3 Hz), 7.78 (IH, d, J= 1.5 Hz), 7.94 (2H, d, J= 8.3 Hz).
Example 25. l-Benzyl-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4-dihydro-lH- pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000094_0003
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (43 mg) was reacted with (4- methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a white solid after preparative reversed- phase HPLC purification (38% yield). LCMS: m/z = 442.23 (MH-H+), 1H-NMR (CD3OD, 400 MHz) δ 2.95 (3H, s), 3.19 (3H, m), 3.31 (4H, m), 3.48 (2H, m), 4.52 (2H, s), 5.36 (2H, s), 7.29 (IH, m), 7.37 (4H, m), 7.53 (5H, m), 7.85 (IH, d, J= 1.8 Hz).
Example 26. 1 -Benzyl-7-[4-(4-(pyrrolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl] -3 ,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000095_0001
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (45 mg) was coupled with 4-(l pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid after preparative reversed-phase HPLC purification (28% yield). LCMS: m/z = 496.15 (MH-H+), 1H-NMR (CD3OD, 400 MHz) δ 1.67 (2H, m), 2.09 (7H, m), 3.17 (3H, m), 3.41 (2H, m), 3.66 (2H, m), 3.86 (2H5 bs), 4.51 (2H, s), 5.36 (2H, s), 7.29 (IH, m), 7.38 (4H, s), 7.50 (IH, d, J = 1.5 Hz), 7.53 (2H, m), 7.85 (IH, d, J= 1.5 Hz). Example 27. 4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl- benzamide
Figure imgf000095_0002
4-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (43 mg) was coupled with ethyiamine as in General Procedure 8 to give the title compound as a tan solid (15 % yield). M.p. = 195° C, LCMS: m/z = 387.31 (M-HH+), 1H-NMR (CDCl3, 400 MHz) δ 1.24 (3H, t, J= 7.3 Hz), 3.44 (2H, quartet, J= 7.3 Hz), 4.51 (2H, s), 5.26 (2H, s), 7.33 (8H, m), 7.76 (IH, d, J= 8.6 Hz), 7.81 (2H, d, J= 8.1 Hz), 8.05 (IH, d, J= 8.3 Hz). Example 28. 5-(l -Benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2- carbonitrile
Figure imgf000096_0001
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (196 mg) was reacted with 2- cyanopyridine-5-boronic acid pinacol ester as in General Procedure 4B to give the title compound as a yellow solid (46% yield). M.p. > 200° C, LCMS: m/z = 342.20 (MH-H+), 1H- NMR (DMSO-rf6, 400 MHz) δ 4.23 (2H, s), 5.27 (2H, s), 7.23 (IH, m), 7.32 (4H, m), 7.49 (2H, m), 8.03 (IH, d, J= 8.3 Hz), 8.18 (2H, m), 8.95 (IH, d, J= 2.0 Hz). Example 29. 5-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2- carboxylic acid ethyl ester
Figure imgf000096_0002
5-(l-Benzyl-2 -oxo-1, 2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile (32 mg) was mixed with ethanol (1.5 mL) and 4 N HCl (2.0 mL) in dioxane and then heated in a microwave oven at 1500C for 80 minutes. The reaction mixture was concentrated and purified with preparative reversed-phase HPLC to give the title compound as an orange solid. LCMS: m/z = 389.22 (M-I-H+), 1H-NMR (CD3OD, 400 MHz) δ 1.42 (3H, t, J= 7.1 Hz), 4.44 (4H, m), 5.35 (2H, s), 7.28 (IH, m), 7.37 (5H, m), 7.55 (IH, d, J= 1.8Hz), 8.00 (IH, d, J= 1.8 Hz), 8.03 (IH, dd, J= 8.1, 2.3 Hz), 8.17 (IH, d, J= 8.3 Hz), 8.69 (IH, d, J= 2.0 Hz). Example 30. 3-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid methyl ester
Figure imgf000096_0003
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (370 mg) was reacted with 3- methoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as a white solid (70 % yield). M.p. 211°C, LCMS: m/z = 374.17 (NH-H+), 1H-NMR (CD3OD, 400 MHz) δ 3.95 (s, 3H), 4.48 (s, 2H), 5.35 ( s, 2H), 7.23-7.35 (m, 2H), 7.38-7.40 (m, 2H), 7.50-7.58 (m, 2H), 7.60-7.66 ( m, 2H), 7.84 ( s, IH), 7.9-8.1 (m, 2H). Example 31. 3-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid
Figure imgf000097_0001
3-(l-Benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid methyl ester (245 mg) was saponified as in General Procedure 7 to give the title compound as a tan film (73% yield). M.p. (film), LCMS: m/z = 360.18 (M+H*), 1H-NMR (CD3OD, 400 MHz) δ 4.53 (s, 2H), 5.37 (s, 2H), 7.28-7.35 (m, IH), 7.37-7.45 (m, 4H), 7.52-7.58 (m, IH), 7.62-7.65 (m, 2H), 7.82 (d, J= 1.8 Hz, IH), 8.03 (s, IH), 8.04 (d, J= 8.8 Hz, IH). Example 32. 1 -Benzyl- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000097_0002
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (50 mg) was dissolved in anhydrous tetrahydrofuran and added to LiAlHU (1 M in tetrahydrofuran, 9.0 eq) over 2 minutes. After stirring for 35 minutes at room temperature, the reaction mixture was quenched with wet ether, diluted with ethyl acetate and H2O, and filtered. The organic phase was isolated, dried, filtered, and concentrated. Silica gel chromatography (0-10% methanol in CH2CI2) gave the title compound as a pale yellow film (10 % yield). M.p. (film), LCMS: m/z = 226.19 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.35-3.40 (m, 2H), 3.52-3.57 (m, 2H), 4.40 (s, 2H), 4.83 (bs, IH), 6.41-6.50 (m, 1 H), 6.56-6.63 (m, IH), 7.20-7.38 (m, 5 H), 7.43 ( d, J= 1.2 H). Example 33. l-Benzyl-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000098_0001
l-Benzyl-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (50 mg) was reduced as in General Procedure 3 to give the title compound as a light brown solid (25% yield). M.p. 147- 148 0C, LCMS: m/z = 352.02 (NH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.09-3.32 (m, 2H), 3.51-3.54 (m, 2H), 4.36 (s, 2H), 6.84 (s, IH), 7.23-7.30 (m, 1 H), 7.31-7.39 (m, 4H), 7.58 ( d, J = 1.5 Hz, IH). Example 34. l-Benzyl-7-pyridin-3-yl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000098_0002
l-Benzyl-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (30 mg) was reacted with pyridine 3- boronic acid as in General Procedure 4A to give the title compound as a light yellow film (23% yield). M.p. (film), LCMS: m/z = 303.40 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.41-3.44 m, 2H), 3.60-3.63 (m, 2H), 4.49 (s, 2H), 6.80 (s, IH), 5.40 (bs, IH), 6.80 (s, IH), 1.21-1 Al (m, 5H), 7.64 (s, IH), 7.65 (d, J= 7.8 Hz, IH), 8.48 ( d, J= 4.8 Hz, IH), 8.63 (s, IH). Example 35. 4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester
Figure imgf000098_0003
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazm-l-yl)phenyl -methadone (293 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as a pale yellow solid (42% yield). M.p. 178-179°C, LCMS: m/z =374.30 (M+HT), 1H-NMR (CDCl3, 400 MHz) δ 1.38 ( t, J= 7.1) Hz, 3H), 3.40 (t, J= 5.1 Hz, 2H), 3.60-3.63 (m, 2H), 4.35 (q, J= 7.1 Hz, 2 H), 4.48 j[s, 2H), 6.85 (s, IH), 7.27-7.49 (m, 5H), 7.43 (d, J= 8.3 Hz, 2H), 7.73 (d, J= 2.0 Hz, 2H), 8.00 (d, J= 8.3 Hz, 2H). Example 36. 4-(l -Benzyl- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid
Figure imgf000099_0001
4-(l -Benzyl- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester (118 mg) was saponified as in General Procedure 7 to give the title compound as a pale yellow solid (90% yield). M.p. >300°C, LCMS: m/z = 346.30 (M+H4), 1H-NMR (DMSO-J6, 400 MHz) δ 3.35- 3.38 (m, 2H), 3.52-3.54 (m, 2H), 4.62 (s, 2H), 7.08 (s, IH), 7.25-7.27 (m, IH), 7.29-7.32 (m, 4 H), 7.62 (d, J = 8.4 Hz, 2H), 7.69 (d, J= 1.8 Hz, IH), 7.92 (d, J= 8.4 Hz, 2H), 12.86 (bs, IH). Example 37. [4-(l -Benzyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4- methylpiperazin- 1 -yl)methanone
Figure imgf000099_0002
4-(l -Benzyl- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20 mg) was reacted with 1 -methyl piperazine as in General Procedure 8 to give the title compound as a yellow solid (32% yield). M.p. 180-1810C, LCMS: m/z = 428.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (s, 3H), 2.33-2.52 (m, 4H), 3.38-3.43 (m, 2H), 3.45-3.55 (m, 2H), 3.46-3.50 (m , 2H), 3.58-3.62 (m, 2H), 3.64-3.82 (m, 2H), 4.48 (s, 2H), 5.29 (s, IH), 6.83 (s, IH), 7.27-7.39 (m, 9H), 7.69 (s, IH).
Example 38. [4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-((S)-2- pyrrolidinylmethylpyrrolidin-l-yl)methanone, trifluoroacetic acid salt
Figure imgf000099_0003
4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20 mg) was reacted with (S)-(+)-l-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a yellow foam after reversed phase preparative HPLC (43% yield). M.p. foam, LCMS: m/z = 482.30, 1H-NMR (CDCl3, 400 MHz) δ 1.82-1.84 (m, IH), 1.92-2.05 (m, 2H), 2.06-2.20 (m, 4H), 2.92-3.08 (m, IH), 3.18-3.25 (m, IH), 3.25-3.35 (m, IH), 3.39-48 (m, 2 H), 3.50-3.5 (m, IH), 3.55-3.63 (m, IH), 3.65-3.71 (m, IH), 3.72-3.77 (m, 2H), 3.82-3.94 (m, IH), 4.01-4.11 (m, IH), 4.48-4.59 (m, 3H), 6.92 (s, IH), 7.26-7 '.42 (m, 8H), 7.56 (d, /= 8.1 Hz, 2H), 11.06 (bs, IH).
Example 39. [4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4- (pyrrόlidin- 1 -yl)piperidin- 1 -yl)methanone
Figure imgf000100_0001
4-(l-Benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20 mg) was reacted with 4-(l pyrrolidinyl)piperidiπe as in General Procedure 8 to give the title compound as a yellow solid (22 % yield). M.p. 1200C, LCMS: m/z = 482.26 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53-1.65 (m, 7H), 1.90-2.04 (m, 3H), 2.25-2.35 (m, IH), 2.53-2.63 (m, 4H), 2.91-3.06 (m, 2H), 3.38-3.44 (m, 2H), 3.59-3.62 (m, 2H), 4.48 (s, 2H), 5.01 (bs, IH), 6.84 (s, IH), 7.28- 7.40 (m, 9 H), 7.70 (s, IH).
Example 40. 7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000100_0002
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (200 mg) was reduced as in General Procedure 3 using 4 eq DIBAL-H to give the title compound as a white solid (31% yield). M.p. 126-128°C, LCMS: m/z = 262.30(M+!!4), 1H-NMR (DMSO-Ci6, 400 MHz) δ 3.13-3.17 (m, 2H), 3.27-3.29 (m, 2H), 5.78 (s, IH), 6.37 (s, IH), 6.78 (d, J= 2.0 Hz, IH), 7.33 (d, J= 2.0 Hz, IH). Example 41. (3,4-Dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone
Figure imgf000101_0001
l,2,3,4-tetrahydropyrido[2,3-b]pyrazine was reacted with benzoyl chloride as in General Procedure 2 to give the title compound as a beige solid (<10% yield). M.p. 166-168 0C, LCMS: m/z =240.12 (M-I-H+), 1H-NMR (DMSO-J6, 400 MHz) δ 3.45-3.49 (m, 2H), 3.84-3.87 (m, 2H), 6.40 (s, IH), 6.77 (dd, J = 4.8 Hz, 4.5 Hz, IH), 6.92 (dd, J= 1.5 Hz, 7.8 Hz, IH), 7.10 (dd, J= 1.5 Hz, 4.6 Hz, IH), 7.25-7.34 (m, 5H). Example 42. (7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone
Figure imgf000101_0002
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with benzoyl chloride as in General Procedure 2 to give the title compound as a pale yellow solid (61% yield). M.p. 164-166°C, LCMS: m/z =366.00 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.50 (m, 2H), 3.90 (t, J= 4.8 Hz, 2H), 7.37-7 '.47 (m, 6H), 7.95 (s, IH). Example 43. Phenyl-(7-pyridin-3-yl-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)methanone
Figure imgf000101_0003
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone (50 mg) was reacted with pyridine 3-boronic acid as in General Procedure 4 A to give the title compound as a yellow solid (25% yield). M.p. 219-220 0C, LCMS: m/z = 317.40(M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.50 (m, 2H), 4.02 (t, J= 4.8 Hz, 2H), 5.39 (s, IH), 7.20-7.22 (m, 2H), 7.40-7.44 (m, 3 H), 7.47-7.51 (m, 3H), 8.03 (s, IH), 8.30 (s, IH), 8.47 (d, J = 4.3 Hz, IH). Example 44. 4-(l-Benzoyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester
Figure imgf000102_0001
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone (215 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as an off-white solid (32% yield). M.p.177-178 0C, LCMS: m/z = 388.23(NH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.38 t, (J= 7.1 Hz, 3H), 3.67-3.72 (m, 2H), 4.01-4.08 (m, 2H), 4.36 (q, J= 7.1 Hz, 2H), 5.21 (bs, IH), 7.12-7.16 (m, 2H), 7.40-7.53 (m, 5H), 7.95 (d, J= 8.3 Hz, 2H), 8.08 (s, IH).
Example 45. 2-Pyrrolidin-l-yl-ethanesulfonic acid [4-(l-benzyl-2-oxo-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide, trifluoroacetic acid salt
Figure imgf000102_0002
2-pyrrolidin- 1 -yl-ethanesulfonic acid [4-(4,4,5 ,5-tetramethyl-[ 1 ,3 ,2]dioxaborolan-2- yl)phenyl]amide was prepared as in General Procedure 11 and then reacted with l-benzyl-7- iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (31 mg) as in General Procedure 4B to give the title compound as a yellow solid after purification by preparative reversed-phase HPLC (38% yield). LCMS: m/z = 492.09 (M-I-H+), 1H-NMR (CD3OD, 400 MHz) δ 2.08 (4H, bs), 3.13 (2H, m), 3.63 (6H, m), 4.51 (2H, s), 5.34 (2H, s), 7.30 (3H, m), 7.37 (6H, m), 7.51 (IH, s), 7.75 (IH, s).
Example 46. 2-Pyrrolidin-l-yl-ethanesulfonic acid [4-(l -benzoyl- 1,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide
Figure imgf000102_0003
2-Pyrrolidin-l-yl-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]amide (50 mg) was prepared as in General Procedure 11 and then reacted with (7- Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone as in General Procedure 4A to give the title compound as an off-white foam (18% yield). M.p. foam, LCMS: m/z = 492.10 (IVMi+), 1H-NMR (CDCl3, 400 MHz) δ 1.33 (s, IH), 1.76- 1.82 (m, 4H), 2.45-2.55 (m, 4H), 3.02 (t, J= 6.3 Hz, 2H), 3.22 (t, J= 6.0 Hz, 2H), 3.63-3.68 (m, 2H), 4.02 (t, J= 4.6 Hz, 2H), 5.33 (bs, IH), 6.98-7.-4 (m, 2H), 7.11 (d, J= 8.3 Hz, 2H), 7.26 (s, IH), 7.47 (d, J= 8.3 Hz, 2H), 7.48-7.54 (m, 3H), 7.98 (<LJ = 2.0 Hz, IH).
Example 47. 2-(4-Methylpiperazin-l-yl)-ethanesulfonic acid [4-( 1 -benzoyl- 1,2, 3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide
Figure imgf000103_0001
2-(4-Methylpiperazin-l-yl)-ethanesulfonic acid [4-(4,4,5,5-tetramethyl [l,3,2]dioxaborolan-2- yl)phenyl]amide (50 mg) was prepared as in General Procedure 11 and then reacted with (7- Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone as in General Procedure 4A to give the title compound as a yellow foam (45 % yield). M.p. foam, LCMS: m/z =521. 20 (M-HH+), 1H-NMR (CDCl3, 400 MHz) δ 3.68 (s, 3H), 2.35-2.58 (m, 8H), 2.90 (t, J = 6.6 Hz, 2H), 3.23 (t, J= 6.3 Hz, 2H), 3.65-3.69 (m, 2H), 3.97-4.05 (m, 2H), 5.45 (bs, IH), 6.99-7.06 (m, 2H), 7.16 (d, J= 8.3 Hz, 2H), 7.27 (s, IH), 7.39-7.53 (m, 5H), 7.99 (d, J= 1.8 Hz, IH). Example 48. 2-Pyrrolidin-l-yl-ethanesulfonic acid {4-[l-(2,5-difluorobenzyl)-2-oxo-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide
Figure imgf000103_0002
2-Pyrrolidin-l-yl-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]amide (40 mg) was prepared as in General Procedure 11 and then reacted with 1- (2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one as in General Procedure 4A with the modification that the reaction was heated to 1300C in a microwave oven for 10 minutes. The title compound was isolated as an off-white solid (36 % yield). M.p. >300 0C, LCMS: m/z = 528.03 (IVB-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.83-1.86 (m, 4H), 2.52-2.64 (m, 4H), 3.06 (t, J= 6.3 Hz, 2H), 3.25 (t, J= 6.3 Hz, 2H), 4.32 (s, 2H), 4.97 (bs, IH), 5.21 (s, 2H), 6.89-6.98 (m, 2H), 7.05-7.11 (m, IH), 7.16 (d, J= 1.8 Hz, IH), 7.21 (d, J= 8.6 Hz, 2H), 7.26 (s, IH), 7.33 (d, J= 8.6 Hz, 2H), 7.92 (s, IH).
Example 49.2-[Ethyl-((S)-l-pyrrolidin-l-ylmethyl-propyl)-amino]-ethanesulfonic acid {4-[l- (2,5-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide
Figure imgf000104_0001
2-[Ethyl-((S)- 1 -pyrrolidin- 1 -ylmethyl-propyl)-amino]-ethanesulfonic acid [4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]amide (40 mg) was prepared as in General
Procedure 11 and then reacted with l-(2,5-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one as in General Procedure 4A with the modification that the reaction was heated to 1300C in a microwave oven for 10 minutes. The title compound was obtained as a light yellow foam (10% yield). M.p. foam, LCMS: m/z = 611.07 (M-HH+), 1H-NMR (CDCl3, 400 MHz) 6 1.44-1.53 (m, IH), 1.82-1.99 (m, 5H), 2.22—2.25 (m, IH), 2.26-2.33 (m, 2H), 2.45- 2.55 (m, 2H), 2.70-2.92 (m, 7 H), 2.90-3.12 (m, 2H), 3.44-3.60 (m, 2H), 4.32 (s, 2H), 4.96 (s, IH), 5.21 (s, 2H), 6.88-6.98 (m, 2H), 7.04-7.12 (m, IH), 7.18 (s, IH), 7.29 (d, J =8.6 Hz, 2H), 7.36 (d, J =8.6 Hz, 2H), 7.98 (d, J=I.89 Hz, IH).
Example 50. 2-Morpholin-4-yl-ethanesulfonic acid {4-[l-(2,5-difluorobenzyl)-2-oxo-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -amide
Figure imgf000104_0002
2-Morpholin-4-yl-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2- yl)phenyl] amide (40 mg) was prepared as in General Procedure 11 and then reacted with 1- (2,5-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one as in General Procedure 4A to give the title compound as a white solid (11% yield), m.p.225 0C, LCMS: m/z = 544.20 (M+ET), 1H-NMR (CDCl3, 400 MHz) δ 2.51 (t, J=
4.5 Hz, 4H), 2.92 (t, J= 6.3 Hz, 2H), 3.28 (t, J= 6.3 Hz, 2H), 4.31 (s, 2H), 4.95 (s, IH), 5.22
(s, 2H), 6.91-6.99 (m, 2H), 7.05-7.10 (m, IH), 7.14 (s, IH), 7.25 (d, J = 8.6 Hz, 2H), 7.34 (d, J
= 8.6 Hz, 2H), 7.92 (s, IH).
Example 51. 2-Pyrrolidin-l-yl-ethanesulfonic acid {4-[l-(2,5-difluorobenzyl)-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide
Figure imgf000105_0001
2-Pyrrolidin-l -yl-ethanesulfonϊc acid [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]amide (39 mg) was prepared as in General Procedure 11 and then reacted with 1- (2,5-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine as in General Procedure 4A with the modification that the reaction was heated to 1300C in a microwave oven for 10 minutes. The title compound was obtained as a light yellow solid (15 % yield). M.p. slow decomp, LCMS: m/z = (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.80-1.84 (m, 4H), 2.54-2.58 (m, 4H), 3.03 (t, J= 6.1 Hz, 2H), 3.23(t, J= 6.1 Hz, 2H), 3.45 (t, J= 5.3 Hz, 2H), 3.60-3.64 (m, 2H), 4.49 (s, 2H), 5.03 (bs, IH), 6.73 (s, IH), 6.92-7.08 (m, 3H), 7.17 (d, J= 8.3 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 1.8 Hz, IH), 8.08 (s, IH).
Example 52. 4-( 1 -Benzoyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino- ethyl)benzamide
Figure imgf000105_0002
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenyl-methanone (50 mg) was reacted with N-(2-dimethylaminoethyl)-4-(4 ,4,5,5 -tetramethyl-[ 1 ,3 ,2]dioxaborolan-2-yl)benzamide as in General Procedure 4A to give the title compound as a light yellow solid (24 % yield). M.p. 145-147 0C, LCMS: m/z = 430.26 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (s, 6H), 2.48- 2.53 (m, 2H), 3.48- 3.54 (m, 2H), 3.66-3.71 (m, 2HO, 4.01 (t, J= 4.8 Hz, 2H), 5.55 (bs, IH), 6.84-6.87 (m, IH), 7.09-7.15 (m, 2H), 7.38-7.52 (m, 6H), 7.71 (d, J = 8.1 Hz, 2H), 8.05 (d, J
= 2.0 Hz, IH).
Example 53. 4-(l-Ben2oyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-dimethylamino- propyl)benzamide
Figure imgf000106_0001
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenyl-methanone (50 mg) was reacted with N-(3-dimethylamino-propyl)-4-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)benzamide as in General Procedure 4A to give the title compound as a light yellow solid (44% yield). M.p. 94 0C, LCMS: m/z = 444.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.72-1.80 (m, 2H), 2.27 (s, 6H), 2.48-2.53 (t, J= 5.8 Hz, 2H), 3.48-3.54 (m, 2H), 3.67-3.73 (m, 2h), 3.98-4.04 (m, 2H), 5.44 (bs, IH), 7.10-7.18 (m, 2H), 7.36-7.48 (m, 6H), 7.69 (d, J= 8.1 Hz, 2H), 8.07 (s, IH), 8.42 (bs, IH).
Example 54. {7-[4-(4-Methylpiperazine-l-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3- b]p yrazin- 1 -yl } phenylmethanone
Figure imgf000106_0002
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenyl-methanone (50 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]doxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a light green foam (53% yield). M.p. foam, LCMS: m/z = 442.30 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.35-2.48 (m, 4H), 3.40-3.50 (m, 2H), 3.62-3.69 (M, 2h), 3.70-3.80 (m, 2h), 3.97- 4.03 (m, 2H), 5.42 (bs, IH), 7.06-7.15 (m, 2H), 7.34 (d, J= 8.1 Hz, 2H), 7.40-7.52 (m, 6H), 8.05 (s, IH).
Example 55. 4-[ l-(2,5-Difluorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]benzoic acid ethyl ester
Figure imgf000107_0001
l-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (600 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as an off-white solid (62% yield). M.p. 201-2030C, LCMS: m/z = 424.2001+H+), 1H-NMR (DMSO-(Z6, 400 MHz) δ 1.32 (t, J= 7.0 Hz, 3H), 3.99 (s, 2H), 4.32 (q, J= 7.0 Hz, 2H), 5.26 (s, 2H), 7.03-7.09 (m, IH), 7.11-7.19 (m, IH), 7.33 (s, IH), 7.34-7.38 (m, IH), 7.39 (s, IH), 7.67 (d, J= 7.0 Hz, 2H), 6.8 Hz, 2H), 8.10 (s, IH).
Example 56.4-[l-(2,5-Difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]benzoic acid
Figure imgf000107_0002
4-[ l-(2,5-Difluorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester (385 mg) was saponified as in General Procedure 7 to give the title compound as an off-white solid (85% yield). M.p. >300°C, LCMS: m/z = 396.13 (M+H+), 1H-NMR (DMSO- d6i 400 MHz) δ 4.21 (s, 2H), 5.26 (s, 2H), 7.05-7.11 (m, IH), 7.12-7.18 (m, IH), 7.27-7.38 (m, IH), 7.66 (d, J= 7.3 Hz, 2H), 7.94 (d, J= 7.1 Hz, 2H), 8.10 (s, IH). Example 57. 1 -(2,5 -Difluorobenzyl)-7-[4-((S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 - carbony l)phenyl] -3 ,4-dihydro - 1 H-pyrido [2,3 -b]pyrazin-2-one
Figure imgf000107_0003
4-[l-(2,5-Difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with (S)-(+)-l-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a white solid (32 % yield). M.p. 125°C, LCMS: m/z = 532.10 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 1.22-1.26 (m, 2H), 1.68-1.82 (m, 4H), 1.89-2.15 (m,
4H), 2.56-2.70 (m, 3H), 2.80-2.90 (m, IH), 3.42-3.52 (m, IH), 4.33 (s, 2H), 4.43-4.50 ( m,
IH), 5.02 (bs, IH), 5,22 (s, 2H), 6.91-6.98 (m, 2H), 7.04-7.10 (m, IH), 7.21 (d, J = 1.5 Hz,
IH), 7.39 (d, J= 8.1 Hz, 2H), 7.54 (bd, J = 7.6 Hz, 2H), 8.01 (d, J= 1.5 Hz, 2H).
Example 58. 4-[l-(2,5-Difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-
(2-pyrrolidin-l-yl-ethyl)benzamide
Figure imgf000108_0001
4-[l-(2,5-Difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with N-(2-aminoethyl)pyrτolidine as in General Procedure 8 to give the title compound as a white solid (25% yield). M.p. 235 0C (dec), LCMS: m/z = 492.20(M-I-H+), 1H- NMR (CDCl3, 400 MHz) δ 1.81-18.5 (m, 4H), 2.55-2.65 (m, 4H), 2.72-2.80 (m, 2H), 3.58- 3.62 (m, 2H), 4.68 (s, 2H), 4.99 (s, IH), 5.23 (s, 2H), 6.85-6.95 (m, 2H), 7.02-7.08 (m, IH), 7.07 (s, IH), 7.44 (d, J= 8.3 Hz, 2H), 7.83 (d, J= 8.1 Hz, 2H), 8.03 (s, IH), 8.08 (s, IH). Example 59. l-(2,5-Difluorobenzyl)-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4- dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one
Figure imgf000108_0002
4-[l-(2,5-Difluorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with 1 -methyl piperazine as in General Procedure 8 to give the title compound as a light yellow solid (38 % yield), m.p. 223 0C (dec), LCMS: m/z = 478.20 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.35-2.48 (m, 4H), 3.48-3.54 (m, 2H), 3.70-3.80 (m, 2H), 4.34 (s, 2H), 5.11 (s, IH), 5.22 (s, 2H), 6.90-6.98 (m, 2H), 7.06-7.13 (m, IH), 7.20 (d, J= 1.8 Hz, IH), 7.41 (d, J= 8.1 Hz, IH), 7.45 (d,J= 8.3 Hz, IH), 8.01 (d, J= 1.8 Hz, IH).
Example 60. l-(2,5-Difluorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]- 3 ,4-dihydro- 1 H-pyrido[2 ,3 -b]pyrazin-2-one
Figure imgf000109_0001
4-[ 1 -(2,5-Difluorobenzyl)-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with 4-(l pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a pale yellow solid (30% yield). M.p. 186 0C (dec) m/z = 532.30 QVH-H+), 1H- NMR (CDCl3, 400 MHz) δ 1.44-1.58 (m, 4H), 1.90-2.06 (m, 2H), 2.28-2.32 (m, IH), 2.52- 2.64 (m, 4H), 2.85-3.11 (m, 3H), 3.70-3.82 (m, 2H), 4.34 (s, 2H), 4.50-4.62 (m, 2H), 5.06 (s, IH), 5.22 (s, 2H), 6.6.88-6.96 (m, 2H), 7.10-7.22 (m, IH), 7.20 (s, IH), 7.40 (dd, J= 8.3 Hz, 2H), 8.01 (s, IH).
Example 61, (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxylic acid {4-[l-(2,5- difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide
Figure imgf000109_0002
l-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (35 mg) was reacted with the product of Preparation 1 (i.e., (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l- carboxyl-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]amide (N)) as in General Procedure 4A to give the title compound as an orange foam (29% yield). M.p. foam, LCMS: m/z = 547.10 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 1.65-1.73 (m, 2H), 1.89-1.95 (m, 4H), 2.45-2.50 (m, IH), 2.55-2.68 (m, 2H), 2.79-2.89 (m, 2H), 2.91-2.99 (m, IH), 3.30-3.38 ( m, IH), 3.42-3.52 (m, IH), 3.79-3.92 (m, 2H), 4.30 (s, IH), 4.88 (bs, IH), 5.20 (s, 2H), 6.87-7.09 (m, 4H), 7.15 (s, IH), 7.23-7.27 (m, 2H), 7.35 (d, J= 8.3 Hz, 2H), 7.98 (s, lH).n 11.09 (bs, IH). Example 62. l-(2,5-Difluorobenzyl)-7-iodo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000110_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (525 mg) was reacted with 2,5- difluorobenzyl bromide as in General Procedure 1 to give l-(2,5-Difluorobenzyl)-7-iodo-3,4- dihydro-lH-pyrido[2,3-b]pyrazin-2-one as a tan solid (70% yield). This amide was then reduced as in General Procedure 3 to give the title compound as a white solid (42% yield). M.p. 175°C, LCMS: m/z = 388.10 (MH-H+), 1H-NMR (DMSO-^6, 400 MHz) δ 3.26-3.30 (m, 2H), 3.36-3.42 (m, 2H), 4.44 (s, 2H), 6.63 (bs, IH), 6.77 (s, IH), 7.05-7.10 (m, IH), 7.15-7.19 (m, IH), 7.20-7.27 (m, IH), 7.41 (s, IH).
Example 63.4-[l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester
Figure imgf000110_0002
l-(2,5-Difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (500 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as an off-white solid (63% yield). M.p.173-174 0C, LCMS: m/z = 410.30 (M-HI+), 1H-NMR (CDCl3, 400 MHz) δ 1.39 (t, J= 7.1 Hz, 3H), 3.45 (t, J= 5.0 Hz, 2H), 3.61-3.66 (m, 2H), 4.37 (q, J= 7.1 Hz, 2H), 4.49 (s, 2H), 5.32 (bs, IH), 6.78 (d, J= 1.5 Hz, IH), 6.89-6.96 (m, IH), 6.99-7.08 (m, 2H), 7.45 (d,J= 8.4 Hz, 2H), 7.76 (d, J= 1.8 Hz, 2H), 8.02 (d, J= 8.6 Hz5 2H).
Example 64. 4-[ 1 -(2S5-Difluorobenzyl)-1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid
Figure imgf000110_0003
4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester (300 mg) was saponified as in General Procedure 7 to give the title compound as a beige solid (91% yield). M.p. >300 0C, LCMS: m/z -382.20 (M+H*), 1H-NMR (DMSO--i6, 400 MHz) δ 3.28-3.33 (m, 2H), 3.40-3.49 (m, 2H), 4.58 (s, 2H), 6.58 (s, IH), 6.77 (s, IH), 7.10-7.20 (m, 2H), 7.26-7.34 (m, IH), 7.59 (d, J= 8.3 Hz, 2H), 7.73 (s, IH), 7.89 (d, J = 8.3 Hz, 2H), 12.92 (bs, IH).
Example 65. {4-[ 1 -(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} - ((S)-2-((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone
Figure imgf000111_0001
4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid
(50 mg) was reacted with (S)-(+)-l-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure
8 to give the title compound as a pale yellow solid (53% yield). M.p. 143-144 0C, LCMS: m/z
= 518.30 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 1.48-1.58 (m, IH), 1.87-2.15 (m, 4H), 2.17-
2,22 (m, 3H), 2.55-2.64 (m, 4H), 2.83-2.89 (m, IH), 3.12-3.23 (m, IH), 3.42-3.50 (m, 2H),
3.60-3.64 (m, 2H), 4.40-4.49 (m, 3H), 5.07 (bs, IH), 6.76 (s, IH), 6.86-7.09 (m, 3H), 7.41 (d,J
= 8.1 Hz, 2H), 7.45-7.52 (m, 2H), 7.73 (s, IH).
Example 66. {4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-
(4-(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone
Figure imgf000111_0002
4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (34 mg) was reacted with 4-(l pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a pale yellow solid (47% yield). M.p. 202-204 0C, LCMS: m/z = 518.10 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.55-1.58 (m, 2H), 1.77-1.84 (m, 4H), 1.88-2.02 (m, 2H), 2.2402.30 (m, IH), 2.56-2.62 (M, 4H), 2.90-3.12 (m, 2H), 3.44-3.48 (m, 2H), 3.64-3.68 (m, 2H), 3.77-3.87 (m, IH), 4.49 (s, 2H), 4.55-4.63 (m, IH), 4.95 (bs, 1H),6.76 (s, IH), 6.93- 7.09 (m, 3H), 7.39 (dd, J= 8.3 Hz, 4H), 7.72 (s, IH), 8.08 (s, IH).
Example 67. {4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}- (4-methylpiperazin- 1 -yl)methanone
Figure imgf000112_0001
4-[ 1 -(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (34 mg) was reacted with 1-methylpiperazine as in General Procedure 8 to give the title compound as a pale yellow solid (25% yield). M.p. 180 0C, LCMS: m/z = 464.10 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.30-2.49 (m, 4H), 3.46 ( t, J= 5.0 Hz, 2H), 3.50-3.55 (m, 2H), 3.62-3.66 (m, 2H), 3.67-3.83 (m, 2H), 4.50 (s, 2H), 5.02 (bs, IH), 6.75 (s, IH), 6.86-7.08 (m, 3H), 7.40 (dd, J = 8.3 Hz, 4H), 7.72 (s, IH).
Example 68. {4-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}- morpholin-4-yl-methanone
Figure imgf000112_0002
4-[l -(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid
(60 mg) was reacted with morpholine as in General Procedure 8 to give the title compound as a light yellow foam (59% yield). M.p. (foam), LCMS: m/z = 451.21 (M-I-H+), 1H-NMR (CDCl3,
400 MHz) δ 3.444-3.48 (m, 2H), 3.62-3.66 (m, 2H), 3.64-3.76 (m, 8H), 4.50 (s, 2H), 5.00 (s,
IH), 6.75 (s, IH), 6.84-7.15 (m, 3H) 7.43 (dd, J= 8.3 Hz, 4H), 7.71 ( d, J= 1.8 Hz, IH).
Example 69. l-(2,5-Difluorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000113_0001
l-(2,5-Difluorobeiizyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazme (50 mg) was reacted with l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4 A to give the title compound as a beige solid (53% yield). M.p. 192-193 0C, LCMS: m/z = 437.07 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.52-2.58 (m, 4H, 3.43-3.50 (m, 2H), 3.52-3.59 (m, 4H), 3.60-3.65 (m, 2H), 4.47 (s, 2H), 4.90 (s, IH), 6.62 (m, 2H), 6.91-7.09 (m, 3H), 7.52 (dd, J = 8.8 Hz, 2.5 Hz, IH), 7.62 (d, J= 1.8 Hz, IH), 8.2 (d, J= 2.5 Hz, IH).
Example 70. l-(2,5-Difluorobenzyl)-7-(6-moφholin-4-yl-pyridin-3-yl)- 1,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000113_0002
l-(2,5-Difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with 4-[5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2-yl]-morpholine as in General Procedure 4A to give the title compound as an off-white solid (48% yield). M.p. 206- 2070C, LCMS: m/z = 423.99 (M-HH+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.53 (m, 6H), 3.60- 3.67 (m, 2H), 3.80-3.87 (m, 4H), 4.48 (s, 2H), 4.86 (s, IH), 6.64 (d, J = 8.6 Hz, IH), 6.66 (s, IH), 6.89-7.06 (m, 3H), 7.55 (dd,J= 8.8 Hz, 2.5 Hz, IH), 7.62 (d,J= 1.8 Hz, IH), 8.24 (d, J= 2.3 Hz, IH). Example 71. 5-[ 1 -(2,5-Difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- pyridine-2-carbonitrile
Figure imgf000113_0003
l-(2,5-Difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (1.0 g) was reacted with 5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridine-2-carbonitrile as in General Procedure 4A to give the title compound as a bright yellow solid (24% yield). M.p. 200 0C (dec) , LCMS: m/z = 364.53 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 3.46-3.52 (m, 2H), 3.62- 3.72 (m, 2H), 4.50 (s, 2H), 5.12 (s, IH), 6.70 (s, IH), 6.92-7.00 (m, 2H), 7.03-7.12 (m, IH), 7.62-7.69 (m, 2H), 7.67 (s, J = 3.0 Hz, IH), 7.75 (m, IH), 8.73 (d, J= 1.5 Hz, IH). Example 72. 5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine- 2-carboxylic acid
Figure imgf000114_0001
5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carbonitrile (45 mg) was hydrolyzed as in General Procedure 9, with the exception that the reaction mixture was heated to 700C for three (3) hours. Filtration gave the title compound as a yellowish brown precipitate (63% yield). M.p. 240 0C (dec), LCMS: m/z = 383.00 (M+H4), 1H-NMR (DMSO-^6, 400 MHz) δ 3.29-3.38 (m, 2H), 3.42-3.49 (m, 2H), 4.60 (s, 2H), 6.95 (s, IH), 7.03 (s, IH), 7.12-7.19 (m, 2H), 7.28-7.35 (m, IH), 7.81 (s, IH), 8.00 (d, 7= 8.1 Hz, IH), 8.07 (dd, J= 8.1 Hz, 2.0 Hz, IH), 8.84 (s, IH).
Example 73. 5-[ 1 -(2,5-Difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pvrazin-7-yl]-nicotinic acid ethyl ester
Figure imgf000114_0002
l-(2,5-Difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (350 mg) was reacted with 5-(4,4,5-trimethyl-[l,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester as in General Procedure 4A to give the title compound as a tan solid (29% yield). M.p. 169-172 0C, LCMS: m/z = 411.03 (M+H1), 1H-NMR (CDCl3, 400 MHz) δ 1.42 (t, J= 7.1 Hz, 3H), 3.47-3.52 (m, 2H), 3.62-3.71 (m, 2H), 4.42 (q, J= 7.1 Hz, 2H), 4.51 (s, 2H), 4.99 (s, IH), 6.75 (s, IH), 6.91- 7.02 (m, 2H)3 7.03-7.11 (m, IH), 7.74 (d, J= 2.0 Hz, IH), 8.28 (d, J= 2.3 Hz, IH), 8.79 (d, J
= 2.3 Hz, IH), 9.08 (d, J= 2.0 Hz, IH).
Example 74. 5-[l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic acid
Figure imgf000115_0001
5-[ 1 -(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic acid ethyl ester (75 mg) was saponified as in General Procedure 7 to give the title compound as a tan solid (22% yield). M.p. 255-260 0C, LCMS: m/z = 382.94 (M+H*), 1H-NMR (DMSO-J6, 400 MHz) δ 3.28-3.36 (m, 2H), 3.42-3.50 (m, 2H), 4.60 (s, 2H), 6.84 (s, IH), 7.02 (s, IH), 7.12- 7.20 (m, 2H), 7.26-7.33 (m, IH), 7.74 (d, J= 1.8 Hz, IH), 8.27 (d, J= 2.0 Hz, IH), 8.89-8.93 (m, 2H).
Example 75. l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester
Figure imgf000115_0002
l-(2,5-Difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was combined with Mo(CO)6 (0.5 eq), DMAP (2.0 eq), and DIEA (2.0 eq) in a mixture of dioxane and ethanol (1:1, v/v) and heated to 1500C in a microwave oven for 15 minutes as described in J. Comb. Chem., 2003, 5, 350-352. The reaction mixture was diluted with ethanol and the black precipitate was filtered. Silica gel chromatography gave the title compound as a yellow solid (16% yield). M.p. 124-125 0C, LCMS: m/z = 334.02 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.0 Hz, 3H), 3.32-3.38 (m, 2H), 3.61-3.68 (m, 2H), 4.28 (q, J= 7.1 Hz, 2H), 4.45 (s, 2H), 5.68 (bs, IH), 6.90-6.99 (m, 2H), 7.01-7.09 (m, IH), 7.16 (d, J= 1.5 Hz, IH), 8.18 (d, J= 1.8 Hz, IH).
Example 76. {5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin- 2-yl} morpholin-4-yl-methanone
Figure imgf000116_0001
5-[l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carboxylic acid (32 mg) was reacted with morpholine as in General Procedure 8 to give the title compound as a yellow solid (26 % yield). M.p. 111-113 0C, LCMS: m/z = 451.92 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.47-3.53 (m, 2H), 3.67-3.76 (m, 8H), 3.77-3.85 (m, 2H), 4.50 (s, 2H), 5.09 (s, IH), 6.71 (d J= 1.5 Hz, IH), 6.92-7.04 (m, 2H), 7.05-7.12 (m, IH), 7.69-7.74 (m, 2H), 7.78-7.83 (m, 2H), 8.60 (d, J = 2.3 Hz, IH).
Example 77. l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile
Figure imgf000116_0002
l-(2,5-Difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (394 mg) was reacted with CuCN as in General Procedure 6 to give the title compound as a brown solid (86% yield).
M.p. 204-206 0C, LCMS: m/z = 287.07 (M+lT), 1H-NMR (DMSO-4 400 MHz) δ 3.23-3.37
(m, 2H), 3.44-3.50 (m, 2H), 4.49 (s, 2H), 6.82 (s, IH), 7.09-7.22 (m, 2H), 7.25-7.33 (m, IH),
7.62 (bs, IH), 7.73 (d, J= 1.8 Hz, IH).
Example 78. l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid
Figure imgf000116_0003
l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile (239 mg) was hydrolyzed as in General Procedure 9. Filtration gave the title compound as a brown solid (58% yield). M.p. 231 0C (dec), LCMS: m/z = 306.00 (MH-H+), 1H-NMR (DMSO-J6, 400 MHz) δ 3.37-3.42 (m, 2H), 3.55-3.60 (m, 2H), 4.55 (s, 2H), 6.94 (d, J= 1.0 Hz, IH), 7.22-7.33 (m, 2H), 7.40-7.48 (m, IH), 7.91 (d, J= 1.3 Hz, Ih), 8.31 (bs, IH). Example 79. [l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- methylpiperazin- 1 -yl)methanone
Figure imgf000117_0001
l-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (40 mg) was reacted with 1 -methyl piperazine as in General Procedure 8 to give the title compound as an orange foam (65% yield). M.p. (foam), LCMS: m/z = 388.08 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (s, 3H), 2.32-2.38 (m, 4H), 3.41 (t, J= 5.0 Hz, 2H), 3.53-3.61 (m, 4H), 3.62-3.65 (m, 2H), 4.44 (s, 2H), 5.07 (bs, IH), 6.61 (s, IH), 6.89-6.94 (m, 2H), 6.98-7.04 (m, IH), 7.59 (d, J= 1.5 Hz, IH).
Example 80. 1 -(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [2(4-methylpiperazin- 1 -yl)ethyl] amide
Figure imgf000117_0002
l-(2,5-Difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (40 mg) was reacted with 2(4-methylpiperazin-l-yl)ethylamine as in General Procedure 8 to give the title compound as an orange/brown foam (82% yield). M.p. (foam), LCMS: m/z = 431.09 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (s, 3H), 2.41-2.58 (m, 6H), 3.12-3.23 (m, 4H), 3.35-3.39 (m, 2H), 3.42-3.51 (m, 2H), 3.58-3.67 (m, 2H), 4.49 (s, 2H), 5.33 s, IH), 6.72 (s, IH), 6.84- 6.91 (m, 2H), 6.93-7.04 (m, IH), 7.10 (s, IH), 7.85 (d, J= 1.5 Hz, IH).
Example 81. 7-Iodo- 1 -(2,4,5-trifluorobenzyl)-3 ,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000118_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.0 g) was reacted with 2,4,5 trifluorobenzyl bromide as in General Procedure 1 to give the title compound as a pale yellow solid (55% yield). M.p. 227-228 0C, LCMS: m/z = 420.00 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 4.26 (s, 2H), 4.89 (bs, IH), 5.06 (s, 2H), 6.91-7.00 (m, 2H), 7.16 (s, IH), 7.91 (s, IH). Example 82. 7-Iodo-l-(2.4,5-trifluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000118_0002
7-Iodo-l-(2,4,5-trifluorobenzyl)-3,4-dihydro-lH-pyrido[2,3-b]pyra2in-2-one (600 mg) was reduced as in General Procedure 3 to give the title compound as a white solid (63% yield). M.p. 154-156 0C, LCMS: m/z = 405.92 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 4.27 (s, 2h), 4.91 (bs, IH), 5.06 (s, 2H), 6.93-7.02 (m, 2H), 7.19 (s, IH), 7.94 (d, J = 1.8 Hz, IH). Example 83. 7-[4-((S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 -carbonyl)phenyl]- 1 -(2,4,5- trifluorobenzyl)-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000118_0003
7-Iodo-l-(2,4,5-trifluorobenzyl)-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (42 mg) was reacted with S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4A to give the title compound as a white solid (31 % yield). M.p.l 17-118 LCMS: m/z = 550.20 (M+lT), 1H-NMR (CDCl3, 400 MHz) δ 1.48-1.69 (m, 4H), 1.88-2.15 (m, 5H), 2.57-2.70 (m, 3H), 2.80-2.92 (m, IH), 3.42-3.53 (m, 2H), 4.33 (s, 2H), 5.12 (bs, IH), 5.18 (s, 2H), 6.95-7.04 (m, IH), 7.08-7.14 (m,
IH), 7.22 (s, IH), 7.41 (d, J= 8.1 Hz, 2H), 7.52-7.60 (m, 2H), 8.03 (s, IH). Example 84. ((S)-2-((pyττolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)- {4-[ 1 -(2,4,5-trifluorobenzyl)- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone
Figure imgf000119_0001
7-Iodo-l-(2,4,5-trifluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with (S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 -carboxyl-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4A to give the title compound as a light orange foam (28 % yield). M.p. foam, LCMS: m/z = 536.13 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.47-1.60 (m, IH), 1.61-1.69 (m, 4H), 1.72-2.12 (m, 5H), 2.53-2.71 (m, 3H), 2.80-3.01 (m, IH), 3.38-3.43 (m, 2H), 3.45-3.51 (m, 2H), 3.63 (s, 2H), 4.46 (s, 2H), 4.96 (bs, 1H).6.75 (s, Ih), 6.94-7.02 (m, IH), 6.91-7.16 (m, IH), 7.41 (d, J= 8.3 Hz, 2H), 7.46-7.54 (m, 2H), 7.74 (s, IH).
Example 85. 7-[4-(4-Methylpiperazine-l-carbonyl)phenyl]-l-(2,4,5-trifluorobenzyl)-3,4- dihydro- 1 H-pyrido[2,3 -b]pyrazin-2-one
Figure imgf000119_0002
7-Iodo-l-(2,4,5-trifluorobenzyl)-3,4-dihydro-lH-pyrido[2,3-b]pyτazin-2-one (42 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white solid (32% yield). M.p. 238 0C, LCMS: m/z = 496.00 (M-J-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.35-2.53 (m, 4H), 3.43-3.58 (m, 2H), 3.72-3.84 (m, 2H), 4.33 (s, 2H), 5.11 (s, IH), 5.30 (s, 2H), 6.97-7.03 (m, IH), 7.05-7.14 (m, IH), 7.21 (s, IH), 7.45 (dd, J= 8.1 Hz, 4H), 8.02 (s, IH).
Example 86. (4-Methylpiperazin- 1 -yl)- {4-[ 1 -(2,4,5-trifluorobenzyl)- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone
Figure imgf000120_0001
7-Iodo-l-(2,4,5-trifluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (30% yield). M.p. (foam), LCMS: m/z = 482.10 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.35-2.52 (m, 4H), 3.39-3.42 (m, 2H), 3.42-3.56 (m, 2H), 3.58-3.66 (m, 2H), 3.68-3.88 (m, 2H), 4.45 (s, 2H), 4.98 (s, IH), 6.72 (s, IH), 6.89-7.02 (m, IH), 7.08-7.15 (m, IH), 7.35-7.44 (m, 4H), 7.70 (s, IH).
Example 87. (2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l- yl)methanone
Figure imgf000120_0002
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (614 mg) was reacted with 2,5-difluorobenzoyl chloride as in General Procedure 2 to give the title compound as an off-white foam (47% yield). M.p. foam, LCMS: m/z = 402.20 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.70-1.90 (m, 2H), 3.50-3.65 (m, 2H), 5.29 (bs, IH), 6.99 (s, IH), 7.10-7.18 (m, 2H), 7.20-7.25 (m, IH), 7.99 (s, IH).
Example 88. (2,5-Difluorophenyl)- {7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4- dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl} -methanone
Figure imgf000120_0003
(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)methanone (35 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3J2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a light yellow solid (36 % yield). M.p. 201-203 0C, LCMS: m/z = 478.10 (M-HJ+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.33-2.52 (m, 4H), 3.40-3.85 (m, 8H), 5.31 (s, IH), 6.70-7.05 (m, 3H), 7.15 (s, IH), 7.24-7.45 (m, 4H), 8.09 (s, IH).
Example 89. (2,5-Difluorophenyl)-{7-[4-((S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l- carbonyl)phenyl] -3,4-dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl} -methanone
Figure imgf000121_0001
(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)methanone (30 mg) was reacted with (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4A to give the title compound as tan film (13% yield). M.p.(film), LCMS: m/z = 532.10 (MW-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.76-1.88 (m, 4H), 1.90-2.15 (m, 5H), 2.62-2.73 (m, 4H), 2.90-2.99 (m, IH), 3.38-3.75 (m, 5H), 4.40-4.45 (m, IH), 5.35 (s, IH), 6.72-6.98 (m, 3H), 7.15 (s, IH), 7.27- 7.53 (m, 4H), 8.09 (s, IH). Example 90. 2-(5-Iodo-3-nitro-pyridin-2-ylamino)-2-methyl-propionic acid methyl ester
2-Chloro-5-iodo-3-nitro-pyridine (1.61 g) was dissolved in ethanol. Methyl a- aminoisobutyrate HCl was added (2.4 eq) followed by triethylamine (2.4 eq). The reaction mixture was heated to 1500C in a microwave oven for 30 minutes. The reaction mixture was concentrated to dryness and triturated with H2O. Silica gel chromatography of the resulting brown solid afforded the title compound as a bright yellow crystalline solid (78 % yield based on recovered starting material). M.p. 121-122 0C, 1H-NMR (CDCl3, 400 MHz) δ 1.56 (s, 3H), 1.66 (s, 3H), 3.67 (s, 3H), 8.53 (s, IH), 8.47 (d, J= 2.0 Hz, IH), 8.68 (d, J= 2.3 Hz, IH). Example 91. 7-Iodo-3,3-dimethyl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000122_0001
2-(5-Iodo-3-nitro-pyridin-2-ylamino)-2-πiethyl-propionic acid methyl ester (618 mg) was dissolved in ethanol. SnCl22H2O (5 eq) was added and the reaction mixture was heated to 800C for three (3) hours. The resulting precipitate was filtered and washed with ethanol to give the title compound as an off-white solid (46% yield). M.p. >300 0C, LCMS: m/z = 304.30 (M-I-H+), 1H-NMR (DMSO-J6, 400 MHz) δ 1.29 (s, 6H), 7.11 (bs, IH), 7.16 (d, J= 1.8 Hz, IH), 7.80 (d, J= 2.0 Hz, IH), 10.38 (bs, IH).
Example 92. 1 -(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro- lH-pyrido[2,3- b]pyrazin-2-one
Figure imgf000122_0002
7-Iodo-3,3-dimethyl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (237 mg) was reacted with 2,5-difluorobenzyl bromide as in General Procedure 1 to give the title compound as a white solid (98% yield). M.p. 198-201 0C, LCMS: m/z = 430.00 (MH-H+), 1H-NMR (DMSO-J6, 400 MHz) δ 1.36 (s, 6H), 5.12 (s, 2H), 6.79-6.83 (m, IH), 7.15-7.22 (m, IH), 7.28-7.32 (m, IH), 7.31 (s, IH), 7.40 (s, IH), 7.90 (s, IH).
Example 93. 1 -(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000122_0003
l-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (60 mg) was reduced as in General Procedure 3 to give the title compound as a white solid (53% yield). M.p. 168-169 0C, LCMS: m/z = 415.98 (M-HH+), 1H-NMR (CDCl3, 400 MHz) δ 1.27 (s, 6H), 3.05 (s, 2H), 4.41 (s, 2H), 4.64 (s, IH), 6.79 (s, IH), 6.92-6.98 (m, 2H), 7.02-7.10 (m,
IH), 7.63 (d, y = 1.0 Hz, IH). Example 94. l-(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-((S)-2-[(pyrrolidin-l- yl)methyl]pyrrolidine- 1 -carbonyl)phenyl]-3 ,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one
Figure imgf000123_0001
l-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3J4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (45 mg) was reacted with (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4A to give the title compound as a white solid (31% yield). M.p. 171-172 0C, LCMS: m/z = 560.16 (IVH-H+), 1H- NMR (CDCl3, 400 MHz) δ 1.56 (s, 6H)7 1.72-1.83 (m, 4H), 1.90-2.02 (m, 3H), 2.08-2.30 (m, 2H), 2.58-2.68 (m, 4H), 2.85-2.92 (m, IH), 3.36-3.56 (m, 2H), 4.43-4.48 (m, IH), 5.01 (s, IH), 5.21 (s, 2H), 6.84-6.88 (m, IH), 6.91-6.97 (m, IH), 7.04-7.11 (m, IH), 7.20 (1.5 Hz, IH), 7.41 (d, J= 8.4 Hz, 2H), 7.52-7.58 (m, 2H), 8.04 (d, J = 1.5 Hz, IH). Example 95. 1 -(2,5-Difluorobenzyl)-3,3-dimethyl-7-[4-(4-methylpiperazine-l - carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000123_0002
l-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-lH-pyrido[2,3-b]pyτazin-2-one (45 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white solid (55% yield). M.p. 204-206 0C, LCMS: m/z = 506.16 (M+H*), 1H-NMR (CDCI3, 400 MHz) δ 1.56 (s, 6H), 2.33 (s, 3H), 2.36-2.54 (m, 4H), 3.36-3.54 (m, 2H), 3.73-3.83 (m, 2H), 5.14 (s, IH), 5.21 (s, 2H), 6.84-6.88 (m, IH), 6.93-6.98 (m, IH), 7.07-7.13 (m, IH), 7.19 (d, J= 1.5 Hz, IH), 7.43 (m, 4H), 8.03 (d, J= 2.0 Hz, IH).
Example 96. {4-[l-(2,5-Difluorobenzyl)-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 7-yl]phenyl} -((S)-2-((pyrrolidin-l -yl)methyl)pyrrolidin- 1 -yl)methanone
Figure imgf000124_0001
l-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazme (44 mg) was reacted with (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4A to give the title compound as a light yellow solid (11 % yield). M.p. 74-77°C, LCMS: m/z = 546.15 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.26 (s, 6H). 1.70-1.83 (m, 4H), 1.85-1.99 (m, 4H), 2.00-2.16 (m, 2H), 2.58-2.69 (m, 4H), 2.82-2.94 (m, IH), 3.13 (s, 2H), 3.46-3.54 (m, 2H), 4.52 (s, 2H), 4.77 (bs, IH), 6.80 (s, IH), 6.94-6.96 (m, IH), 7.03-7.07 (m, 2H), 7.42 (d, J= 8.1 Hz, 2H), 7.42-7.53 (m, 2H), 7.74 (s, IH).
Example 97. {4-[l-(2,5-Difluorobenzyl)-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 7-yl]phenyl}-(4-methylpiperazin-l-yl)methanone
Figure imgf000124_0002
l-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine (44 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as an off-white solid (55% yield). M.p. 191-192 0C, LCMS: m/z = 492.10 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.34 (s, 6H), 2.32 (s, 3H), 2.38-2.50 (m, 4H), 3.13 (s, 2H), 3.45-3.58 (m, 2H), 3.65- 3.85 (m, 2H), 4.52 (s, 2H), 4.90 (bs, IH), 6.79 (d, J = 1.3 Hz, IH), 6.90-6.97 (m, IH), 6.99- 7.08 (m, 2H), 7.42 (dd, J= 8.6 Hz, 4H), 7.74 (d, J= 1.5 Hz, IH).
Example 98. 1 -(2-Chloro-3,6-difluorobenzyl)-7-iodo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000124_0003
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (34S mg) was reduced as in General Procedure 3 to give the title compound as an off-white solid (42 % yield). M.p. 156-157 0C, LCMS: m/z = 422.00 (MH-H+), 1H-ISIMR (CDCl3, 400 MHz) δ 3.12- 3.20 (m, 2H), 3.42-3.50 (m, 2H), 4.41 (s, 2H), 4.89 (bs, IH), 6.98-7.05 (m, IH), 7.08 (s, IH), 7.10-7.18 (m, IH), 7.62 (d, J= 1.5 Hz, IH).
Example 99. {4-[l-(2-Chloro-3,6-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -(4-(pyrrolidin-l-yl)piperidin-l -yl)methanone
Figure imgf000125_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (42 mg) was reacted with (4-(pyrrolidin-l-yl)piperidin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (36 % yield). M.p. 93-95 0C, LCMS: m/z = 553.00 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.75-1.85 (m, 5H), 1.87-2.04 (m, 2H), 2.22-2.33 (m, IH), 2.88-3.08 (m, 2H), 3.28- 3.33 (m, 2H), 3.52-3.58 (m3 2H), 3.82-3.90 (m, IH), 4.53 (s, IH), 4.90 (bs, IH), 6.96-7.02 (m, IH), 7.17 (s, IH), 7.18-7.20 (m, IH), 7.42 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.75 (s, IH).
Example 100. {4-[l-(2-Chloro-3,6-difluorobenzyl)-l,2,3J4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -((S)-2-((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone
Figure imgf000125_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (42 mg) was reacted with (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4,5,5-tetram ethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4A to give the title compound as a pale yellow foam (33% yield). M.p. (foam) , LCMS: m/z = 553.00 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.73-1.80 (m, 4H), 1.90-2.04 (m, 3 H), 2.10-2.29 (m, 2H), 2.58-2.70 (m, 4H), 2.85-2.95 (m, IH), 3.26-3.33 (m, 2H), 3.48-3.58 (m, 2H), 4.42-4.50 (m, IH), 4.53 (s, 2H),
4.95 (s, IH), 6.96-7.04 (m, IH), 7.11 (s, IH), 7.10-7.18 (m, IH), 7.47-7.56 (m, 4H), 7.74 (s,
IH).
Example 101. l-(2-Chloro-3,6-difluorobenzyl)-7-(3-chloro-2-inoφholin-4-yl-pyridin-4-yl)- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000126_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 rag) was reacted with 4-[3-chloro-4-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)pyridin-2 -yl]morpholine as in General Procedure 4A to give the title compound as a tan foam (49% yield). M.p. (foam), LCMS: m/z = 493.59 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (t, J= 5.3 Hz, 2H), 3.38 (t, J = 4.8 Hz, 4H), 3.52-3.58 (m, 2H), 3.89 (t, J= 4.3 Hz, 4H), 4.47 (d, J = 1.3 Hz, 2H), 5.16 (bs, IH), 6.89 (d, J= 5.0 Hz, IH), 6.97-7.06 (m, 2H), 7.08-7.15 (m, IH), 7.56 (d, J= 1.8 Hz, IH), 8.17 (d, J= 5.0 Hz, IH).
Example 102. l-(2-Chloro-3,6-difluorobenzyl)-7-(3-fluoro-2-moφholin-4-yl-pyridin-4-yl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000126_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 4-[3-fluoro-4-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)pyridin-2 -yljmorpholine as in General Procedure 4A to give the title compound as a tan foam (35% yield). M.p. (foam), LCMS: m/z = 476.02 (M+Ef), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (t, J= 4.8 Hz, 2H), 3.48 (t, J= 4.8 Hz, 4H), 3.52-3.65 (m, 2H), 3.87 (t, J= 4.6 Hz, 4H), 4.50 (s, 2H), 5.38 (bs, IH), 6.82-6.86 (m, IH), 6.97-7.04 (m, IH), 7.08 (s, IH), 7.04-7.15 (m, IH), 7.70 (s, IH), 8.00 (d, J= 5.0 Hz, IH). Example 103. l-(2-Chloro-3,6-difluorobenzyl)-7-(3,5-dimethyl-isoxazol-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000127_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyτido[2,3-b]pyrazine (75 mg) was reacted with 3,5-dimethylisoxazole-4 boronic acid as in General Procedure 4A to give the title compound as a pale yellow solid (45% yield). M.p. 215-216 0C, LCMS: m/z = 393.42 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.22 (s, 3H), 2.36 (s, 3H), 3.31 (t, J= 5.0 Hz, 2H), 3.52-3.58 (m, 2H), 4.47 (s, 2H), 4.98 (bs, IH), 6.71 (s, IH), 6.98-7.05 (m, IH), 7.09-7.17 (m, IH), 7.36 (d, J= 1.3 Hz, IH).
Example 104. {4-[l-(2-Chloro-3,6-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljphenyl} -(4-methylpiperazin-l -yl)methanone
Figure imgf000127_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanόne as in General Procedure 4A to give the title compound as a pale yellow foam (17 % yield). M.p. (foam), LCMS: m/z = 499.43 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.36-2.52 (m, 4H), 3.26-3.33 (m, 2H), 3.52-3.56 (m, 2H), 3.52-3.86 (m, 4H), 4.53 (s, 2H), 5.00 (bs, IH), 6.97-7.04 (m, IH), 7.10 (s, IH), 7.11-7.17 (m, IH), 7.44 (dd, J= 8.4 Hz, 1.8 Hz, 2H), 7.52 (dd, J= 8.3 Hz, 1.8 Hz, 2H), 7.74 (d, J= 1.8 Hz, IH). Example 105. l-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000128_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-morpholino)pyridine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as a beige foam (52% yield). M.p. (foam), LCMS: m/z = 458.04 (M+H1"), 1H-NMR (CDCl3, 400 MHz) δ 3.28-3.34 (m, 2H), 3.51-3.59 (m, 6H), 3.81-3.88 (m, 4H), 4.54 (s, 2H), 5.30 (s, IH), 6.69 (d, J = 8.8 Hz, IH), 7.00-7.08 (m, 2H), 7.11-7.18 (m, IH), 7.53 (s, IH), 7.61 (dd, J = 8.8 Hz, 2.5 Hz, IH), 8.33 (s, J= 2.2 Hz, IH).
Example 106. l-(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-l-yl)-pyrimidin-5-yl]- 1 ,2,3,4-tetrahydropyrido[2>3-b]pyrazine
Figure imgf000128_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-methylpiperazin-l-yl)pyrimidine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as a pale orange solid (27 % yield). M.p. 194-195 0C, LCMS: m/z = 472.09 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.38 (s, 3H), 2.51-2.58 (m, 4H), 3.31 (t, J= 4.8 Hz, 2H), 3.49-3.58 (m, 2H), 3.89-3.97 (m, 4H), 4.51 (s, 2H), 4.95 (bs, IH), 6.96 (s, IH), 6.99-7.08 (m, IH), 7.10-7.18 (m, IH), 7.57 (s, IH), 8.45 (s, IH). Example 107. l-(2-Chloro-3,6-difluorobenzyl)-7-(2-moφholin-4-yl-pyrimidin-5-yl)-l,2,3,4- tetrahydropyrido [2,3 -b]pyrazine
Figure imgf000128_0003
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-moφholino)pyrimidine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as an off-white solid (27% yield). M.p. 250-251 0C, LCMS: m/z
= 459.17 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.29-3.35 (m, 2H), 3.52-3.56 (m, 2H), 3.78-
3.84 (m, 8H), 4.51 (s, 2H), 4.86 (bs, IH), 6.96 (s, IH), 7.00-7.08 (m, IH), 7.10-7.17 (m, IH),
7.59 (d, J = 1.8 Hz, IH), 8.46 (s, IH).
Example 108. l-(2-Chloro-3,6-difluorobenzyl)-7-(4-moφholin-4-yl-phenyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000129_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 4-morpholine phenyl-boronic acid pinacol ester as in General Procedure 4A to give the title compound as a pale yellow solid (49% yield). M.p. 217-219 0C, LCMS: m/z = 456.56 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.19 (t, J = 4.8 Hz, 4H), 3.27 (t, J= 4.8 Hz, 2H), 3.49-3.55 (m, 2H), 3.88 (t, J= 4.6 Hz, 4H), 4.52 (s, 2H), 4.78 (bs, IH), 6.96 (d, J = 8.8 Hz, 2H), 6.98-7.05 (m, IH), 7.09 (s, IH), 7.10-7.15 (m, IH), 7.42 (d, J= 8.6 Hz, 2H), 7.70 (d, J = 1.5 Hz, IH).
Example 109. 7-[6-(4-Methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000129_0002
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazme (704 mg) was reacted with l-methyl-4-[5- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow solid (20% yield). M.p. 225 0C (dec) , LCMS: m/z = 311.13 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 2.49-2.56 (m, 4H), 3.36-3.42 (m, 2H), 3.53-3.63 (m, 6H), 4.90 (bs, IH), 6.68 (d, J= 8.8 Hz, IH), 6.77 (d, J = 1.5 Hz, IH), 7.58 (dd, J= 8.8 Hz, 2.3 Hz, IH), 7.63 (d, J= 1.3 Hz, IH), 8.31 (d, J= 2.0 Hz, IH). Example 110. l-(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)-2-phenylethanone
Figure imgf000130_0001
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with phenyl acetyl chloride as in General Procedure 2 to give the title compound as a pale yellow foam (31% yield). M.p. (foam), LCMS: m/z = 379.86 (NU-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.32-3.45 (m, 2H), 3.75-3.85 (m, 2H), 3.87 (s, 2H), 5.25 (bs, IH), 7.21-7.38 (m, 5H), 8.01 (s, IH). Example 111. 2-Phenyl- 1 - {7-[4-(4-(pyττolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl] -3,4- dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl} -ethanone
Figure imgf000130_0002
l-(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)-2-phenylethanone (30 mg) was reacted with (4-(pyrrolidin-l-yl)piperidin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white foam (52 % yield). M.p. (foam), LCMS: m/z = 510.13 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 1.47-1.62 (m, 2H), 1.75-2.05 (m, 3H), 2.22-2.29 (m, IH), 2.53-2.62 (m, 5H), 2.82-3.10 (m, 3H), 3.33-3.52 (m, 2H), 3.71-3.88 (m, 3H), 3.95 (s, 2H), 4.51-4.63 (m, IH), 5.25 (bs, IH), 7.12-7.34 (m, 5H), 7.35-7.48 (m, 4H), 8.16 (s, IH).
Example 112. 2-(2,5-Difluorophenyl)-l-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l- yl)ethanone
Figure imgf000130_0003
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with 2,5-difluorophenyl acetyl chloride as in General Procedure 2 to give the title compound as an off-white solid (14% yield). M.p. 152-153 0C, LCMS: m/z = 415.90 OVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.47- 3.54 (m, 2H), 3.80-3.87 (m, 4H), 5.44 (bs, IH), 6.90-7.04 (m, 3H), 8.03 (s, IH). Example 113. 2-(2,5-Difluorophenyl)-l-{7-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]r3,4- dihydro-2H-pyrido[2,3-b]pyrazin-l -yl} ethanone
Figure imgf000131_0001
2-(2,5-Difluorophenyl)-l -(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl)-ethanone (30 mg) was reacted with l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yljpiperazine as in General Procedure 4A to give the title compound as a light yellow solid (15% yield). M.p. >300 0C, LCMS: m/z = 465.02 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (s, 3H), 2.52-2.57 (m, 2H), 3.52-3.62 (m, 6H), 3.90-3.96 (m, 4H), 5.11 (bs, IH), 6.70 (d, J = 8.8 Hz, IH), 6.90-7.04 (m, 3H), 7.41-7.58 (m, 2H), 8.07 (s, IH), 8.32 (s, IH). Example 114. 2-(2,5-Difluoroρhenyl)-l-{7-[4-(4-(pyrrolidin-l-yl)piperidine-l- carbonyl)phenyl]-3 ,4-dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl} ethanone
Figure imgf000131_0002
2-(2,5-Difluorophenyl)-l-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)ethanone (30 mg) was reacted with (4-(pyrrolidin-l-yl)piperidin-l-yl)-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4 A to give the title compound as a white foam (20% yield). M.p. (foam), LCMS: m/z = 546.09 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42-1.72 (m, 6H), 2.22-2.42 (m, 2H), 2.54-2.64 (m, 5H), 2.85-3.11 (m, 3H), 3.56-3.62 (m, 2H), 3.88-3.92 (m, 4H), 4.55-4.66 (m, IH), 5.23 (s, IH), 6.91-7.07 (m, 3H), 7.41-7.49 (m, 4H), 8.16 (s, IH). Example 115. l-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000132_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (968 mg) was reacted with 5-chloro-2- (trifluoromethyl)benzyl bromide as in General Procedure 1. The resulting l-(2-chloro-5- trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one was reduced as in General Procedure 2 to give the title compound as an orange solid (17% yield). M.p. 189- 191°C, LCMS: m/z = 454.08(NH-H+), 1H-NMR (DMSO-^6, 400 MHz) δ 3.28-3.34 (m, 2H), 3.41-3.46 (m, 2H), 4.53 (s, 2H), 6.52 (s, IH), 6.75 (s, IH), 7.44 (s, 2H), 7.59 (d, J= 8.4 Hz, IH), 7.82 (d, J= 8.6 Hz, IH).
Example 116. l-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one
Figure imgf000132_0002
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (924 mg) was reacted with 2-chloro-5- (trifluoromethyl)benzyl bromide as in General Procedure 1 to give the title compound as a white solid (39% yield). M.p. 252-253°C, LCMS: m/z = 468.02 (M+H1"), 1H-NMR (DMSO- d6, 400 MHz) δ 4.16 (d, J= 1.2 Hz, 2H), 5.16 (s, 2H), 7.20 (s, IH), 7.26 (d, J= 1.3 Hz, IH), 7.42 (s, IH), 7.71 (dd, J= 8.3Hz, 1.5 Hz, IH), 7.77 (d, J= 8.6 Hz, IH), 7.83 (d, J= 1.5 Hz, IH). Example 117. {4-[l-(5-Chloro-2-trifluoromethylbenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]phenyl} -(4-(p yrrolidin- 1 -yl)piperidin- 1 -yl)methanone
Figure imgf000133_0001
l-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with (4-(pyrrolidin-l-yl)piperidin-l-yl)-[4-(4,4,5,5-tetramethyl [l,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as an orange foam (19% yield). M.p. (foam), LCMS: m/z = 487.19, 1H-NMR (CDCl3, 400 MHz) δ 1.43-1.62 (m, 3H), 1.65-1.99 (m, 3H), 2.21-2.30 (m, 2H), 2.52-2.61 (m, 6H), 2.87-3.08 (m, 3H), 3.47-3.51 (m, 2H), 3.65-3.71 (m, 2H), 4.62 (s, 2H), 5.02 (s, IH), 6.59 (d, J= 1.5 Hz, IH), 7.31-7.39 (m, 5H), 7.50 (s, IH), 7.65 (d, J= 8.4 Hz, IH), 7.74 (s, IH). Example 118. l-(5-Chloro-2-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000133_0002
l-(5-Chloro-2-trifIuoromethylbenzyl)-7-iodo-l ,2)3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yI)pyridin-2- yl]piperazine as in General Procedure 4A to give the title compound as a pale orange solid (28% yield). M.p. 226-227 0C, LCMS: m/z = 503.90 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.51 (t, J= 5.0 Hz, 4H), 3.47-3.56 (m, 6H), 3.62-3.69 (m, 2H), 4.61 (s, 2H), 4.92 (bs, IH), 6.49 (d, J= 1.0 Hz, IH), 6.64 (d, J= 8.8 Hz, IH), 7.34 (d, J= 8.3 Hz, IH), 7.52- 7.58 (m, 2H), 7.61-7.65 (m, 2H), 8.18 (d, J= 2.3 Hz, IH). Example 119. l-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000134_0001
l-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (590 mg) was reduced as in General Procedure 2 to give the title compound as a yellow solid (28% yield). M.p. 120-125 0C, LCMS: m/z = 454.01 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.38 (t, J = 5.0 Hz, 2H), 3.55-3.61 (m, 2H), 4.45 (s, 2H), 5.11 (s, IH), 6.66 (s, IH), 7.47 (s, IH), 7.53 (dd, J = 8.3 Hz, 2H), 7.62 (d, J=1.8 Hz, IH).
Example 120. l-(2-Chloro-5-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin-l -yl)pyridin-3- yl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000134_0002
l-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2",3-b]pyrazine (40 mg) was reacted with l-methyl-4-[5-(4,4,5,5-tetτamethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yljpiperazine as in General Procedure 4A to give the title compound as a yellow film (13% yield). M.p. (film), LCMS: m/z = 502.98 (M+ET), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.51 (t, J= 5.3 Hz, 4H), 3.28 (X, J= 5.3 Hz, 2H), 3.54 (t, J= 5.0 Hz, 4H), 3.66-3.72 (m, 2H), 4.53 (s, 2H), 4.89 (bs, IH), 6.53 (s, IH), 6.64 (d, J= 8.8 Hz, IH), 7.46-7.54 (m, 4H), 7.63 (d, J= 1.8 Hz, IH), 8.18 (d, ./=2.3 Hz, IH).
Example 121. 1 -(2,5-Difluorobenzenesulfonyl)-7-iodo- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000134_0003
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was dissolved in anhydrous pyridine. 2,5-difluorobenzene sulfonyl chloride (1.0 eq) was added and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography to give the title compound as a pale yellow solid (13% yield). M.p. 187-188 0C, LCMS: m/z = 437.73 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.29-3.33 (m, 2H), 3.83 (t, J = 4.8 Hz, 2H), 5.08 (bs, IH), 7.11-7.19 (m, IH), 7.26-7.33 (m, IH), 7.58-7.63 (m, IH), 7.96 (d, J= 1.5 Hz, IH), 8.03 (d, J= 1.8 Hz, IH).
Example 122. 1 -(2,5-Difluorobenzenesulfonyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000135_0001
l-(2,5-Difluorobenzenesulfonyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yl]piperazine as in General Procedure 4 A to methyl-piperazine as a yellow foam (35% yield).
M.p. (foam), LCMS: m/z = 487.04 (TvH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.54
(t, J= 5.3 Hz, 4H), 3.35-3.38 (m, 2H), 3.60 (t, J= 5.0 Hz, 4H), 3.91 (t, J= 4.8 Hz, 2H), 5.05
(bs, IH),
6.71 (d, J= 8.8 Hz, IH), 7.11-7.17 (m, IH), 7.24-7.29 (m, IH), 7.58-7.63 (m, 2H), 7.90 (d, J=
2.0 Hz, IH), 8.05 (d, J= 2.3 Hz, IH), 8.34 (d, J= 2.6 Hz, IH).
Example 123. l-Benzenesulfonyl-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000135_0002
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous pyridine. Phenylsulfonyl chloride (1.0 eq) was added and the reaction mixture was heated to 1000C in a microwave oven for 10 minutes. Silica gel chromatography gave the title compound as a pale orange solid (23% yield). M.p. 145-146 0C, LCMS: m/z = 407.71 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.94-2.99 (m, 2H)3 3.74 (t, J = 5.0 Hz, 2H), 4.83 (bs, IH), 7.45-7.49 (m, 2H),
7.58-7.65 (m, 3H), 8.06 (d, J = 2.0 Hz, IH), 8.17 (d, J= 2.0 Hz, IH).
Example 124. l-(2-Chlorobenzenesulfonyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000136_0001
7-Iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous pyridine. 2-chlorobenzene sulfonyl chloride (1.0 eq) was added and the reaction mixture was heated to 1000C in a microwave oven for 10 minutes. Silica gel chromatography gave the title compound as a pale orange solid (10% yield). M.p. 146-147 0C, LCMS: m/z = 435.94 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.30-3.35 (m, 2H), 3.80 (t, J= 5.0 Hz, 2H), 5.02 (bs, IH), 7.42-4.57 (m, 3H), 7.81 (d, J= 1.8 Hz, IH), 8.00 (d, J= 1.8 Hz, IH), 8.10 (dd, J= 8.6 Hz, 1.5 Hz, IH).
Example 125. 1 -Benzenesulfonyl-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000136_0002
l-Benzenesulfonyl-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was reacted with l-Methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow foam (72% yield). M.p. (foam), LCMS: m/z = 450-98 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.39 (s, 3H), 2.60 (t, J= 5.0 Hz, 4H), 2.98-3.03 (m, 2H), 3.64 (t, J = 5.0 Hz, 4H), 3.80 (t, J= 5.0 Hz, 2H), 5.16 (bs, IH), 6.73 (d, J= 8.8 Hz, IH), 7.40-7.45 (m, 2H), 7.51-7.54 (m, IH), 7.62 (d, J = 8.6 Hz, 2H), 7.67 (dd, J= 8.8 Hz, 2,5 Hz, IH), 8.08 (s, IH), 8.40 (d, J= 2.0 Hz, IH).
Example 126. l-(2-Chlorobenzenesulfonyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4 tetrahydropyrido[2,3-b]pyrazine
Figure imgf000137_0001
l-(2-Crilorobenzenesulfonyl-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (44 mg) was reacted with l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yI)pyridin-2- yl]piperazine as in General Procedure 4A to give the title compound as a yellow solid (41% yield). M.p. 164-165 0C, LCMS: m/z = 486.79 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (s, 3H), 2.54 (t, J= 5.1 Hz, 4H), 3.39-3.42 (m, 2H), 3.60 (t, J= 4.5 Hz, 4H), 3.88 (t, J = 4.5 Hz, 2H), 5.17 (bs, IH), 6.69 (d, J= 8.8 Hz, IH), 7.39-7.45 (m, IH), 7.51-7.56 (m, 3H), 7.73 (s, IH), 8.01 (d, J = 1.0 Hz, IH), 8.13 (dd, J= 8.6 Hz, 1.0 Hz, IH), 8.27 (d, J = 2.6 Hz, IH). Example 127. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile
Figure imgf000137_0002
l-(2,5-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (2.0 g) was reacted with CuCN as in General Procedure 6 to give the title compound as an off-white solid (46% yield). M.p. 221-222 0C, LCMS: m/z = 320.77 (M+H*), 1H-NMR (DMSO -Z6, 400 MHz) δ 3.28 (t, J= 4.6 Hz, 2H), 3.45-3.54 (m, 2H), 4.48 (s, 2H), 6.69 (s, IH), 7.29 (d, J= 2.5 Hz, IH), 7.41 (dd,J= 8.6 Hz, 2.5 Hz, IH), 7.54 (d, J= 8.6 Hz, IH), 7.67 (bs, IH), 7.75 (d, J= 1.8 Hz, IH).
Example 128. 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid
Figure imgf000137_0003
l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile (680 mg) was hydrolyzed as in General Procedure 9. Filtration gave the title compound as an orange solid (quantitative yield). M.p. 273 0C (dec), LCMS: m/z = 340.23 (M+lT), 1H-NMR (DMSO-^6, 400 MHz) δ 3.48-3.53 (m, 2H), 3.61-3.71 (m, 2H), 4.62 (s, 2H), 6.87 (s, IH), 7.42 (d, J= 7.6 Hz, IH), 7.43 (s, IH), 7.57 (d, J= 7.8 Hz, IH), 7.88 (s, IH), 9.33 (bs, IH), 13.20 (bs, IH). Example 129. 1 -(2,5-Dichlorobenzyl)-7-(2-methoxypyrimidin-5-yl)- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000138_0001
l-(2,5-dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (500 mg) was reacted with 2-methoxypyrimidine-5-boronic acid as in General Procedure 4A to give the title compound as a pale orange foam in 42 % yield. M.p. (foam), LCMS: m/z = 404.36 (M+H1"), 1H-NMR (CDCl3, 400 MHz) B 3.51 (t, J= 5.3 Hz, 2H), 3.66-3.70 (m, 2H), 4.01 (s, 3H), 4.49 (s, 2H), 4.99 (bs, IH), 6.46 (d, J= 1.5 Hz, IH), 7.18-7.26 (m, 2H), 7.35 (d, J= 8.3 Hz, IH), 7.62 (d, J= 2.0 Hz, IH), 8.50 (s, IH).
Example 130.4-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3 ,6- dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester
Figure imgf000138_0002
l-(2,5-dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with 4-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester as in General Procedure 4A to give the title compound as a beige solid (35% yield). M.p. 92-95 0C, LCMS: m/z = 477.28 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 2.32-2.38 (m, 2H), 3.39-3.46 (m, 2H), 3.52-3.59 (m, 2H), 3.60-3.65 (m, 2H), 3.95-3.99 (m, 2H), 4.43 (s, 2H), 5.18 (s, IH), 5.69-5.72 (m, IH), 6.43 (s, IH), 7.17-7.20 (m, IH), 7.23 (s, IH), 7.34 (d, J= 8.3 Hz, IH), 7.50 (s, IH). Example 131. l-(2,5-Dichlorobenzyl)-7-(l,2,3,6-tetrahydropyridin-4-yl)-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000139_0001
4-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H- pyridine- 1-carboxylic acid tert-butyl ester (105.mg) was dissolved in CH2Cl2ZIn fluoroacetic acid (3:1, v/v) and stirred at room temperature for two (2) hours. The reaction mixture was concentrated, diluted with CH2Cl2, washed with NaHCO3 (x2), dried, filtered, and concentrated to give the title compound as a pale orange solid (84% yield). M.p. 133-136 0C, LCMS: m/z = 375.13 (MH-H+), 1H-NMR (DMSCW6, 400 MHz) δ 2.30-2.38 (m, 2H), 3.00- 3.06 (m, IH), 3.28-3.34 (m, 2H), 3.52-3.58 (m, 2H), 4.49 (s, 2H), 5.80 (s, IH), 6.47 (s, IH), 6.59 (s, IH), 7.29 (d, J= 2.5 Hz, IH), 7..37-7 '.42 (m, 2H), 7.54 (d, J= 8.6 Hz, IH). Example 132. {4-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -(4-methylpiperazin- 1 -yl)methanone
Figure imgf000139_0002
l-(2,5-dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (49% yield). M.p. (foam), LCMS: m/z = 498.07 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (s, 3H), 2.32-2.50 (m, 4H), 3.44-3.51 (m, 2H), 3.45-3.84 (m, 4H), 3.63-3.68 (m, 2H), 4.49 (s, 2H), 5.21 (s, IH), 6.62 (d, J= 1.5 Hz, IH), 7.18-7.21 (m, IH), 7.24-7.29 (m, IH), 7.34 (d, J = 8.6 Hz, IH), 7.39-7.42 (m, 4H), 7.72 (d, J= 1.8 Hz, IH).
Example 133. l-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one
Figure imgf000140_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.07 g) was reacted with 5-fluoro-2- trifluoromethylbenzyl bromide as in General Procedure 1 to give the title compound as an off- white solid (51% yield). M.p. 244-245 0C, LCMS: m/z = 453.03 (IVH-H+), 1H-NMR (DMSO- d6, 400 MHz) δ 4.21 (s, 2H), 5.15 (s, 2H), 6.97 (s, IHO, 7.12 (d, J= 9.8 Hz, IH), 7.25 (s, IH), 7.36 (dd, J= 8.3 Hz, IH), 7.84 (s, IH), 7.88-7.94 (m, IH).
Example 134. 1 -(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-2-ol
Figure imgf000140_0002
l-(5-Fluoro-2-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (870 mg) was reduced as in General Procedure 3 to give the title compound as an off-white solid (30% yield). M.p. 142 0C (dec) , LCMS: m/z = 455.10 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.51 (d, J= 11.4 Hz, IH), 3.61 (dd, J= 11.4 Hz, 1.5 Hz, IH), 4.57 (d, J= 18.2 Hz, IH), 4.87 (d, J= 18.2 Hz, IH), 4.95 (s, IH), 5.32 (bs, IH), 6.49 (d, J= 1.6 Hz, IH), 7.01-7.11 (m, 2H), 7.56 (d, J= 1.5 Hz, IH), 7.73 (dd, J= 8.6 Hz, 3.3 Hz, IH).
Example 135.4-(2-Oxo-l,2,3,4-tetrahydropyrido[2,3-b]pvrazin-7-yl)benzoic acid ethyl ester
Figure imgf000140_0003
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (520 mg) was reacted with A- ethoxycarbonylphenyl boronic acid as in General Procedure 4B to give the title compound as a light yellow solid in 79% yield. M.p. >200°C, LCMS: m/z = 298.14 (M+H*), 1H-NMR (DMSO-(Z6, 400 MHz) δ 1.33 (3H, t, J= 7.1 Hz), 4.32 (2H, q, J= 7.1 Hz), 7.26 (IH, d, J= 2.0
Hz), 7.67 (2H, d, J= 8.3 Hz), 7.99 (2H, d, J= 8.1Hz), 8.04 (IH, d, J= 2.3 Hz).
Example 136. l-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000141_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (500 mg) was treated with 2,6- dichlorobenzyl bromide as in General Procedure 1 to give the title compound as an off-white solid. M.p. >200°C, LCMS: m/z = 434.37 (M+H+), 1H-NMR (DMSCW6, 400 MHz) δ 3.30 (2H, s), 5.29 (2H, s), 7.31 (IH, d, J=8.6 Hz), 7.34 (IH, d, J=7.6 Hz), 7.45 (IH, s), 7.47 (IH, s), 7.76 (IH, d, J=LO Hz). Example 137. l-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one
Figure imgf000141_0002
l-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (150 mg) was reacted with pyridine-3-boronic acid as in General Procedure 4B to give the title compound as a brown solid. M.p. >200°C, LCMS: m/z = 385.48 (M+H*), 1H-NMR (DMSO-^6, 400 MHz) δ 4.06 (2H, s), 5.45 (2H, s), 7.07 (IH, s), 7.45 (5H, m), 7.85 (IH, d, J= 7.8 Hz), 8.01 (IH, s), 8.49 (IH, d, J= 4.8 Hz), 8.67 (IH, s) (NMR and LCMS indicate presence of triphenylphosphine impurity) Example 138. 1 -(2,6-Dichlorobenzyl)-7-pyridin-3-yl-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine, trifluoroacetic acid salt
Figure imgf000142_0001
l-(2,6-Dichlorobenzyl)-7-pyridin-3-yl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (83 mg) was reduced as in General Procedure 3 to give the title compound as a green solid after preparative reversed-phase HPLC purification (3% yield). LCMS: m/z = 371.35 (IVH-H+), 1H- NMR (CDCl3, 400 MHz) δ 3.24 (2H, t, , J= 4.9 Hz), 3.62 (2H, t, J= 4.9 Hz), 4.72 (2H,s), 7.19 (IH7S), 7.43 (2H, d, J= 8.1 Hz), 7.47 (IH, d, J= 1.5 Hz), 7.54 (IH, m), 7.96 (IH, m), 8.65 (IH, d, J= 4.3 Hz), 8.80 (IH, s).
Example 139. 4-[ 1 -(2,6-Dichlorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljbenzoic acid ethyl ester
Figure imgf000142_0002
l-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (231 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid. M.p. = 226°C, LCMS: m/z = 456.52 (M+H4), 1H-NMR (DMSO- d6, 400 MHz) δ 1.35 (3H, t, J= 6.9 Hz), 4.09 (3H, s), 4.33 (3H, q, J= 7.1 Hz), 5.47 (2H, s), 7.32 (2H, m), 7.48 (2H, d, J= 8.1 Hz), 7.57 (3H, m), 7.63 (IH, m), 7.9O(1H, m), 7.98 (2H,d, J = 8.2 Hz), 8.03 (lH,d, J= 2.0 Hz).
Example 140. 4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]benzoic acid
Figure imgf000142_0003
4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester (243 mg) was saponified as in General Procedure 7 to give the title compound as an off-white solid (87% yield). M.p. > 2000C, LCMS: m/z = 428.47 (M+H+), 1H-NMR (DMSO- dβ, 400 MHz) δ 4.07 (2H,d, J= 1.3 Hz), 5.44 (2H,s), 7.10 (IH, bs), 7.32 (2H,m), 7.48 (2H,d, J = 8.1 Hz), 7.54 (2H7d, J= 8.3 Hz), 7.95 (2H,d, J= 8.3 Hz), 8.03 (lH,d, J= 2.0 Hz). Example 141. Sr-l-(2,6-Dichlorobenzyl)-7-[4-((2-pyrrolidin-l-yl)methylpyrrolidine-l - carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000143_0001
4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (43 mg) was coupled to (S)-(+)-l-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a brown solid (41% yield). M.p. = 188°C, LCMS: m/z = 564.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 0.88 (IH, m), 1.26 (2H, m), 1.76 (5H, m), 2.04 (6H, m), 2.23 (IH, m), 2.64 (4H, m), 2.89 (IH, m), 3.49 (3H, m), 4.25 (2H, s), 4.45 (IH, bs), 4.84 (IH, bs), 5.56 (2H, s), 7.16 (IH, m), 7.33 (4H, m), 7.52 (2H,d, J= 8.3 Hz), 7.94 (lH,d, J= 1.5 Hz).
Example 142. 4-[l-(2,6-Dichlorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- N-(2-pyrrolidin- 1 -yl-ethyl)benzamide
Figure imgf000143_0002
4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (40 mg) was coupled to 2-pyrrolidin-l-yl-ethylamine as in General Procedure 8 to give the title compound as an off-white solid (26% yield). M.p. > 2000C, LCMS: m/z = 524.11 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.82 (4H, m), 2.60 (4H, m), 2.74 (2H, m), 3.59 (2H, m), 4.26 (2H, s), 4.85 (IH, bs), 5.56 (2H, s), 7.16 (IH, m), 7.32 (2H,d, J= 8.1 Hz), 7.39 (2H,d, J= 8.3 Hz), 7.82 (2H,d, J= 8.3 Hz), 7.96 (lH,d, J= 1.8 Hz). Example 143. 4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3J4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- N-(6-dimethylaminohexyl)benzamide, trifluoroacetic acid salt
Figure imgf000144_0001
4-[ 1 -(2,6-Dichlorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (43 mg) was coupled to 3-dimethylaminohexylamine as in General Procedure 8 to give the title compound as an off-white solid after preparative reversed-phase HPLC purification (33% yield). M.p. = 1500C, LCMS: m/z = 554.28 (IvM-H+), 1H-NMR (CD3OD, 400 MHz) δ 1.47 (4H, m), 1.71(4H, m), 2.88 (6H, s), 3.13 (2H,t, J= 8.1 Hz), 3.41 (2H,t, J= 7.1 Hz), 4.30 (2H,s), 5.63 (2H,s), 7.28 (lH,m), 7.42 (3Hjn), 7.48 (2H,d, J= 8.3 Hz), 7.88 (3H,m). Example 144. 4-[l-(2,6-Dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- N-(4-dimethylaminobutyl)benzamide, trifluoroacetic acid salt
Figure imgf000144_0002
4-[l -(2,6-Dichlorobenzyl)-2-oxo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (36 mg) was coupled to 3-Dimethylaminobutylamine as in General Procedure 8 to give the title compound as a tan solid after preparative reversed-phase HPLC purification (50% yield). M.p. = 147°C, LCMS: m/z = 526.11 (M+H*), 1H-NMR (CD3OD, 400 MHz) δ 1.71 (2H, m), 1.80 (2H, m), 2.90 (6H, s), 3.20 (2H, t, J= 7.8 Hz), 3.46 (2H, t, J= 6.7 Hz), 4.35 (2H, s), 5.64 (2H, s), 7.29 (IH, t, J= 8.1 Hz), 7.43 (2H, d, J= 8.1 Hz), 7.48 (2H, d,J= 6.1 Hz), 7.51 (IH, s), 7.89 (2H, s), 7.90 (IH, s). Example 145. 7-Iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin- 2-one
Figure imgf000145_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (297 mg) was alkylated with 1-(1- bromoethyl)-2,4,5-trifluorobenzene as in General Procedure 1 to give the title compound. Example 146. 7-[4-(4-Methylpiperazine-l -carbonyl)phenyl]- 1 -[I -(2,4,5- trifluorophenyl)ethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000145_0002
7-Iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (45 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4B to give the title compound as a colorless solid after preparative reversed-phase HPLC purification (15% yield). LCMS: m/z = 510.11 (M+H*), 1H-NMR (CD3OD, 400 MHz) δ 1.91 (3H, d, J= 7.1 Hz), 2.96 (3H, s,), 3.22 (2H, m), 3.52 (3H, m), 4.28 (2H, d), 6.22 (IH, m), 7.17 (IH, m), 7.64 (5H, m), 7.82 (IH, s), 7.93 (IH, s).
Example 147. 7-Iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000145_0003
7-Iodo-l -[I -(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (551 mg) was reduced as in General Procedure 3 to give the title compound as a yellow foam (52% yield). LCMS: m/z = 419.94 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.54 (3H, d, J= 6.8 Hz), 3.15 (IH, m), 3.30 (IH, m), 3.43 (2H, t, J= 4.7 Hz), 5.02 (IH, quartet, J= 6.9 Hz), 5.47 (IH, bs), 6.86 (IH, s), 6.96 (IH, m), 7.11 (IH, m), 7.55 (IH, d, J= 1.5 Hz). Example 148. S- {2-[(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl} -(4- { 1 -[ 1 -(2,4,5- trifluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone, trifluoroacetic acid salt
Figure imgf000146_0001
7-Iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (44 mg) was reacted with (S)-2-pyrrolidin-l-yl-methylpyrrolidine-l-carboxyl-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4B to give the title compound as a yellow solid after reversed-phase HPLC purification (45% yield). LCMS: m/z = 550.09 (M+HT), 1H-NMR (CD3OD, 400 MHz) δ 3.31 (3H, d, J= 6.8 Hz), 2.06 (8H, m), 3.21 (3H, m), 3.49 (6H, m), 3.74 (IH, m), 4.05 (IH, m), 4.58 (IH, m), 5.50 (IH, quartet, J= 6.8 Hz), 7.24 (IH, m), 7.41 (IH, s), 7.53 (2H, m), 7.69 (4H, m).
Example 149. (4-Methylpiperazin-l -yl)-(4- { 1 - [ 1 -(2,4,5-trifluorophenyl)ethyl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000146_0002
7-Iodo-l-[l-(2,4J5-trifluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (30 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid
(2% yield). LCMS: m/z = 560.73 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.26 (8H, m), 2.44
(7H, m), 3.64 (4H, m), 7.38 (IH, m), 7.47 (4H, m), 7.61 (4H, m).
Example 150. 1 -[ 1 -(2,5-Di£luorophenyl)ethyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one
Figure imgf000147_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.030 g) was alkylated with 2,5-difluoro- alpha-bromoethylbenzeπe as in General Procedure 1 to give the title compound as a yellow solid. LCMS: m/z = 415.93 (M-HH+)
Example 151.5-(4-{l-[l-(2,5-Difluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-
7-yl}phenyl)-{2-[(pyrrolidin-l-yl)methyl]pyrrolidin-l-yl}methanone
Figure imgf000147_0002
1 -[ 1 -(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-l H-pyrido[2,3-b]pyrazin-2-one (59 mg) was reacted with (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4)5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4B to give the title compound as a yellow solid (4% yield). LCMS: m/z = 546.15(MH-H+), 1H-NMR (CD3OD, 400 MHz) δ 1.57 (IH, m), 1.84 (4H, m), 1.89 (3H, d, J= 7.1 Hz), 1.98 (3H, m), 2.15 (2H, s), 2.71 (4H, m), 2.93 (IH, m), 3.44 (IH, m), 3.61 (IH, m), 4.07 (2H, d, J= 4.3 Hz), 4.43 (IH, bs), 6.23 (IH, m), 7.05 (2H, m), 7.49 (6H, m), 7.95 (IH, s).
Example 152. l-[l-(2,5-Dϊfluorophenyl)ethyl]-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]- 3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one, trifluoroacetic acid salt
Figure imgf000147_0003
1 -[ 1 -(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one (55 mg) was reacted with (4-methylpiperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid after preparative reversed-phase HPLC purification (7% yield). LCMS: m/z = 492.13 (M+H*), 1H-NMR (CD3OD, 400 MHz) δ 1.91 (3H, d, J= 7.1 Hz), 2.96 (3H, s), 3.22 (5H, m), 3.52 (3H, m), 4.31 (2H, m), 6.32 (IH, quartet, J= 6.8 Hz), 7.09 (2H, m), 7.51 (IH, m), 7.58 (4H, m), 7.74 (IH, s), 7.90 (IH, d, J= 1.5 Hz).
Example 153. l-[l-(2,5-Difluorophenyl)ethyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000148_0001
1 -[I -(2,5-Difluorophenyl)ethyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (438 mg) was reduced as in General Procedure 3 to give the title compound as a yellow solid. LCMS: m/z = 402.01 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 1.55 (3H, d, J= 6.8 Hz), 3.34 (2H, m), 3.44 (2H, m), 4.81 (IH, s), 5.05 (IH, m), 7.00 (4H, m), 7.58 (IH, d, J= 1.5 Hz). Example 154.5-(4-{l-[l-(2,5-Difluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 7-yl}phenyl)- {2-[(pyrrolidin-l-yl)methyl]pyrrolidin-l -yl}methanone
Figure imgf000148_0002
l-[l-(2,5-Difluorophenyl)ethyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (73 mg) was reacted with (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4B to give the title compound as an orange foam (6% yield). LCMS: m/z = 532.12 (M+H+), 1H-NMR (CD3OD, 400 MHz) 6 1.61 (3H, m), 1.84 (4H, m), 2.03 (3H, m), 2.24 (2H, m), 2.73 (2H, m), 2.94 (IH, m), 3.44 (3H, m), 3.58 (IH, m), 4.15 (4H, m), 4.43 (IH, bs), 5.28 (IH, m), 7.04 (2H, m), 7.14 (IH, m), 7.22 (IH, m), 7.54 (5H, m). Example 155. l-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000148_0003
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.012 g) was reacted with 2,5- dichlorobenzyl bromide as in General Procedure 1 to give the title compound as a brown solid
(69% yield). M.p. > 200° C, LCMS: m/z = 434.36 (NM-H+), 1H-NMR (DMS(W6, 400 MHz) δ 4.18 (2H, s), 5.07 (2H, s), 4.18 (2H, s), 7.14 (IH, d, J = 1.8 Hz), 7.15 (IH, d, J= 2.3 Hz),
7.40 (IH, dd, J= 8.6, 2.5 Hz), 7.56 (IH, d, J= 8.6 Hz), 7.85 (IH, d, J= 1.8 Hz).
Example 156. l-(2,5-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l -carbonyl)phenyl]-
3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000149_0001
l-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (62 mg) was reacted with (4-(pyrrolidin-l-yl)piperidin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4B to give the title compound as a brown solid (42% yield). M.p. > 200° C, LCMS: m/z = 564.14 (MH-H+), 1H-NMR (DMSCW6, 400 MHz) δ 1.37 (2H, m), 1.67 (4H, m), 1.81 (2H, m), 3.22 (6H, m), 3.51 (3H, m), 4.22 (2H, s), 5.23 (2H, s), 7.22 (3H, m), 7.38 (3H, m), 7.55 (3H, m), 8.06 (IH, s).
Example 157. S- 1 -(2,5-Dichlorobenzyl)-7-[4-(2-[(pyrrolidin-l -yl)methyl]pyrrolidine-l - carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000149_0002
l-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (47 mg) was reacted with (S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 -carboxyl-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4B to give the title compound as a brown solid (47% yield). M.p. = 180 ° C, LCMS: m/z = 564.09 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.99 (HH, m), 2.64 (3H, m), 2.87 (IH, m), 3.48 (2H, m), 4.38 (2H, s), 4.44 (IH, bs), 5.26 (2H, s), 5.44 (IH, s), 7.05 (2H, m), 7.21 (IH, dd, J = 8.6, 2.3 Hz), 7.37 (3H, m), 7.54 (2H, m), 8.02 (IH, s).
Example 158. l-(2,5-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000150_0001
l-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (991 mg) was reduced as in General Procedure 3 to give the title compound as a brown solid (85% yield). M.p. = 169 ° C, LCMS: m/z = 421.39 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.40 (3H, m), 3.59 (2H, m), 4.39 (2H, s), 4.85(1H, bs), 6.64 (IH, s), 7.18 (IH, d, J = 2.8 Hz), 7.22 (IH, dd, J = 8.6, 2.8 Hz), 7.35 (IH, d, J= 8.6 Hz), 7.63 (IH, d, J= 1.5 Hz). Example 159. S'-{4-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} - {2- [(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl } methanone
Figure imgf000150_0002
l-(2,5-Dichlorobenzyl)-7-iodo-3J4-dihydro-lH-pyrido[2,3-b]pyrazine (106 mg) was reacted with (S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine-l -carboxyl-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4B to give the title compound as a brown solid (1% yield). LCMS: m/z = 550.03 (M+KT), 1H-NMR (CDCl3, 400 MHz) δ 1.78 (4H, m), 1.99 (1 H, m), 2.17 (2H, s), 2.64 (3H, m), 2.87 (IH, m), 3.48 (4H, m), 3.66 (2H, m), 4.44 (IH, m), 4.50 (2H, s), 4.92 (IH, bs), 6.64 (IH, s), 7.21 (IH, dd, J = 8.5, 2.4 Hz), 7.30 (IH, d, J= 2.3 Hz), 7.35 (IH, ά,J= 8.6 Hz), 7.39 (2H, d, J= 8.3 Hz), 7.50 (2H, m), 7.61 (IH, m), 7.73 (IH, d, J= 1.8 Hz).
Example 160. {4-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -(4-(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone
Figure imgf000150_0003
l-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazine (64 mg) was reacted with (4-(pyrrolidin-l-yl)piperidin-l-yl)-[4-(4,4,5,5-tetramethyl-[l,3j2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (10% yield). LCMS: m/z = 550.11 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53 (2H, m), 1.80 (7H3 m), 2.25 (IH, m), 2.57 (4H, m), 2.98 (2H, m), 3.48 (2H, t, J= 4.7 Hz), 3.65 (2H, m), 3.82 (IH, bs), 4.49 (2H, s), 4.59 (IH, m), 5.00 (IH, bs), 6.63 (IH, d, J= 1.3 Hz), 7.21 (IH, dd, J= 8.6, 2.5 Hz), 7.29(1H, d, J= 2.5 Hz), 37.38 (5H, m), 7.73 (IH, d, J= 1.8 Hz). Example 161. l-(2,6-Dichlorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]- 3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
Figure imgf000151_0001
l-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (60 mg) was reacted with (4-(pyrrolidin- 1 -yl)piperidin- l-yl)-[4-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4B to give the title compound as a brown solid (35% yield). M.p. = 199 ° C, LCMS: m/z = 564.03 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.89 (6H, m), 2.25 (IH, m), 2.59 (5H, s), 2.99 (3H, m), 3.80 (IH, bs), 4.26 (2H, d, J= 1.3 Hz), 4.60 (IH, bs), 4.84(1H, bs), 5.56 (2H, s), 7.17 (IH, m), 7.33 (5H, m), 7.41 (2H, d, J= 8.1 Hz), 7.94 (IH, d, J= 1.8 Hz),
Example 162. 1 -(2,6-Dichlorobenzyl)-7-iodo- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000151_0002
l-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one was reduced as in General Procedure 3 to give the title compound as a light yellow solid. M.p. > 200 ° C, LCMS: m/z = 420.31 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.03 (2H, t, J= 4.8 Hz), 3.42 (2H, m), 4.48 (2H, s), 4.81 (IH, s), 7.09 (IH, s), 7.24 (IH, m), 7.36 (2H, d, J= 8.2 Hz), 7.63 (IH, d, J= 1.6 Hz). Example 163. {4-[l-(2,6-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -(4-(pyrrolidin- 1 -yl)piperidin-l -yl)methanone
Figure imgf000152_0001
l-(2,6-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (56 mg) was reacted with (4-(pyτrolidin- 1 -yl)piperidin-l -yl)- [4-(4,4,5,5-tetramethyl-[ 1 ,3 ,2]dioxaborolan-2- yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (10% yield). LCMS: m/z = 470.05 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.56 (3H, m), 1.90 (1 IH, m), 2.17 (IH, s), 2.28 (IH, m), 2.59 (5H, m), 2.98 (3H, m), 3.14 (2H, t, J= 4.7 Hz), 3.50 (2H, m), 3.85 (IH, bs), 4.61 (3H, s), 4.92 (IH, bs), 7.12 (IH, s), 7.23 (IH, m), 7.48 (6H, m), 7.75 (IH, d, J= 1.5 Hz).
Example 164. {4-[l-(2,6-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} - {2-[(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl} methanone
Figure imgf000152_0002
l-(2,6-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (72 mg) was reacted with (S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxyl-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)phenyl]amide as in General Procedure 4B to give the title compound as a yellow solid (22% yield). LCMS: m/z = 549.94 (M+H1), 1H-NMR (CDCl3, 400 MHz) 6 1.83 (7H, m), 2.26 (2H, m), 3.01 (5H, m)s 3.57 (4H, m), 4.46 (IH, bs), 4.61 (2H, s), 5.17 (IH, bs), 7.11 (IH, d, J= 1.5 Hz), 7.25 (IH, m), 7.37 (2H, d, J= 8.1 Hz), 7.56 (4H, m), 7.74 (IH, s).
Example 165- 7-(6-Chloropyridin-3-yl)-l-(2J5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000153_0001
1 -(2,5-DiChIoTObCnZyI)-T-IOdO- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (115 mg) was reacted with 2-chloro-5-(4,4,5,5-tetτamethyl-l,3,2-dioxaborolan-2-yl)pyridine as in General Procedure 4B to give the title compound as a yellow solid (54% yield). M.p. = 205 ° C, LCMS: m/z = 405.57 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.50 (2H, t, J = 4.8 Hz), 3.67 (2H, m), 4.49 (2H, s), 5.10 (IH, bs), 6.52 (IH, s), 7.21 (IH, dd, J= 8.3, 2.3 Hz), 7.29 (2H, m), 7.35 (IH, d, J = 8.3 Hz), 7.55 (2H, m), 8.36 (IH, d, J= 2.5 Hz).
Example 166. l-(2,5-Dichlorobenzyl)-7-(6-pyrrolidin-l-yl-pyridin-3-yl)-l ,2,3,4- tetrahydropyrido[2,3 -b]pyrazine
Figure imgf000153_0002
Pyrrolidine (1 mL) was added to 7-(6-chloropyridin-3-yl)-l -(2,5-dichlorobenzyl)- 1,2,3,4- tetrahydropyrido[2,3-b]pyrazine (49 mg), and the mixture was stirred at 87°C for 16 hours. The reaction mixture was then concentrated, and CH2Cl2 and H2O were added. The organic phase was isolated, dried with magnesium sulfate, filtered and then purified by normal phase column chromatography eluting with 3% methanol in CH2Cbto give the title compound as a yellow solid (36% yield). M.p. > 200 ° C, LCMS: m/z = 440.19 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 1.99 (4H, m), 3.47 (6H, m), 3.64 (2H, t, J= 4.0 Hz), 4.47 (2H, s), 4.98 (IH, bs), 6.35 (IH, d, J= 8.8 Hz), 6.52 (IH, d, J= 1.8 Hz), 7.18 (IH, dd, J= 8.3, 2.5 Hz), 7.26 (IH, m), 7.32 (IH, d, J= 8.6 Hz), 7.48 (IH, dd, J= 8.7, 2.4 Hz), 7.62 (IH, d, J = 1.8 Hz), 8.17 (IH, d, J == 2.3 Hz).
Example 167. 7-(2-Chloropyridin-4-yl)-l-(2,6-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000154_0001
l-(2,6-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (511 mg) was reacted with 2-chloropyridine-4-boronic acid as in General Procedure 4B to give the title compound as a yellow solid (31% yield). M.p. = 194° C, LCMS: m/z = 405.56 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.17 (2H, t, J= 4.8 Hz), 3.53 (2H, m), 4.62 (2H, s), 5.12 (IH, bs), 7.06 (IH, s), 7.42 (4H, m), 7.68 (IH, m), 7.81 (IH, d, J= 1.8 Hz), 8.35 (IH, d, J= 5.1 Hz). Example 168. {3-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynyl}carbamic acid tert-butyl ester
Figure imgf000154_0002
l-(2,5-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was coupled with N-boc propargylamine as in General Procedure 5 to give the title compound as a yellow solid (63% yield). LCMS: m/z = 447.49 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.45 (9H, s),
3.41 (2H, t, J= 4.8 Hz), 3.62 (2H, s), 4.05(2H, m), 4.40 (2H, s), 4.81 (IH, m), 5.41 (IH, bs),
6.41 (IH, s), 7.21 (2H, m), 7.34 (IH, d, J= 8.3 Hz), 7.61 (IH, s).
Example 169. 3-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynylamine
Figure imgf000154_0003
{3-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl} carbamic acid tert-butyl ester (19 mg), trifluoroacetic acid (250 μL) and CH2Cl2 (1 mL) were stirred under nitrogen at room temperature for 1.5 hours. 2 N NaOH (2 mL) and CH2Cl2 (approx. 10 mL) were added. The organic phase was isolated, washed twice with H2O, washed once with brine, dried over sodium sulfate, filtered and then purified by normal phase column chromatography, eluting with 5% methanol in methylene chloride, to give the title compound as an off-white solid (37% yield). M.p. = 183° C, LCMS: m/z = 347.35 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.42 (2H, t, J= 4.8 Hz), 3.61 (4H, m), 4.41 (2H, s), 5.04 (IH, bs), 6.42 (IH, s), 7.21 (2H, m), 7.34 (IH, d, J= 8.3 Hz), 7.59 (IH, s, J= 1.0 Hz).
Example 170. {3-[l-(2,6-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynyl}carbamic acid tert-butyl ester
Figure imgf000155_0001
l-(2,6-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (1.951 g) was coupled with N-boc propargylamine as in General Procedure 5 to give the title compound as an orange solid. LCMS: m/z = 447.53 (MH-H+), 1H-NMR (DMSO-Ci6, 400 MHz) δ 1.40 (9H, s), 2.86
(2H, m), 3.27 (2H, m), 3.95 (2H, d, J= 5.6 Hz), 4.46 (2H, s), 6.86 (IH, s), 6.89 (IH, s), 7.29
(IH, m), 7.42 (2H, m), 7.54 (2H, d, J= 8.3 Hz).
Example 171. 3-[l-(2,6-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynylamine, trifluoroacetic acid salt
Figure imgf000155_0002
{3-[ 1 -(2,6-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl} carbamic acid tert-butyl ester (641 mg), trifluoroacetic acid (3.1 mL) and CH2Cl2 (31 mL) were stirred overnight under nitrogen at room temperature, then concentrated to give the title compound. Example 172. N- {3-[ 1 -(2,6-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido [2,3-b]pyrazin-7- yl]prop-2-ynyl}-2-dimethylamino-acetamide
Figure imgf000156_0001
3-[ 1 -(2,6-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynylamine, trifluoroacetic acid salt(s) (99 mg) and 1 N NaOH (4 mL) were stirred at room temperature for two (2) hours. The reaction mixture was then concentrated, anhydrous CH2CI2 (4 mL), dimethylaminoacetyl chloride HCl (48 mg) and triethylamine (45 μL) were added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then concentrated and purified with normal phase column chromatography, eluting with 9/1 CH2Cl2/methanol to 97/3/1 CH2Cl2/methanol/NH4θH to give the title compound as a yellow solid. M.p. > 200° C, LCMS: m/z = 432.04 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (6H, s), 3.00 (4H, m), 3.44 (2H, m), 4.31 (2H, d, J= 5.6 Hz), 4.50 (2H, s), 5.11 (IH, bs), 6.93 (IH, d, J= 1.0 Hz), 7.23 (IH, m), 7.37 (2H, m), 7.63 (IH, d, J= 1.5 Hz).
Example 173. {3-[ 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynyl } -dimethylamine
Figure imgf000156_0002
l-(2,5-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (113 mg) was coupled with l-dimethylamino-2-propyne as in General Procedure 5 to give the title compound as a yellow solid (49% yield). M.p. = 168° C, LCMS: m/z = 375.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (6H, s), 3.38 (4H, m), 3.61 (2H, t, J= 4.0 Hz), 4.40 (2H, s), 5.54 (IH, bs), 6.45 (IH, d, J= 1.5 Hz), 7.21 (2H, m), 7.33 (IH, m), 7.61 (IH, d, J= 1.5 Hz). Example 174. l-(2,5-Dichlorobenzyl)-7-[3-(l,l-dioxo-lλ6-thiomorpholin-4-yl)prop-l-ynyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000157_0001
l-(2,5-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (108 mg) was coupled with 4-prop-2-ynyl-thiomorpholine 1,1 -dioxide as in General Procedure 5 to give the title compound as an off-white solid (34% yield). M.p. > 200° C, LCMS: m/z = 467.33 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.11 (8H, s), 3.40 (2H, t, J= 4.8 Hz), 3.56 (2H, s), 3.61 (2H, t, J = 4.7 Hz), 4.41 (2H, s), 6.42 (IH, dt, J= 1.5 Hz), 7.22 (2H, m), 7.35 (IH, d, J= 8.3 Hz), 7.58 (IH, d, J= 1.5 Hz).
Example 175. l-[l-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one
Figure imgf000157_0002
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (2.935 g) was treated with 2-(l- bromoethyl)-3-chloro-l,4-difluorobenzene (Preparation 3) as in General Procedure 1 to give the title compound as an orange solid (11% yield). LCMS: m/z = 449.86 (M+H*), 1H-NMR (DMSO-rfe, 400 MHz) δ 1.79 (3H, m), 2.73 (IH, s), 2.89 (IH, s), 5.76 (IH, m), 6.96 (IH, s), 7.29 (IH, m), 7.43 (IH, m), 7.62 (IH, s), 7.83 (IH, m).
Example 176. l-[l-(2-Chloro-3,6-dif-uorophenyl)ethyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000157_0003
l-[l-(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (514 mg) was reduced as in General Procedure 3 to give the title compound as an orange solid (59% yield). M.p. = 166° C, LCMS: m/z = 436.07 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 1.63 (3H, m), 3.46 (4H, m), 4.75 (IH, bs), 5.16 (IH, quartet, J = 7.2 Hz), 6.81 (IH, s), 6.97(1H, m), 7.08 (IH, m), 7.54 (IH, d, J= 1.5 Hz).
Example 177. 1 -[ 1 -(2-Chloro-3 ,6-difluorophenyl)ethyl]-7-[6-(4-methylpiperazin- 1 -yl)pyridin- 3-yl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000158_0001
1 -[I -(2-Chloro-3,6-difluorophenyl)ethyl]-7-iodo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine (53 mg) was coupled to l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yl]piperazine as in General Procedure 4B to give the title compound as an orange solid (15% yield). LCMS: m/z = 435.02 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.66 (3H, d, J= 7.1 Hz), 2.35 (3H, s), 2.54 (4H, t, J = 4.9 Hz), 3.54 (8H, m), 4.89 (IH, bs), 5.31 (IH, m), 6.68 (IH, d, J= 8.9 Hz), 6.72 (IH, s), 6.96 (IH, m), 7.05 (IH, m), 7.52 (IH, dd, J= 8.8, 2.5 Hz), 7.57 (IH, s), 8.29 (IH, d, J= 2.3 Hz).
Example 178. l-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one
Figure imgf000158_0002
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.051 g) was alkylated with 3-fluoro-2-
(trifluoromethyl)benzyl bromide as in General Procedure 1 to give the title compound as a light brown solid (54% yield). M.p. > 200 ° C, LCMS: m/z = 451.79 (M+H4), 1H-NMR (DMSO-^6,
400 MHz) δ 4.17 (2H, s), 5.20 (2H, bs), 7.01 (IH, d, J= 7.6 Hz), 7.17 (IH, s), 7.23 (IH, s),
7.42 (IH, m), 7.63 (IH, m), 7.86 (IH, m).
Example 179. 1 -[3-Fluoro-2-(trifluorornethyl)benzyl]-7-iodo-l ,2,3,4-tetrahydropyrido[2,3- bjpyrazine
Figure imgf000159_0001
l-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one
(922 mg) was reduced as in General Procedure 3 to give the title compound as a brown solid
(64% yield). LCMS: m/z = 437.80 (M-I-H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.28 (2H, m),
3.40 (2H, m), 4.60 (2H, s), 4.68 (IH, m), 6.59 (IH, d, J= 1.3 Hz), 6.70 (IH, s), 7.22 (IH, d, J
= 7.8 Hz), 7.43 (IH, d, J= 1.5 Hz), 7.69 (IH, m).
Example 180. l-(2,5-Dichlorobenzyl)-7-[6-(4-methylpiperazm-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000159_0002
l-(2,5-Dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (94 mg) was coupled to l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a brown solid (50% yield). LCMS: m/z = 468.97 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.51 (4H, t, J= 5.1 Hz), 3.48 (2H, m), 3.55 (4H, t, J= 5.1 Hz), 3.64(2H, t, J= 4.7 Hz), 4.46 (2H, s), 5.20 (IH, bs), 6.52 (IH, d, J= 1.5 Hz), 6.65 (IH, d, J= 8.8 Hz), 7.19 (IH, dd, J= 8.5, 2.4 Hz), 7.26 (IH, d, J= 2.3 Hz), 7.33 (IH, d, J= 8.3 Hz), 7.52 (IH, dd, J= 8.6, 2.5 Hz), 7.62 (IH, d, J= 1.5 Hz), 8.20 (IH, d, J = 2.5 Hz).
Example 181. l-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000159_0003
l-tS-Fluoro^-CtrifluoromethyObenzy^-V-iodo-l^.S^-tetrahydropyridotZ.S-bJpyrazine ClOl mg) was coupled to l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yl]piperazine as in General Procedure 4B to give the title compound as a yellow solid (31% yield). LCMS: m/z = 487.09 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.51 (4H, t, J= 4.9 Hz), 3.49 (2H, m), 3.55 (4H, t, J= 4.9 Hz), 3.63 (2H, m), 4.65 (2H, s), 5.08 (IH, bs), 6.48 (IH, d, J= 1.8 Hz), 6.64 (IH, d, J= 8.8 Hz), 7.09 (IH, m), 7.26 (IH, m), 7.45 (2H, m), 7.62 (IH, d, J= 1.8 Hz), 8.18 (IH, d, J= 2.5 Hz).
Example 182. l-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000160_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (308 mg) was coupled to 2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine as in General Procedure 4B to give the title compound (50% yield). LCMS: m/z = 407.32 (M+H"), 1H-NMR (CDCl3, 400 MHz) δ 3.30 (2H, X, J= 4.8 Hz), 3.56 (2H, m), 4.34 (2H, s), 5.35 (IH, bs), 7.06 (2H, m), 7.15 (IH, m), 7.33 (IH, dd,J= 5.3, 1.5 Hz), 5.46 (IH, m), 7.80 (IH, d, J= 1.5 Hz), 8.34 (IH, d, J= 5.3 Hz).
Example 183. l-(2-Chloro-3,6-difluorobenzyl)-7-(2-pyrrolidin-l-yl-pyridin-4-yl)-l,2,3,4- tetrahydrop yrido[2,3 -b] pyrazine
Figure imgf000160_0002
Pyrrolidine (1 mL) was added to l-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (32 mg). The reaction mixture was stirred at 87°C for 72 hours and then concentrated. The residue was purified by normal phase column chromatography eluting with 5% methanol in CH2CI2 to give the title compound as a yellow solid (35% yield). LCMS: m/z = 442.21 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.03 (4H, m), 3.33 (2H, m), 3.53 (6H, m), 4.53 (2H, d, J = 1.3 Hz), 5.06 (IH, bs), 6.43 (IH, d, J= 0.8 Hz), 6.68 (IH, dd, J= 5.4, 1.4 Hz), 7.02 (IH, m), 7.12 (2H, m), 7.79 (IH, d, J= 1.8 Hz), 8.15 (IH, d, J= 5.6 Hz).
Example 184. 5-[l-(2-Chloro-3,6-difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl] -pyridin-2-ylamine
Figure imgf000161_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (87 mg) was coupled to 5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2-ylamine as in General Procedure 4B to give the title compound as a light brown solid (52% yield). M.p. > 200° C, LCMS: m/z = 388.10 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (2H, m), 3.51 (2H, m), 4.52 (2H, d, J- 1.3 Hz), 6.58 (IH, dd, J= 8.6, 0.8 Hz), 7.00 (IH, d, J= 2.0 Hz), 7.05 (IH, m), 7.14 (IH, m), 7.30 (2H, s), 7.54 (IH, d, J= 2.0 Hz), 7.58 (IH, dd, J= 8.6, 2.5 Hz), 8.13 (IH, dd, J= 2.4, 0.6 Hz).
Example 185. l-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000161_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was coupled to l-Methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yl]piperazine as in General Procedure 4B to give the title compound as a light brown solid (16% yield). M.p. = 219° C, LCMS: m/z = 471.12 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (3H, s), 2.54 (4H, t, J= 5.1 Hz), 3.27 (2H, t, J= 4.8Hz), 3.51 (2H, t, J= 4.7 Hz), 3.59 (4H, t, J= 5.1 Hz), 4.50 (2H, d, J= 1.0 Hz), 5.01 (IH, bs), 6.70 (IH, d,J= 8.8 Hz), 7.03 (2H, m), 7.11 (IH, m), 7.61 (IH, dd, J= 8.8, 2.5 Hz), 7.64 (lH,d,J = 1.8 Hz), 8.35 (IH, d, J= 2.3
Hz).
Example 186. l-(2-Chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyridin-4-yl)-l,2,3,4- tetrahydropyrido [2,3 -b]ρyrazine
Figure imgf000162_0001
Morpholine (2 mL) was added to l-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (61 mg), and the mixture was heated in a microwave oven for two (2) hours at 180° C. The mixture was then concentrated, and the residue was purified through silica gel chromatography followed by preparative reversed-phase HPLC. The trifluoroacetic acid salt was neutralized with saturated sodium bicarbonate, and the free base extracted into methylene chloride, washed with brine and dried with magnesium sulfate. The solution was concentrated to give the title compound as a yellow solid (21% yield). M.p. = 157° C, LCMS: m/z = 458.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.38 (2H, t, J= 4.7 Hz), 3.56 (4H, t, J= 4.8 Hz), 3.62 (2H, t, J= 4.5 Hz), 3.86 (4H, t, J= 4.8 Hz), 4.58 (2H, s), 6.65 (IH, s), 6.76 (IH, d, J= 5.1 Hz), 7.06 (2H, m), 7.16 (IH, m), 7.59 (2H, m), 8.22 (IH, d, J = 5.1 Hz).
Example 187. 1 -(2,5 -Dichlorobenzyl)-7-iodo-4-methyl- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000162_0002
To a solution of l-(2,5-dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (305 mg) in anhydrous N,N-dirnethylformamide was added NaH (1.6 eq) followed by iodomethane (1.4 eq). The reaction mixture was stirred at room temperature for 48 hours and then concentrated. Column chromatography gave the title compound as a yellow solid (56% yield). LCMS: m/z = 434.17 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.09 (3H, s), 3.42 (2H, m), 3.48 (2H, m), 4.36 (2H, s), 6.54 (IH, d, J = 1.8 Hz), 7.17 (IH, d, J = 2.3 Hz), 7.21 (IH, dd,J= 8.6, 2.5 Hz), 7.34 (IH, d, J= 4.3 Hz), 7.72 (IH, d, J= 1.8 Hz).
Example 188. l-(2,5-Dichlorobenzyl)-4-methyl-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000163_0001
l-(2,5-Dichlorobenzyl)-7-iodo-4-methyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (83 mg) was coupled to l-methyl-4-[5-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)p>τidin-2- yl]piperazine as in General Procedure 4B to give the title compound as a brown solid (43% yield). LCMS: m/z = 483.33 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.52 (4H, t, J= 5.1 Hz), 3.16 (3H, s), 3.53 (8H, m), 4.45 (2H, s), 6.45 (lH,d, J= 1.8 Hz), 6.65 (IH, d, J= 8.8 Hz), 7.18 (IH, dd, J= 8.5, 4.8 Hz), 7.25 (IH, d, J= 2.3 Hz), 7.32 (IH, d, J= 8.3 Hz), 7.52 (IH, dd, J= 8.6, 2.5 Hz), 7.75 (IH, d, J= 1.8 Hz), 8.22 (IH, d, J= 2.5 Hz). Example 189. l-(2-Chloro-3,6-difluorobenzyl)-7-(3-morpholin-4-yl-phenyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000163_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine (100 mg) was coupled to 4-[3-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2- yl)phenyl]-morpholine as in General Procedure 4B to give the title compound as a yellow solid. LCMS: m/z = 457.05 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.21 (4H, t, J= 4.8 Hz), 3.29 (2H, t, J= 4.7 Hz), 3.52 (2H, t, J= 4.2 Hz), 3.89 (4H, t, J= 4.8 Hz), 4.52 (2H, s), 5.09 (IH, bs), 6.84 (IH, dd, J= 8.0, 1.9 Hz), 7.00 (3H, m), 7.10 (2H, m), 7.29 (IH, m), 7.72 (IH, d, J= 1.8 Hz).
Example 190. l-(2-Chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000164_0001
l-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine (88 mg) was coupled to l-methyl-4-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a light yellow solid (15% yield). LCMS: m/z = 471.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (3H, s), 2.56 (4H, t, J= 4.9 Hz), 3.33 (2H, t, J= 4.7 Hz), 3.55 (2H, m), 3.62 (4H, t, J= 4.9 Hz), 4.53 (2H, s), 5.23 (IH, bs), 6.72 (IH, s), 6.78 (IH, dd, J= 5.3, 1.3 Hz), 7.03 (2H, m), 7.12 (IH, m), 7.77(1H, d, J= 1.8 Hz), 8.18 (IH, d,J= 5.1 Hz).
Example 191. 1 -(2-ChIoro-3,6-difluorobenzyl)-7-[ 1 -(3-methylbutyl)- 1 H-pyrazol-4-yl] - 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000164_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (99 mg) was reacted with l-(3-methylbutyl)-lH-pyrazole-4-boronic acid, pinacol ester as in General Procedure 4B to give the title compound as a brown solid (21% yield). M.p. = 134° C, LCMS: m/z = 431.92 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 0.96 (6H, d, J= 6.6 Hz), 1.61 (IH, m), 1.80 (2H, m), 3.28 (2H, t, J= 4.8 Hz), 3.51 (2H, m), 4.15 (2H, t, J= 7.5 Hz), 4.50 (2H, s), 4.90 (IH, bs), 6.96 (IH, d, J= 1.5 Hz), 7.02 (IH, m), 7.12 (IH, m), 7.51 (IH, s), 7.63 (2H, m). Example 192. l-(2-Chloro-3,6-difluorobenzyl)-7-(l H-pyrazol-4-yl)- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000164_0003
1 -[(2-Chloro-3,6-difluoro)benzyl]-7-iodo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine (224 mg) was reacted with 4-(4,4,5,5-tetramethyl-l>3,2-dioxaborolan-2-yl)pyrazole-l-carboxylic acid- tert-butyl ester as in General Procedure 4B to give the title compound as an off-white solid. m.p. = 272° C, LCMS: m/z = 361.78 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.30 (2H, t, J= 4.7 Hz), 3.41 (IH, m), 3.50 (2H, m), 4.51 (2H, s), 7.00 (IH, d, J= 1.5 Hz), 7.04 (IH, m), 7.13 (IH, m), 7.59 (IH, d, J= 1.5 Hz), 7.72 (2H, s).
Example 193. 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoic acid ethyl ester
Figure imgf000165_0001
l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (7.0 g) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A. The title compound was obtained as a yellow solid (71% yield). M.p. = 154°C, LCMS: m/z = 476.04 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.40, (t, 3 H), 3.49 (m, 2H), 3.71 ( m, 2H), 4.35 (q, 2H), 4.61 (s, 2H), 5.72 (bs, IH), 6.62 (s, IH), 7.44 (m, 3H), 7.50 (s, IH), 7.63 (d, IH), 7.72 (s, IH), 8.07 (d, 2H).
Example 194. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoic acid ethyl ester
Figure imgf000165_0002
l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (7.5 g) was reacted with 3-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A. The title compound was obtained as a white solid (72% yield), m.p. = 174° C, LCMS: m/z = 475.95 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.40 (t, 3H), 3.48 (m, 2H), 3.69 (m, 2H), 4.32 (q, 2H), 4.63 (s, 2H), 5.51 (bs, IH), 6.52 (s, IH), 7.35 (m, IH), 7.42 (m, IH), 7.48 (s, IH), 7.54 (m, IH), 7.65 (d, IH), 7.70 (s, IH), 7.90 (d, IH), 8.03 (s, IH).
Example 195. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzoic acid
Figure imgf000166_0001
4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[253-b]pyrazin-7- yl}benzoic acid ethyl ester (5.1 g) was saponified as in General Procedure 7 to give the title compound as a light orange solid (88% yield). LCMS: m/z = 447.88 (TVH-H+), 1H-NMR (DMSO-^6, 400 MHz) δ 3.41 (m, 2H), 3.60 (m, 2H), 4.80 (s, 2H), 7.07 (s, IH), 7.63 (m, 3H), 7.74 (s, IH), 7.82 (d, IH), 7.95 ( m, 2H), 8.81 (s, IH), 13.01 (bs, IH). Example 196. S-tl-CS-Chloro^-^fluoromethyObenzylJ-l^^^-tetrahydropvrido^.S- b]pyrazin-7-yl} benzoic acid
Figure imgf000166_0002
3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid ethyl ester (5.5 g) was saponified as in General Procedure 7 to give the title compound as a tan solid (97% yield). LCMS: m/z = 448.07 (M+ET), 1H-NMR (DMSCW6, 400 MHz) 53.42
(m, 2H), 3.51 (m, 2H), 4.62 (s, 2H), 6.61 (s, IH), 6.75 (s, IH), 7.35 (m, 2H), 7.52 (m, 3H),
7.62 (s, IH), 7.74 (d, IH), 7.82 (d, IH), 7.88 (s, IH).
Example 197. (2-{4-[l-(2-Chloro-3,6-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-
7-yl]-pyrazol- 1 -yl} ethyl)dimethylamine
Figure imgf000167_0001
Anhydrous DMF (2 mL) was added to a mixture of l-(2-chloro-3,6-difluorobenzyl)-7-(lH- pyrazol-4-yl)-l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (57 mg, .000158 mol), cesium carbonate (0.110 g) and 2-dimethyIaminoethyl chloride HCl (0.025 g). The reaction mixture was stirred at room temperature under nitrogen for 13 days and then concentrated and dissolved in methylene chloride. The organic phase was washed with water, dried with magnesium sulfate, filtered, and concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as an off-white solid (9% yield). LCMS: m/z = 433.13 04+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.30 (6H, s), 2.79 (2H, t, J= 6.8 Hz), 3.29 (2H, t, J= 4.7 Hz), 3.51 (2H, m), 4.24 (2H, t, J= 6.8 Hz), 4.50 (2H, s), 4.77 (IH, bs), 6.97 (IH, s), 7.02 (IH, m), 7.12 (IH, m), 7.60 (IH, s), 7.63 (IH, d, J= 1.5 Hz), 7.66 (IH, s). Example 198. 1 -[5-Chloro-2-(trifluρromethyl)benzyl]-7-(2-piperazin- 1 -yl-pyridin-4-yl)- l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine
Figure imgf000167_0002
1 -[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-l ,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (293 mg) was reacted with 2-(piperazin-l-yl)pyridine-4-borom'c acid, pinacol ester as in General Procedure 4B to give the title compound as an off-white solid, m.p. = 189° C, LCMS: m/z = 489.08 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.98 (4H, m), 3.49 (6H, m), 3.71 (2H, m), 4.61 (2H, s), 5.29 (IH, s), 5.34 (IH, bs), 6.55 (2H, m), 6.64 (IH, dd, J= 5.2, 1.4 Hz), 7.36 (IH, d, J= 8.1 Hz), 7.52 (IH, s), 7.64 (IH, d, J= 8.3 Hz), 7.77 (IH, d, J= 2.0 Hz), 8.12 (IH, d, J= 5.3 Hz).
Example 199. l-[4-(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydro-pyrido[2,3- b]pyrazin-7-yl}pyridin-2-yl)ρiperazin-l-yl]ethanone
Figure imgf000168_0001
To a solution of l-[5-chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-l-yl-pyridin-4-yl)- l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (63 mg, .000129 mol) in anhydrous DMF (1 mL) was added acetyl chloride (0.012 mL) and triethylamine (0.020 mL). The mixture was stirred at room temperature under nitrogen overnight and then concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as a yellow solid (56% yield). m.p. = 241° C, LCMS: m/z = 531.31 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.15 (3H, s),
3.47 (2H, m), 3.52 (2H, m), 3.57 (2H, m), 3.62 (2H, m), 3.73 (4H, m), 4.61 (2H, s), 5.25 (IH, bs), 6.55 (2H, m), 6.69 (IH, d, J = 5.3 Hz), 7.37 (IH, d, J= 8.3 Hz), 7.52 (IH, s), 7.65 (IH, d,
J= 8.3 Hz), 7.78 (IH, bs), 8.12 (IH, d, J= 5.3 Hz).
Example 200. 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-7-(lH-pyrazol-4-yl)-l ,2,3,4-tetrahydro- pyrido[2,3-b]pyrazine
Figure imgf000168_0002
l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (109 mg) was reacted with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-l-carboxylic acid-tert-butyl ester as in General Procedure 4B, then added 6 mL CH2Cl2 and TFA (.6 mL), and purified on normal phase silica gel chromatography to give the title compound as an off- white solid (44% yield). m.p. = 271° C, LCMS: m/z = 394.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.50 (2H, m), 3.66 (2H, m), 4.05 (3H, s), 4.61 (2H, s), 6.50 (IH, d, J= 1.5 Hz), 7.40 (IH, s), 7.50 (IH, s), 7.56 (3H, m), 7.68 (IH, d, J= 8.6 Hz). Example 201. l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(l -triisopropylsilanyl-lH-pyrrol-3- yl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000169_0001
l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (111 mg) was reacted with l-(triisopropylsilyl)-lH-pyrrole-3-boronic acid as in General Procedure 4B to give the title compound as an off-white solid (80% yield). LCMS: m/z = 349.34 (M+H4), 1H-NMR (CDCl3, 400 MHz) δ 1.08 (18H, d, J= 7.6 Hz), 1.41 (3H, m), 3.49 (2H, m), 3.65 (2H, m), 4.58 (2H, s), 4.92 (IH, bs), 6.37 (IH, m), 6.54 (IH, d, J= 1.8 Hz), 6.72 (IH, m), 6.76 (IH, m), 7.32 (IH, d, J = 8.6 Hz), 7.54 (IH, s), 7.61 (IH, d, J= 8.6 Hz), 7.70 (IH, m). Example 202. 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-7-(l H-pyrrol-3-yl)-l ,2,3,4-tetrahydro- pyrido[2,3-b]pyrazine
Figure imgf000169_0002
Anhydrous tetrahydrofiiran (1 mL) and tetrabutylammonium fluoride, 1 M solution in tetrahydrofiiran (0.761 mL) were added to l-[5-chloro-2-(trifluoromethyl)benzyl]-7-(l- triisopropylsilanyl- lH-pyrrol-3-yl)- 1 ,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (107 mg, 0.000195 mol). The reaction was stirred at room temperature under nitrogen for two (2) hours and then concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as an off-white solid. LCMS: m/z = 393.24 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.35 (2H, bs), 3.48 (2H, m), 3.63 (2H, m), 4.59 (2H, s), 6.26 (IH, s), 6.56 (IH, d, J= 1.3 Hz), 6.74 (IH, t, J= 2.0 Hz), 6.82 (IH, s), 7.34 (IH, d, J= 8.3 Hz), 7.50 (IH, s), 7.60 (IH, s), 7.64 (IH, d, J= 8.3 Hz).
Example 203. l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-(l -methyl- lH-pyrazol-4-yl)- 1,2,3, 4- tetrahydropyrido[2,3-b]pyrazine
Figure imgf000170_0001
l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (112 mg) was reacted with l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as in General Procedure 4B to give the title compound as a brown solid (74% yield), m.p. = 156° C, LCMS: m/z = 408.25 (NH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.48 (2H, m), 3.65 (2H, m), 3.87 (3H, s), 4.58 (2H, s), 5.06 (IH, s), 6.45 (IH, s), 7.36 (2H, m), 7.49 (2H, m), 7.63 (2H, m). Example 204. {l-[(5-Chloro-2-trifluoromethyl)benzyl]-l,2,3,4-tetrahydro-pyrido[2,3- b]pyrazin-7-yl} piperidin- 1 -yl-methanone
Figure imgf000170_0002
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid (89 mg) was reacted with piperidine as in General Procedure 8 to give the title compound as an orange solid (64% yield), m.p. = 216° C, LCMS: m/z = 515.27 (M+ET), 1H- NMR (CDCl3, 400 MHz) δ 1.61 (6H, m), 2.88 (IH, s), 2.95 (IH, s), 3.38 (2H, s), 3.49 (2H, m), 3.69 (2H, m), 4.62 (2H, s), 5.26 (IH, s), 6.60 (IH, s), 7.37 (5H, m), 7.51 (IH, s), 7.64 (IH, d, J= 8.3 Hz), 7.75 (IH, ά, J= 1.5 Hz).
Example 205. { l-[(5-Chloro-2-trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-(4-methoxy-piperidin-l-yl)methanone
Figure imgf000170_0003
4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid (80 mg) was reacted with 4-methoxypiperidine HCl as in General Procedure 8 to give the title compound as an orange solid (58% yield). LCMS: m/z = 545.26 (M+H4), 1H-
NMR (CDCl3, 400 MHz) δ 1.73 (4H, m), 2.88 (IH, s), 2.95 (IH, s), 3.36 (3H, s), 3.47 (4H, m), 3.68 (3H, m), 4.62 (2H, s), 5.35 (IH, bs), 6.59 (IH, d, J= 1.3 Hz), 7.38 (5H, m), 7.51 (IH, s), 7.64 (IH, d, J= 8.3 Hz), 7.75 (IH, s).
Example 206. [l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- phenylpiperazin- 1 -yl)-methanone
Figure imgf000171_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 1-phenylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 481.97 (M-I-H+); retention time = 1.12 minutes.
Example 207. [l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- pyrimidin-2-yl-piperazin- 1 -yl)-methanone
Figure imgf000171_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(2-pyrimidyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 483.93 (M+H*); retention time = 0.99 minutes.
Example 208. [4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone
Figure imgf000172_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 530.89 (M+H*); retention time = 1.1 minutes. Example 209. l-{l-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]piperidin-4-yl} - 1 ,3-dihydrobenzoimidazol-2-one
Figure imgf000172_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2J3-b]pyrazin-7-yl]benzoic acid was reacted with 1 ,3-dihydrobenzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z = 536.96 (M-I-H+); retention time = 0.97 minutes.
Example 210. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2- methoxyphenyl)piperazin- 1 -yl]methanone
Figure imgf000172_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound.
LCMS: m/z = 511.94 (M+H*); retention time = 1.09 minutes.
Example 211. [ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- {4-[3-
(trifluoromethyl)phenyl]piperazin-l-yl}methanone
Figure imgf000173_0001
[l-(2,5-Dichlorobenzyl)-l,2,3»4-tetrahydropyrido[2,3-b]ρyrazin-7-yl]benzoic acid was reacted with l-[3-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 549.92 (M-I-H+); retention time = 1.24 minutes. Example 212. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- phenylpiperidin- 1 -yl)methanone
Figure imgf000173_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-phenylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 480.99 OVH-H+); retention time = 1.17 minutes.
Example 213. [l-(2,5-Dichlorobenzyl)-l,2)334-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(3,4- dichlorophenyl)-piperazin- 1 -yl]methanone
Figure imgf000173_0003
[l-(2,5-Dichlorobenzyl)-l,2,3J4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(3,4-dichlorophenyl)piperazine as in General Procedure 10 to give the title compound.
LCMS: m/z = 549.85 (MH-H+); retention time = 1.31 minutes.
Example 214. (4-Benzhydrylpiperazin-l-yl)-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone
Figure imgf000174_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 1-benzhydrylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 571.95 (M+H*); retention time = 1.2 minutes.
Example 215. (4-Benzylpiperidin-l-yl)-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]methanone
Figure imgf000174_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 1-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 495.02 (M+H+); retention time = 1.25 minutes.
Example 216. 8-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]- 1 -phenyl- 1 ,3 ,8-triaza-spiro[4.5]decan-4-one
Figure imgf000174_0003
[l-(2,5-Dichlorobenzyl)-l,2,3j4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with -l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one as in General Procedure 10 to give the title compound. LCMS: m/z = 550.97 (M+H*); retention time = 1.02 minutes.
Example 217. [l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- thieno[3,2-d]pyrimidin-4-yl-piperazin-l-yl)methanone
Figure imgf000175_0001
[l-(2,5-Dichlorobenzyl)-l,2,3»4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(thieno[3,2-d]pyrimidin-4-yl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 539.89 (M+H*); retention time = 0.81 minutes. Example 218. [l-(2,5-Dichlorobenzyl)-l,2J3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4- methoxybenzyl)piperazin- 1 -yl]methanone
Figure imgf000175_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(4-methoxybenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 525.95 (M+H1"); retention time = 0.81 minutes.
Example 219. (4-Benzoylpiperazin-l-yl)-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone
Figure imgf000175_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 1-benzoylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 509.83 01+H+); retention time = 0.97 minutes.
Example 220. [l-(2,5-Dichlorobenzyl)-l,2)3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl] -(4-furo[3,2-c]pyridin-4-yl-piperazin-l-yl)methanone
Figure imgf000176_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(furo[3,2-c]pyridin-4-yl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 522.95 (M+H4); retention time = 0.82 minutes. Example 221. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(6- fluorobenzo[d]isoxazol-3-yl)piperidin- 1 -yl]methanone
Figure imgf000176_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 539.95 (MH-H+); retention time = 1.15 minutes. Example 222. [4-(3-Chlorophenyl)piperazin- 1 -yl] -[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone
Figure imgf000176_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(3-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 515.91 (M-HH+); retention time = 1.21 minutes.
Example 223. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2-pyridin-2-yl-ethyl)amide
Figure imgf000177_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-(2-pyridyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 441.87 (VH-H+); retention time = 0.77 minutes.
Example 224. 4-{[l-(2J5-Dichlorobenzyl)-l52,3,4-tetrahydropyrido[2,3-b]pyrazine-7 -carbonyl] amino} piperidine-1-carboxylic acid ethyl ester
Figure imgf000177_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with ethyl 4-amino-l-piperidinecarboxylate as in General Procedure 10 to give the title compound. LCMS : m/z = 491.94 (MH-H+); retention time = 1.02 minutes.
Example 225. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropvrido[2,3-b]pyrazine-7-carboxylic acid (l-benzyl-piperidin-4-yl)amide
Figure imgf000177_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-amino-l-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 509.99 (M+H4"); retention time = 0.82 minutes.
Example 226. 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2,2-diphenylethyl)amide
Figure imgf000178_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2,2-diphenylethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 516.96 (M+H*); retention time = 1.23 minutes.
Example 227. 1 - {4-[ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]piperazin-l -yl} ethanone
Figure imgf000178_0002
[1 -(2,5-Dichlorobenzyl)- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 1-acetylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 447.97 (M+H*); retention time = 0.84 minutes.
Example 228. l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 3-chlorobenzylamide
Figure imgf000178_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 3-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 460.9 (M+H*); retention time = 1.14 minutes.
Example 229. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl] -[4-(2-pyridin-2-yl-ethyl)piperazin- 1 -yl]methanone
Figure imgf000179_0001
[l-(2,5-Dichlorobenzyl)-l,2s3,4-tetrahydropyrido[2,3-b]pyra2in-7-yl]benzoic acid was reacted with l-(2-(2-pyridyl)ethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 510.96 (IVH-H+); retention time = 0.72 minutes.
Example 230. 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4-(trifluoromethoxy)benzylamide
Figure imgf000179_0002
[l-(2,5-Dichlorobenzyl)-l,2,3»4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-(trifluoromethoxy)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 510.89 (M-I-H+); retention time = 1.21 minutes.
Example 231. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- morpholin-4-yl-piperidin- 1 -yl)methanone
Figure imgf000179_0003
[l-(2,5-Dichlorobenzyl)-l,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-morpholin-4-yl-piperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 489.99 (M-I-H+); retention time = 0.68 minutes.
Example 232. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2-thiophen-2-yl-ethyl)amide
Figure imgf000180_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-(2-thiophenyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 446.92 (M-HH+); retention time = 1.08 minutes.
Example 233. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid benzhydrylamide
Figure imgf000180_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with benzhydrylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 502.95 (M-I-H+); retention time = 1.23 minutes.
Example 234. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (pyridin-4-ylmethyl)amide
Figure imgf000180_0003
[l-(2,5-Dichloroben2yl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with (4-pyridyl)methylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 427.98 (M-I-H+); retention time = 0.73 minutes.
Example 235. 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (pyridin-3-ylmethyl)amide
Figure imgf000181_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with (3-pyridyl)methylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 427.98 (MMH+); retention time = 0.76 minutes.
Example 236. 2-{4-[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine -7-carbonyl]piperazin- 1 -yl } -N-isopropylacetamide
Figure imgf000181_0002
[l-(2,5-Dichloroben2yl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with N-isopropyl-1-piperazineacetamide as in General Procedure 10 to give the title compound. LCMS: m/z = 504.97 (M-I-H+); retention time = 0.78 minutes.
Example 237. [l-(2}5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2- methylquinolin-4-yl)piperazin- 1 -yl]methanone
Figure imgf000181_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(2-methylquinolin-4-yl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 546.97 (VH-H+); retention time = 0.8 minutes. Example 238. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-((S)-2- pyrrolidin- 1 -ylmethyl-pyrrolidin- 1 -yl)methanone
Figure imgf000182_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with (S)-I -(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 474.04 (M+H*); retention time = 0.76 minutes. Example 239. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 3,5-bis-(trifluoromethyl)benzylamide
Figure imgf000182_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 562.86 (MH-H+); retention time = 1.32 minutes. Example 240. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pvrazine-7-carboxylic acid [2-(4-sulfamoylphenyl)ethyl]amide
Figure imgf000182_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 519.88 (MH-H+); retention time = 0.94 minutes.
Example 241. [1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2,3,5,6- tetrahydro-[ 1 ,2']bipyrazinyl-4-yl)methanone
Figure imgf000183_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2,3,5,6-tetrahydro-[l,2']bipyrazine as in General Procedure 10 to give the title compound.
LCMS: m/z = 483.94 (IVH-H+); retention time = 0.94 minutes.
Example 242. 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2-phenylthiazol-4-yl-methyl)amide
Figure imgf000183_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-(aminomethyl)-2-phenylthiazole as in General Procedure 10 to give the title compound.
LCMS: m/z = 509.91 (M+H*); retention time = 1.17 minutes.
Example 243. [ 1 -(2,5-Dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]morpholin-4-yl-methanone
Figure imgf000183_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with morpholine as in General Procedure 10 to give the title compound. LCMS: m/z = 407.01 (M-I-H+); retention time = 0.9 minutes.
Example 244. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (naphthalen-l-yl-methyl)amide
Figure imgf000184_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(aminomethyl)naphthalene as in General Procedure 10 to give the title compound. LCMS: m/z = 476.96 (IVM-H+); retention time = 1.17 minutes. Example 245. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid indan-1-ylamide
Figure imgf000184_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 1-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z = 452.99 (M+H4); retention time = 1.14 minutes.
Example 246. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid benzylamide
Figure imgf000184_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z =
427.01 (MH-H+); retention time = 1.07 minutes.
Example 247. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]
-[4-(4-methoxyphenyl)piperazin-l-yl]methanone
Figure imgf000185_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(4-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 511.94 (M+H*); retention time = 1.07 minutes.
Example 248. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxyiic acid cyclohexylamide
Figure imgf000185_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with cyclohexylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 419.07 CM*!!*); retention time = 1.11 minutes.
Example 249. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (biphenyl-4-ylmethyl)amide
Figure imgf000185_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-phenylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z
= 502.95 (M+H*); retention time = 1.25 minutes.
Example 250. [4-(4-Chlorophenyl)piperazin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone
Figure imgf000186_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyra2in-7-yl]benzoic acid was reacted with l-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 515.91 (M+lT); retention time = 1.21 minutes.
Example 251. l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2-phenoxyethyl)amide
Figure imgf000186_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-phenoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 456.96 (MH-H+); retention time = 1.11 minutes.
Example 252. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4- (tetrahydrofuran-2-carbonyl)piperazin- 1 -yl]methanone
Figure imgf000186_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-(2-tetrahydrofuranylcarbonyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 503.96 (M+H4); retention time = 0.88 minutes. Example 253. l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid phenethyl-amide
Figure imgf000187_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with phenethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 441.01 01+H+); retention time = 1.11 minutes.
Example 254. 1 -(2,5-Dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido [2,3-b]pyrazine-7-carboxylic acid (tetrahydrofuran-2-yl-methyl)amide
Figure imgf000187_0002
[l-(2-5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-tetrahydrofuranylmethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 421.02 (M+KT); retention time = 0.95 minutes.
Example 255. [4-(4-Chlorobenzyl)piperazin- 1 -yl]- [ 1 -(2, 5-dichlorobenzyl)- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone
Figure imgf000187_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(4-chlorobenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 529.92 (M+H*); retention time = 0.9 minutes.
Example 256. 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 2-chloro-benzyl amide
Figure imgf000188_0001
[l-(2,5-Dichlorobenzyl)-l,2,3)4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 460.93 (M+H*); retention time = 1.14 minutes.
Example 257. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2- (trifluoromethyl)phenyl)piperazin- 1 -yl]methanone
Figure imgf000188_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(2-(trifluoromethyl)phenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 549.92 (M+ϊT); retention time = 1.24 minutes. Example 258. 1 -(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4-methoxybenzylamide
Figure imgf000188_0003
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 456.96 (MH-H+); retention time = 1.08 minutes.
Example 259. 1 -(2,5-Dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid indan-2-ylamide
Figure imgf000189_0001
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z = 452.99 (MB-H+); retention time = 1.13 minutes.
Example 260. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl] -(4-phenethyl-piperazin- 1 -yl)methanone
Figure imgf000189_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(2-phenethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 509.99 (M-I-H+); retention time = 0.84 minutes.
Example 261. [4-(2-Chlorophenyl)piperazin- 1 -yl]-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone
Figure imgf000189_0003
[l-(2>5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(2-chlorophenyl)piperazine as in General Procedure 10 to give the title compound.
LCMS: m/z = 515.91 (M+H*); retention time = 1.21 minutes.
Example 262. [(4-Cyclohexylmethyl)piperazin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2>3-b]pyrazin-7-yl]methanone
Figure imgf000190_0001
[l-(2,5-Dichlorobenzyl)-l,2,3»4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with l-(cyclohexylmethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 502.04 (M-HH+); retention time = 0.85 minutes.
Example 263. l-(2,5-Dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4-sulfamoyl-benzylamide
Figure imgf000190_0002
[l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 505.87 (M+H*); retention time = 0.93 minutes.
Example 264. [l-(2,5-Dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2- pyridin-3-yl-pyrτolidin- 1 -yl)methanone
Figure imgf000190_0003
[l-(2,5-Dichlorobenzyl)-l,2,3»4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 467.97 (M+H*); retention time = 0.82 minutes. Example 265. 3-(6-bromo-pyridin-2-ylamino)propionic acid
Figure imgf000190_0004
2-Amino-6-bromopyridine (25.0 g) was added to a mixture of ethyl acrylate (17.39 g) (1.2 eq) and acetic acid (4.55 g, 0.52 eq). The reaction mixture was heated at 1300C for 70 hours and then cooled to room temperature. An aqueous NaOH solution (6N, 60 mL, 2.50 eq) was added and the resulting mixture was heated at reflux for one (1) hour and then cooled to room temperature. The solution was washed twice with ether and then acidified to pH 4-5 with concentrated HCl. The precipitate was collected by filtration to give the title compound as a tan solid (68% yield). M.p. 108-109 0C, LCMS: m/z = 245.06 (M+H+), 1H-NMR (DMSO-</6, 400 MHz) δ 3.33-3.40 (m, 4H), 6.46 (d, J= 8.2 Hz, IH), 6.63 (d, J= 7.3 Hz, IH), 7.02 (t, J= 5.4 Hz, IH), 7.27 (dd, J= 8.2 and 7.3 Hz, IH), 12.22 (bs, IH). Example 266. 7-bromo-2,3-dihydro-lH-[ 1 ,8]naphthyridin-4-one
Figure imgf000191_0001
3-(6-Bromo-pyridin-2-ylamino)propionic acid (5.0 g) was combined with Eaton's reagent (100 mL) in a ratio of 5 g 3-(6-bromo-pyridin-2-ylamino)propionic acid per 100 mL Eaton's reagent. The resulting mixture was heated at 75°C for 2.5 hours. Ice cold water (50 mL) was added to the reaction mixture, followed by aqueous NaOH (50% w/w) to pH 12. The mixture was then extracted twice with ethyl acetate (200 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel chromatography using a gradient of 0-80% ethyl acetate/hexane as the eluting solvent to give the title compound as a yellow solid (34% yield). M.p. 196-197 0C, LCMS: m/z = 227.26 (M+H+), 1H-NMR (DMSO-^5, 400 MHz) δ 2.57 (t, J= 7.2 Hz, 2H), 3.34-3.49 (m, 2H), 6.80 (d, J= 8.0 Hz, IH), 7.74 (d, J= 8.0 Hz, IH), 7.96 (bs, IH). Example 267. 7-bromo-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol
Figure imgf000191_0002
7-Bromo-2,3-dihydro-lH-[l,8]naphthyridin-4-one (1.459 g) was placed in methanol (25 mL) and sodium borohydride (437 mg, 1.84 eq) was added portionwise over five (5) minutes. The reaction was stirred at room temperature for 15 minutes and then quenched with acetic acid (3 mL). The reaction mixture was concentrated under reduced pressure and the residue was taken up in toluene (100 mL). Silica gel was added and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography using dry loading and a gradient of 0-80% ethyl acetate/hexane as the eluting solvent gave the title compound as a pale yellow solid (78% yield). M.p. 130-131 0C, LCMS: m/z = 230.71 (IvH-H+), 1H-NMR (MeOH-^4, 400 MHz) δ 1.80-1.94 (m, 2H), 3.33-3.48 (m, 2H), 4.66 (t, J= 4.4 Hz, IH), 6.66 (d, J= 7.6 Hz, IH), 7.31 (d, J= 7.6 Hz, IH).
Example 268. 6-bromo-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol
Figure imgf000192_0001
7-Bromo-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol (460 mg) was dissolved in anhydrous tetrahydrofuran (25 mL) and cooled to -78 0C. A solution of w-butyllithium in tetrahydrofuran was added (1.6 M, 8.5 mJL) (5—7 equiv.) and the reaction was warmed slowly to room temperature. After 2-5 hours, methanol (2 mL) was added and the contents were concentrated to dryness. The residue was dissolved in a mixture of dichloromethane and acetic acid (1:1, v/v, 20 mL) and N-bromosuccinimide (450 mg) (1.2 equiv.) were added. After 45 minutes, the mixture was concentrated to dryness onto silica gel, and purified by silica gel chromatography to give the title compound as yellow solids (25-65% yield). M.p. 125-128 0C, LCMS: m/z = 229 (M-I-H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.72 (m, 2H), 3.25 (m, 2H), 4.56 (m, IH), 5.33 (d, J= 5.0 Hz, IH), 6.8 (bs, IH), 7.47 (d, J= 2.5 Hz, IH), 7.87 (d, J= 2.5 Hz, IH). Example 269. 6-[6-(4-Methyl-piperazin-l-yl)pyridin-3-yl]-l,2,3,4-tetrahydro- [ 1 ,8]naphthyridin-4-ol
Figure imgf000192_0002
6-Bromo-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol (89 mg) was reacted with l-methyl-4-[5-
(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (125 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-10% (5% NH4OH in methanol)/methylene chloride as the eluting solvent gave the title compound as brown solids (22% yield). M.p. 124-128 0C, LCMS: m/z = 326 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ
2.00 (m, IH), 2.08 (s, IH), 2.62 (t, J= 5.0 Hz, 4H), 3.49 (m, 2H), 3.58 (m, 2H), 3.63 (t, J= 5.0 Hz, 4H), 4.85 (t, J= 4.0 Hz, IH), 6.68 (s, IH), 6.71 (s, IH), 7.59 (dd, J= 2.6, 8.8 Hz, IH), 7.66 (d, J= 2.2 Hz, IH), 8.01 (d, J= 2.3 Hz, IH), 8.32 (d, J= 2.5 Hz, IH). Example 270. [4-(5-Hydroxy-5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-3-yl)phenyl]-4-methyl- piperazin- 1 -yl)methanone
Figure imgf000193_0001
6-Bromo-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol (300 mg) was reacted with (4-methyl- piperazin-l-yl)-[4-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-phenyl]rnethanone (450 mg) as in General Procedure 13. Basic alumina chromatography using a gradient of 0-10% methanol/ethyl acetate as the eluting solvent gave the title compound as a white foam (49% yield). LCMS: m/z = 353 (M+H4), 1H-NMR (DMSO-d6, 400 MHz) δ 1.78 (m, IH), 2.19 (s, 3H)5 2.32 (bs, 4H), 3.27 (m, IH), 3.36 (m, IH), 3.50 (bs, 4H), 4.65 (m, IH), 5.27 (d, J= 4.8 Hz, IH), 6.81 (s, IH), 7.41 (d, J= 8.3 Hz, 2H), 7.62 (d, J= 8.3 Hz, 2H), 7.71 (d, J= 2.2 Hz, IH), 8.22 (d, J= 2.2 Hz, IH). Example 271. 6-Bromo-4-(3-chlorophenoxy)-l,2,3,4-tetrahydro-[l,8]naphthyridine
Figure imgf000193_0002
6-Bromo-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol (225 mg) was reacted with 3-chlorophenol (0.30 mL) as in General Procedure 12. Basic alumina chromatography using a gradient of 0- 1% methanol/methylene chloride as the eluting solvent gave the title compound as a white film (60% yield). LCMS: m/z = 339 (M+lT), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, IH), 2.21 (m, IH), 3.40 (m, IH), 3.51 (m, IH), 5.04 (s, IH), 5.27 (t, J= 3.9 Hz, IH), 6.87 (d, J= 8.3 Hz, IH), 7.00 (m, 2H), 7.24 (m, IH), 7.48 (d, J= 2.1 Hz, IH), 8.06 (d, J= 2.1 Hz, IH). Example 272. {4-[5-(2,5-Dichlorophenoxy)-5,6,7,8-tetrahydro-[l ,8]naphthyridin-3- yl]phenyl}-4-methyl-piperazin-l-yl)methanone
Figure imgf000194_0001
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[l,8]naphthyridin-3-yl)phenyl]-4-methylpiperazin-l- yl)methanone (26 mg) was reacted with 2,5-chlorophenol (22 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-10% methanol/CϊkCl∑ as the eluting solvent gave the title compound as an off-white film (33% yield). LCMS: m/z = 497 (MH-H+), 1H- NMR (CDCl3, 400 MHz) δ 2.12 (m, IH), 2.37 (m, IH), 2.71 (s, 3H), 2.98 (bs, 4H), 3.59 (m, IH), 3.79 (m, IH), 3.97 (bs, 4H), 4.95 (m, IH), 5.36 (s, IH), 7.03 (d, J= 8.3 Hz, IH), 7.11 (s, IH) 7.34 (d, J= 8.3 Hz, IH), 7.43 (d, J = 8.1 Hz, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.67 (s, IH), 8.14 (s, IH).
Example 273. 4-(2-Chloro-3,6-difluorophenoxy)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]- 1 ,2,3,4-tetrahydro-[ 1 ,8]naphthyridine
Figure imgf000194_0002
6-[6-(4-Methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol (85 mg) was reacted with 2-chloro-3,6-difluorophenol (50 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-10% methanol/CH∑Ck as the eluting solvent gave the title compound as a yellow foam (54% yield). LCMS: m/z = 472 (M+HT), 1H-NMR (DMSO- d6, 400 MHz) δ 1.89 (m, IH), 2.21 (s, 3H), 2.24 (m, IH), 2.39 (t, J = 4.8 Hz, 4H), 3.40 (m, IH), 3.47 (t, J= 4.8 Hz, 4H), 3.63 (m, IH), 6.82 (d, J= 8.8 Hz, IH), 7.03 (d, J= 2.3 Hz, IH), 7.17 (d, J= 2.3 Hz, 1H)7.25 (m, IH), 7.39 (m, IH), 7.52 (dd, J= 2.5, 8.8 Hz, IH), 8.08 (d, J= 2.5 Hz, IH), 8.19 (d, J= 2.5 Hz, IH).
Example 274. {4-[5-(3-Chlorophenoxy)-5,6,7,8-tetrahydπ>-[ 1 ,8]naphthyridin-3-yl]-phenyl} -4- methylpiperazin- 1 -yl)methanone
Figure imgf000195_0001
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[l,8]naphthyridin-3-yl)phenyl]-4-methylpiperazin-l- yl)methanone (20 mg) was reacted with 3-chlorophenol (21.8 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methano 1/CH2Ct as the eluting solvent gave the title compound as a yellow foam (50% yield). LCMS: m/z = 463.12 (M-I-H+), 1H- NMR (CDCl3, 400 MHz) δ 2.00-2.12 (m, IH), 2.27-2.33 (m, IH), 2.33 (s, 3H), 2.34-2.6 (m, 4H), 3.4-3.7 (m, 4H), 3.7-3.9 (m, 2H), 5.18 (bs, IH), 5.38 (t, J = 3.6 Hz, IH), 6.91 (dd, J= 1.6 and 8.3 Hz, IH), 6.99-7.04 (m, 2H), 7.23-7.27 (m, IH), 7.43-7.50 (m, 4H), 7.61 (d, J= 2.0 Hz), 8.30 (d, J= 2.2 Hz).
Example 275. {4-[5-(3,5-Dichlorophenoxy)-5,6,7,8-tetrahydro-[l,8]naphthyridin-3- yljphenyl } -4-methylpiperazin- 1 -yl)methanone
Figure imgf000195_0002
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[l,8]naphthyridin-3-yl)phenyl]-4-methylpiperazin-l- yl)methanone (20 mg) was reacted with 3,5-dichlorophenol (27.7 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (82% yield). LCMS: m/z = 497.12 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.13 (m, IH), 2.24-2.35 (m, IH), 2.33 (s, 3H), 2.35-2.60 (m, 4H), 3.40-3.66 (m, 4H), 3.70-3.92 (m, 2H), 5.30 (bs, IH), 5.37 (t, J= 3.3 Hz, IH), 6.93 (d, J= 1.6 Hz, 2H), 7.02 (dd, J= 1.6 and 1.6 Hz, IH), 7.44-7.51 (m, 4H), 7.60 (d, J= 2.1 Hz, IH), 8.31 (d, J= 2.1 Hz, IH).
Example 276. (4-Methylpiperazin-l-yl)-{4-[5-(pyridine-3-yloxy)-5,6,7,8-tetrahydro- [ 1 ,8]naphthyridin-3-yl]phenyl} methanone
Figure imgf000196_0001
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[l,8]naphthyridin-3-yl)phenyl]-4-methylpiperazin-l- yl)methanone (20 mg) was reacted with 3-hydroxypyridine (16.2 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (20% yield). LCMS: m/z = 430.17 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.12 (m, IH), 2.30-2.34 (m, IH), 2.33 (s, 3H), 2.34-2.56 (m, 4H), 3.40-3.70 (m, 4H), 3.70-3.90 (m, 2H), 5.24 (bs, IH), 5.44 (t, J= 3.5 Hz, IH), 7.26- 7.29 (m, IH), 7.31-7.37 (m, IH), 7.41-7.50 (m, 4H), 7.58 (d, J= 2.0 Hz, IH), 8.28-8.33 (m, 2H), 8.43 (d, J= 2.5 Hz, IH).
Example 277. 1 -(4-Fluoro-2- {6-[4-(4-methylpiperazine- 1 -carbonyl)phenyl]- 1 ,2,3,4- tetrahydro-[ 1 ,8]naphthyridin-4-yloxy} phenyl)ethanone
Figure imgf000196_0002
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-3-yl)phenyl]-4-methylpiperazin- 1 - yl)methanone (30 mg) was reacted with l-(4-fluoro-2-hydroxyphenyl)ethanone (39.4 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (53% yield). LCMS: m/z = 489.14 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.11-2.25 (m, 2H), 2.32 (s, 3H), 2.32-2.58 (m, 4H), 2.45 (s, 3H), 3.40-3.68 (m, 4H), 3.70-3.90 (m, 2H), 5.31 (bs, IH), 5.51 (t, J= 3.3 Hz, IH), 6.75-6.82 (m, IH), 6.89 (dd, J= 2.1 and 10.7 Hz, IH), 7.41-7.51 (m, 4H), 7.57-7.61 (m, IH), 7.80 (dd, J= 7.1 and 8.6 Hz, IH, 8.33 (bs, IH).
Example 278. 4-(3-Chlorophenoxy)-6-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]-l,2,3,4- tetrahydro-[ 1 ,8]naphthyridine
Figure imgf000197_0001
6-Bromo-4-(3-chlorophenoxy)-l,2,3,4-tetrahydro-[l,8]naphthyridine (20 mg) was reacted with 1 -methyl-4-[4-(4,4,5 ,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (25 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a white foam (36% yield). LCMS: m/z = 436.06 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, IH), 2.24-2.40 (m, IH), 2.35 (s, 3H), 2.54 (t, J= 4.9 Hz, 4H), 3.4-3.51 (m, IH), 3.57-3.68 (m, 5H), 5.27 (bs, IH), 5.38 (t, J= 3.4 Hz, IH), 6.64 (s, IH), 6.73 (dd, J= 1.0 and 5.2 Hz, IH), 6.90 (dd, J= 2.2 and 8.3 Hz, IH), 6.95-7.03 (m, IH), 7.04-7.08 (m, IH), 7.22-7.28 (m, IH), 7.57 (d, J= 1.9 Hz, IH), 8.17 (d, J= 5.2 Hz, IH), 8.31 (d, J= 2.2 Hz).
Example 279. 4-(3-Chlorophenoxy)-6-(3-morpholin-4-yl-phenyl)-l ,2,3,4-tetrahydro- [ 1 ,8]naphthyridine
Figure imgf000197_0002
6-Bromo-4-(3-chlorophenoxy)-l,2,3,4-tetrahydro-[l,8]naphthyridine (20 mg) was reacted with 4-[3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]morpholine (23.9 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow foam (49% yield). LCMS: m/z = 422.18 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00-2.11 (m, IH), 2.22-2.26 (m, IH), 3.19 (t, J= 4.8 Hz, 4H), 3.40-3.45 (m, IH), 3.58-3.64 (m, IH), 3.88 (t, J= 4.8 Hz, 4H), 5.14 (bs, IH), 5.37 (t, J= 1.0 Hz, IH), 6.82-6.92 (m, 2H), 6.92 (s, IH), 6.95-7.02 (m, 2H), 7.03-7.08 (m, IH), 7.20-7.33 (m, 2H), 7.55 (d, J= 1.9 Hz, IH), 8.27 (d, J= 2.1 Hz, IH). Example 280. 4-(3-Chlorophenoxy)-6-(4-morpholin-4-yl-phenyl)-l ,2,3,4-tetrahydro- [ 1 ,8]naphthyridine
Figure imgf000198_0001
6-Bromo-4-(3-chlorophenoxy)-l,2,3,4-tetrahydro-[l,8jnaphthyridine (20 mg) was reacted with 4-morpholinophenylboronic acid (20.7 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (73% yield). M.p. 124-126 0C, LCMS: m/z = 422.28 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, IH), 2.22-2.5 (m, IH), 3.17 (t, J = 4.7 Hz, 4H), 3.38-3.48 (m, IH), 3.54-3.67 (m, IH), 3.87 (t, J= 4.7 Hz, 4H), 5.10 (s, IH), 5.37 (t, J = 1.0 Hz, IH), 6.88-7.02 (m, 4H), 7.03-7.07 (m, IH), 7.21-7.26 (m, IH), 7.37 (d, J= 8.6 Hz, 2H), 7.56 (d, J= 1.9 Hz, IH), 8.25 (d, J= 1.9 Hz, IH).
Example 281. 4-(3-Chlorophenoxy)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydro-[ 1 ,8]naphthyridine
Figure imgf000198_0002
6-Bromo-4-(3-chlorophenoxy)-l,2,3,4-tetrahydro-[l,8]naphthyridine (20 mg) was reacted with 1 -methyl-4-[5-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (25.0 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent gave the title compound as an orange foam (55% yield). LCMS: m/z = 436.12 (M-J-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, IH), 2.21- 2.32 (m, IH), 2.36 (s, 3H), 2.54 (t, J= 5.0 Hz, 4H), 3.39-3.49 (m, IH), 3.53-3.68 (m, IH), 3.59 (t, J= 5.0 Hz, 4H), 5.10 (s, IH), 5.37 (t, J= 3.5 Hz, IH), 6.68 (d, J= 8.8 Hz, IH), 6.90 (dd, J= 2.3 and 8.3 Hz, IH), 6.98-7.07 (m, 2H), 7.20-7.27 (m, IH), 7.50 (d, J= 2.1 Hz, IH), 7.56 (dd, J= 2.5 and 8.8 Hz, IH), 8.20 (d, J= 2.2 Hz, IH), 8.29 (d, J= 2.4 Hz, IH). Example 282. 7-Bromo-4-[ 1 -iodomethylidene]- 1 ,2,3,4-tetrahydro-[ 1 ,8]naphthyridine
Figure imgf000199_0001
To a suspension of 7-bromo-2,3-dihydro-lH-[l,8]naphthyridin-4-one (1.5 g) in anhydrous tetrahydrofuran (195 mL) was added a solution OfCrCl2 (6.79 g, 8.35 eq) and CHI3 (5.55 g, 2.13 eq) in anhydrous tetrahydrofuran (66 mL). The reaction was stirred at room temperature for 16 hours, diluted with methylene chloride (300 mL), and then washed with saturated
NaHCC>3 (300 mL). The aqueous phase was extracted twice with methylene chloride (100 mL) and the combined organic layers were washed with brine and then dried over Na2SO4. The solution was filtered and concentrated under reduced pressure. Silica gel chromatography using a gradient of 0-30% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (27% yield). Alkene geometry was determined by nθe. LCMS: m/z = 352 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.69 (t, J= 6.0 Hz, 2H), 3.43-3.51 (m, 2H), 5.25 (bs, IH), 6.23 (s, IH), 6.74 (d, J= 8.0 Hz, IH), 8.19 (d, J= 8.0 Hz, IH). Example 283. 7-Bromo-4-[l-(2,5-difluorophenyl)methylidene]-l,2,3,4-tetrahydro- [ 1 ,8]naphthyridine
Figure imgf000199_0002
Na2CO3 (2N, 3.46 mL, 10.0 eq) was added to a mixture of 7-bromo-4-[l-iodomethylidene]- l,2,3,4-tetrahydro-[l,8]naphthyridine (607 mg), 2,5-difluorophenylboronic acid (328 mg, 1.2 eq), and Pd(PPh3)4 (150 mg, 0.075 eq) in toluene/ethanol (4:1 v/v). The reaction was heated at 85°C for five (5) hours, Celite was added, and the mixture was then concentrated under reduced pressure. The dry powder was then dry loaded onto a silica gel column and a gradient of 0-20% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (70% yield). M.p. 178-179 0C, LCMS: m/z = 337 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 2.62 (t, J= 5.8 Hz, 2H), 3.55-3.62 (m, 2H), 5.25 (bs, IH), 6.26 (s, IH), 6.45 (d, J= 7.9 Hz, IH), 6.85-6.95 (m, IH), 6.96-7.12 (m, 3H). Example 284. 4-(2,5-Difluorobenzyl)-l,2,3,4-tetrahydro-[l,8]naphthyridine
Figure imgf000200_0001
7-Bromo-4-[l-(2,5-difluorophenyl)methylidene]-l,2,3,4-tetrahydro-[l,8]naphthyridine (200 mg) was dissolved in methanol (20 mL) and Pd/C (20 mg) was added. The reaction was hydrogenated at atmospheric pressure for 1.5 hours, filtered through Celite, and then concentrated under reduced pressure to give the title compound as a clear colorless oil (near quantitative yield). LCMS: m/z = 261.11 (M+H4), 1H-NMR (MeOH-^4, 400 MHz) δ 1.68- 1.86 (m, 2H), 2.80 (dd, J= 9.0 and 13.3, IH), 2.96 (dd, J = 10.0 and 13.3 Hz, IH), 3.02-3.12 (m, IH), 3.34-3.41 (m, IH), 3.46-3.55 (m, IH), 6.44 (dd, J= 5.2 and 7.2 Hz, IH), 6.93-7.03 (m, 2H), 7.03-7.11 (m, 2H), 7.72 (dd, J= 1.0 and 5.0 Hz, IH). Example 285. 6-Bromo-4-(2,5-difluorobenzyl)-l,2,3,4-tetrahydro-[l,8]naphthyridine
Figure imgf000200_0002
To a solution of 4-(2,5-difluorobenzyl)-l,2,3,4-tetrahydro-[l,8]naphthyridine (23 mg) in CH2C.2/acetic acid (5.5 mL, 10:1, v/v) was added N-bromosuccinimide (18.8 mg, 1.2 eq). The reaction was stirred at room temperature for one (1) hour, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-60% ethyl acetate/hexane as the eluting solvent to give the title compound as a clear, colorless oil (30% yield). LCMS: m/z = 339 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.66-1.75 (m, IH), 1.75-1.86 (m, IH), 2.73 (dd, J= 9.6 and 13.4 Hz, IH), 2.95 (dd, J= 6.0 and 13.4 Hz, IH), 2.99-3.08 (m, IH), 3.34-3.43 (m, IH), 3.45-3.55 (m, IH), 5.22 (bs, IH), 6.80-6.86 (m, IH), 6.88-6.96 (m, IH), 6.98-7.05 (m, IH), 7.16 (d, J= 1.9 Hz, IH), 7.91 (d, J= 1.9 Hz, IH).
Example 286. 4-(2,5-Difluorobenzyl)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydro-[ 1 ,8]naphthyridine
Figure imgf000201_0001
Na2CO3 (2N, 53 μL) (4.0 eq) was added to a mixture of 6-bromo-4-(2,5-difluorobenzyl)- l,2,3,4-tetrahydro-[l,8]naphthyridine (9.0 mg) (1 eq), l-methyl-4-[5-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (11.3 mg) (1.4 eq), and Pd(PPh3)4 (3.0 mg, 0.1 eq) in toluene/ethanol (4: 1, v/v, 2 mL). The reaction was heated at 9O0C for six (6) hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (15 mL) and washed with water (15 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent to give the title compound as a yellow foam (26% yield). LCMS: m/z = 436 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.7-2.0 (m, 2H), 2.37 (s, 3H), 2.55-2.60 (m, 4H), 2.81 (dd, J= 9.1 and 13.3 Hz, IH), 2.98 (dd, J= 6.4 and 13.3 H, IH), 3.08-3.18 (m, IH), 3.40-3.50 (m, IH), 3.53-3.70 (m, 5H), 5.18 (bs, IH), 6.68 (d, J= 8.8 Hz, IH), 6.81-6.87 (m, IH), 6.89-6.96 (m, IH), 6.98-7.06 (m, IH), 7.16 (d, J= 1 Hz, IH), 7.50 (dd, J= 2.5 and 8.8 Hz, IH), 8.05 (d, J= 1 Hz, IH), 8.24 (d, J= 2.5 Hz, IH).
Example 287. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2, 3-b]pyrazin-7-yl}phenyl)-(4-morpholin-4-yl-piperidin-l-yl)methanone
Figure imgf000201_0002
4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7- yl}benzoic acid (70 mg) was reacted with 4-piperidin-4-yl-morpholine as in General Procedure 8 to give the title compound as a light yellow foam (43% yield). M.p. (foam), LCMS: m/z = 600.14 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42-1.58 (m, 2H), 1.72-1.94 (m, 2H), 2.35- 2.45 (m, IH), 2.52-2.58 (m, 4H), 2.86-3.03 (m, 2H), 3.47-3.53 (m, 2H), 3.63-3.74 (m, 6H), 3.88-3.96 (m, IH), 4.58 (s, 2H), 5.12 (s, iH), 6.59 (d, J= 1.3 Hz, IH), 7.32-7.49 (m , 5H), 7.64
( d, J= 8.3 Hz, IH), 7.74 ( d, J= 1.76 Hz, IH).
Example 288. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,
3 -b]pyrazin-7-yl} phenyl)-(4-thiazol-2-yl-piperazin- 1 -yl)methanone
Figure imgf000202_0001
4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7- yl}benzoic acid (70 mg) was reacted with l-thiazol-2-yl-piperazine as in General Procedure 8 to give the title compound as a yellow solid (61% yield). M.p. 243-244, LCMS: m/z = 598.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.49-3.92 (m, 12H), 4.63 (s, 2H), 5.06 ( bs, IH), 6.57- 6.64 (m, 2H), 7.21 (d,J= 3.52 Hz, IH), 7.35-7.43 (m, 5H), 7.51 (s, IH), 7.65 (d, J= 8.4 Hz, IH) , 7.76 (s, IH).
Example 289. 3,6-Difluoro-2-[7-(6-morpholin-4-yl-pyridin-3-yl)-3,4-dihydro-2H-pyrido[2,3- bjpyrazin- 1 -ylmethyl]benzonitrile
Figure imgf000202_0002
l-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous DMF. CuCN (5.0 eq) was added and the resulting mixture was heated to 1500C in a microwave for 30 minutes. The reaction mixture was concentrated, taken up in CH2Cl2 , washed three (3) times with an aqueous solution OfNH4OH (10%), and the organic phase was dried, filtered, and concentrated. The residue was purified via silica gel chromatography (0-100% ethyl acetate in hexanes followed by 5% methanol in ethyl acetate) to give the title compound (37% yield). M.pl88-190°C, LCMS: m/z = 449.05 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.24-3.31 (m, 2H), 3.48-3.56 (m, 6H), 3.80-3.88 (m, 4H), 4.51 (s, 2H), 4.86 (bs, IH), 6.65-6.73 (m, IH), 6.98-7.06 (m, 2H), 7.09-7.19 (m, 2H), 7.59-7.64 (m, 2H), 8.36 (s, IH). Example 290. 7-Iodo-l-[5-(trifluoromethyl)furan-2-ylmethyl]-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one
Figure imgf000203_0001
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (659 mg) was reacted with 2- (chloromethyl)-5-(trifluoromethyl)furan as in General Procedure 1 to give the title compound as a beige solid (87% yield). M.p. 189-191 0C, LCMS: mix = 424.20 (IVH-H+), 1H-NMR (CDCl3, 400 MHz,) δ 4.21 (s, 2H), 4.95 (bs, IH), 5.05 (s, 2H), 6.39 (s, IH), 6.75 (s, IH), 7.50 (s, IH), 7.96 (s, IH).
Example 291. 7-Iodo-l-[5-(trifluoromethyl)furan-2-ylmethyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000203_0002
7-Iodo-l-[5-(trifluoromethyl)furan-2-yhnethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (860 mg) was reduced as in General Procedure 3 to give the title compound as a white solid (18% yield). M.p. 153-154 0C, LCMS: m/z = 409.89 (M-J-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.33-3.40 (m, 2H), 3.47-3.59 (m, 2H), 4.38 (s, 2H), 5.10 (bs, IH), 6.28 (s, IH), 6.73 (s, IH), 6.90 (s, IH), 7.61 (s, IH).
Example 292. 7-(6-Morpholin-4-yl-pyridin-3-yl)-l -[5-(trifluoromethyl)furan-2-ylmethyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000203_0003
7-Iodo-l-[5-(trifluoromethyl)furan-2-yhnethyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine (60 mg) was reacted with 4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yljmorpholine as in General Procedure 4A to give the title compound as an orange foam (30% yield). M.p. (foam), LCMS: m/z = 446.13 (IVH-H+), 1H-NMR (CDCl3, 400 MHz) δ 3.42-3.47
(m, 2H), 3.48-3.54 (m, 4H), 3.58-3.67 (m, 2H), 3.80-3.89 (m, 4H), 4.47 (s, IH), 5.02 (bs, IH),
6.30 (s, IH), 6.67 (d, J= 5.2 Hz, IH), 6.72 (s, IH), 6.85 (s, IH), 7.55-7.62 (m, 2H), 8.31 (s,
IH).
Example 293. 7-[2-(4-Methylpiperazin- 1 -yl)pyridin-4-yl]- 1 -[5-(trifluoromethyl)furan-2- ylmethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000204_0001
7-Iodo-l-[5-(trifluoromethyl)furan-2-ylmethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (60 mg) was reacted with l-methyl-4-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridin-2- yl]piperazine as in General Procedure 4A to give the title compound as a beige foam (30% yield). M.p. (foam), 1H-NMR (CDCl3, 400 MHz) δ 2.31-3.36 (m, 4H), 2.38-2.53 (m, 4H), 3.42-3.48 (m, 2H), 3.48-3.58 (m, IH), 3.61-3.66 (m, 2H), 3.74-3.84 (m, 2H), 5.02 (bs, IH), 6.31 (s, IH), 6.74 (s, IH), 6.93 (s, IH), 7.41-7.50 (m, 3H), 7.73 (s, IH). Example 294. 7-Iodo-l-[2-(trifluoromethoxy)benzyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one
Figure imgf000204_0002
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (942 mg) was reacted with 2- (trifluoromethoxy)benzyl bromide as in General Procedure 1 to give the title compound as a light yellow solid (61% yield), m.p. = 235° C, LCMS: m/z = 449.92 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 4.29 (2H, s), 4.89 (IH, s), 5.16 (2H, s), 7.09 (2H, m), 7.24 (IH, m), 7.34 (2H, m), 7.92 (IH, s).
Example 295. 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazine-7-carboxylic acid [4-(dimethylamino)butyl]amide
Figure imgf000205_0001
4- { 1 -[5-Chloro-2-(trifluoromethyl)beπzyl]-l ,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7- yl}benzoic acid (84 mg) was reacted with 4-(dimethylamino)butylamine as in General Procedure 8 to give the title compound as a yellow solid (45% yield), m.p. = 182° C, LCMS: m/z = 545.86 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.60 (2H, m), 1.69 (2H, m), 2.20 (6H, s), 2.31 (2H, m), 3.43 (2H, m), 3.49 (2H, m), 3.69 (2H, m), 4.62 (2H, s), 5.27 (IH, bs), 6.61 (IH, s), 7.35 (IH, d, J = 8.3 Hz), 7.39 (2H, d, J= 7.8 Hz), 7.51 (IH, s), 7.63 (IH, d, J= 8.3 Hz), 7.70 (IH, m), 7.75 (3H, m). Example 296. 7-Iodo-l-[2-(trifluoromethoxy)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine
Figure imgf000205_0002
7-Iodo-l-[2-(trifluoromethoxy)benzyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (940 mg) was reduced as in General Procedure 3 to give the title compound as a brown sticky solid. LCMS: m/z = 435.82 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 3.38 (2H, m), 3.55 (2H, m), 4.44 (2H, s), 4.95 (IH, s), 6.71 (IH, s), 7.30 (4H, m), 7.59 (IH, s). Example 297. 4-{l-[2-(Trifluoromethoxy)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid ethyl ester
Figure imgf000205_0003
7-Iodo-l-[2-(trifluoromethoxy)benzyi]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (699 mg) was reacted with (4-ethoxycarbonylphenyl)boronic acid as in General Procedure 4B to give the title compound as a yellow solid, m.p. = 153°C, LCMS: m/z = 458.00 (MH-H+), 1H-NMR (CDCl3, 400 MHz) δ 1.38 (3H, t, J = 7.1 Hz), 3.47 (2H, m), 3.64 (2H, m), 4.36 (2H, quartet, J= 7.1 Hz), 4.56 (2H, s), 5.22 (IH, bs), 6.73 (IH, s), 7.25 (IH, m), 7.31 (2H, m), 7.37 (IH, d, J= 7.3 Hz), 7.42 (2H, d, J= 7.8 Hz), 7.75 (IH, s), 8.00 (2H, d, J= 8.1 Hz).
Example 298. 4- {l-[2-(Trifluoromethoxy)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]ρyrazin-7- yl} benzoic acid
Figure imgf000206_0001
4-{l-[2-(Trifluoromethoxy)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid ethyl ester (356 mg) was saponified as in General Procedure 7 to give the title compound as an orange solid (76% yield), m.p. = 2500C, LCMS: m/z = 430.14 (M+lT), 1H-NMR (DMSO-tfs,
400 MHz) δ 3.55 (2H, s), 4.70 (2H, s), 7.03 (IH, s), 7.43 (4H, m), 7.61 (2H, d, J= 8.1 Hz),
7.72 (IH, s), 7.93 (2H, d, J= 8.1 Hz).
Example 299. l-(2-Chloropyridin-3-yknethyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-
2-one
Figure imgf000206_0002
7-Iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.189 g) was reacted with 3-
(bromomethyl)-2-chloropyridine as in General Procedure 1 to give the title compound as an orange solid (58% yield), m.p. = 249°C, LCMS: m/z = 401.18 (M-I-H+), 1H-NMR (CDCl3,
400 MHz) δ 4.29 (2H, s), 5.16 (2H, s), 7.04 (IH, s), 7.26 (IH, m), 7.36 (IH, d, J= 7.6 Hz),
7.91 (IH, s), 8.34 (IH, d, J= 4.3 Hz).
Example 300. 1 -(2-Chloropyridm-3-ylmethyl)-7-iodo- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazine
Figure imgf000207_0001
l-(2-Chloropyridin-3-ylmethyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one (1.005 g) was reduced as in General Procedure 3 to give the title compound as a brown sticky solid. LCMS: m/z = 387.16 (IVH-H+).
Example 301. 4-[l-(2-Chloropyridin-3-ylmethyl)-lJ2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljbenzoic acid ethyl ester
Figure imgf000207_0002
l-(2-Chloropyridin-3-ylmethyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (389 mg) was reacted with (4-ethoxycarbonylphenyl) boronic acid as in General Procedure 4B to give the title compound as a yellow solid. LCMS: m/z = 409.34 (M-HH+).
Example 302. 4-[l-(2-Chloropyridin-3-ylmethyl)-l,2,3)4-tetrahydropyrido[2,3-b]pyrazin-7- yljbenzoic acid
Figure imgf000207_0003
4-[l-(2-Chloropyridin-3-ylmethyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester (51 mg) was saponified as in General Procedure 7 to give the title compound as a yellow solid (82% yield). LCMS: m/z = 381.29 (M+H*), 1H-NMR (DMSO-^6, 400 MHz) δ
4.64 (2H, s), 6.87 (IH, s), 7.40 (IH, m), 7.60 (2H, d, J= 8.3 Hz), 7.74 (2H, m), 7.90 (2H, d, J
= 8.3 Hz), 8.34 (IH, m).
Example 303. {4-[l-(2-Chloropyridin-3-ylmethyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljphenyl} -(4-pyrrolidin-l -yl-piperidin-1 -yl)methanone
Figure imgf000208_0001
4-[l-(2-Chloropyridin-3-ylmethyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyraziπ-7-yl]benzoic acid (38 mg) was reacted with 4-(l-pyτrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (20% yield). LCMS: m/z = 516.89 (M+H*), 1H-NMR (CDCl3, 400 MHz) δ 1.50 (IH, m), 1.80 (5H, m), 1.97 (2H, m), 2.27 (IH, m), 2.58 (4H, m), 3.01 (2H, m), 3.50 (2H, m), 3.67 (2H, m), 3.79 (IH, m), 4.54 (2H, s), 4.95 (IH, bs), 6.58 (IH, d, J= 1.5 Hz), 7.23 (IH, m),7.36 (4H, m), 7.62 (IH, dd, J= 7.6, 1.8 Hz), 7.73 (IH, d, J= 1.8 Hz), 8.34 (IH, dd, J= 4.8, 1.8 Hz).
Example 304. N-(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)acetamide
Figure imgf000208_0002
l-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine (90 mg) was reacted with 4-acetamidophenylboronic acid as in General Procedure 4B to give the title compound as a light gray solid (42% yield), m.p. = 244°C, LCMS: m/z = 461.24 OvH-H+), 1H-NMR (CDCl3, 400 MHz) δ 2.13 (3H, s), 3.49 (2H, m), 3.65 (2H, m), 3.82 (2H5 s), 4.61 (2H, s), 6.58 (IH, s), 7.28 (2H, d, J= 8.1 Hz), 7.36 (IH, d, J= 7.3 Hz), 7.51 (3H, m), 7.60 (IH, s), 7.65 (IH, d, J= 8.6 Hz).
Example 305. (4-Pyrrolidin- 1 -yl-piperidin- l-yl)-(4- { 1 -[2-(trifluoromethoxy)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000209_0001
4-{l-[2-(Trifluoromethoxy)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid (98 mg) was reacted with 4-(l-pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (65% yield). LCMS: m/z = 565.98 (M+HT), 1H-NMR (CDCl3, 400 MHz) δ 1.53 (2H, bs), 2.88 (7H, m), 2.27 (IH, m), 2.57 (4H, s), 2.98 (2H, m), 3.46 (2H, m), 3.63 (2H, m), 3.81 (IH, bs), 4.55 (2H, s), 5.21 (IH, s), 6.71 (IH, s), 7.33 (8H, m), 7.71 (IH, s).
Example 306. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-(4-phenylpiperazin- 1 -yl)methanone
Figure imgf000209_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 1-phenylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 591.97 (M+H+); retention time = 0.97 minutes. Example 307. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin- 1 -yl)methanone
Figure imgf000209_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2J3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(2-pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 593.97 (M+H1"); retention time = 0.84 minutes. Example 308. [4-(4-Chlorophenyl)-piperazin-l-yl]-(3-{l-[5-Chloro-2- (trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000210_0001
(3-{l-[5-chloro-2-(trifluoromethyl)ben2;yl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with l-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 625.95 (TvH-H+); retention time = 1.05 minutes. Example 309. [4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl]-(3-{l-[5-Chloro-2- (trifluoromethyl)benzyl]-l,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000210_0002
(S-ll-fS-chloro^-CtrifluoromethyObenzyll-l^.S^-tetrahydropyrido^.S-blpyrazin-?- yl} benzoic acid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as in General
Procedure 10 to give the title compound. LCMS: m/z = 640.96 (M-I-H+); retention time = 0.95 minutes.
Example 310. 1 -[f-(3- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-l,3-dihydrobenzoimidazol-2-one
Figure imgf000210_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with l,3-dihydro-l-(4-piperidinyl)benzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z = 647.02 (M+H4); retention time = 0.83 minutes. Example 311. (3- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b3pyrazin-7-yl}phenyl)-[4-(2-methoxyphenyl)piperazin- 1 -yljmethanone
Figure imgf000211_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 621.97 (MH-H+); retention time = 0.95 minutes. Example 312. (3- {l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-l -yljmethanone
Figure imgf000211_0002
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with l-[3-(trifluoromethyl)phenyl]piperazine as in General
Procedure 10 to give the title compound. LCMS: m/z = 659.98 (M-J-H+); retention time = 1.07 minutes.
Example 313. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin-l-yl)methanone
Figure imgf000211_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-phenylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 590.98 (M-I-H+); retention time = 1.03 minutes. Example 314. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(lH-indol-3-yl)piperidin-l-yl]methanone
Figure imgf000212_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-(lH-indol-3-yl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 630.02 (M+H*); retention time = 0.98 minutes. Example 315. (4-Benzhydrylpiperazin-l-yl)-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000212_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2>3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-benzhydrylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 680.97 (M-I-H+); retention time = 1.03 minutes. Example 316. (4-Benzylpiperidin-l-yl)-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido [2,3 -b]pyrazin-7-yl } phenyl)methanone
Figure imgf000212_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 605.01 (M+H*); retention time = 1.09 minutes. Example 317. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-l-yl]methanone
Figure imgf000213_0001
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl] - 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(3,4-dichlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 661.88 (M-HH+); retention time = 1.11 minutes. Example 318. S-CS-ll-tS-Chloro^-CtrifluoromethyObenzyll-l^.S^-tetrahydropyrido^.S- b]pyrazin-7-yl} benzoyl)-! -phenyl- 1 ,3,8-triaza-spiro[4.5]decan-4-one
Figure imgf000213_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one as in General
Procedure 10 to give the title compound. LCMS: m/z = 661.00 (M-I-H+); retention time = 0.87 minutes.
Example 319. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-l-yl}methanone
Figure imgf000213_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-[2-(trifluoromethyl)phenyl]piperazine as in General
Procedure 10 to give the title compound. LCMS: m/z = 659.99 (M-I-H+); retention time = 1.1 minutes.
Example 320. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2>3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } phenyl)-(4-thieno [3 ,2-d]pyrimidin-4-ylpiperazin- 1 -yl)methanone
Figure imgf000214_0001
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-thieno[3,2-d]pyrimidinyl)piperazine as in General
Procedure 10 to give the title compound. LCMS: m/z = 649.98 (MB-H+); retention time = 0.65 minutes.
Example 321. [4-(4-Chlorobenzyl)piperazin-l-yl]-(3-{l-[5-Chloro-2-
(trifluoromethyl)benzyl]-lJ2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000214_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-chlorobenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 639.99 (M+H*); retention time = 0.7 minutes. Example 322. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-l-yl]methanone
Figure imgf000214_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with l-(4-methoxybenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 636.01 (MH-H+); retention time = 0.62 minutes. Example 323. (4-Benzoylpiperazin- 1 -yl)-(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000215_0001
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-benzoylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 619.98 (MH-H+); retention time = 0.82 minutes. Example 324. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-furo[3,2-c]pyridin-4-ylpiperazin-l-yl)methanone
Figure imgf000215_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-furo[3,2-c]pyridinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 633.99 (M+H*); retention time = 0.64 minutes. Example 325. (S-fl-tS-Chloro^-Ctrifluoromethy^benzyll-l^.S^-tetrahydropyrido^.S- b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d] isoxazol-3-yl)piperidin- 1 -yl]methanone
Figure imgf000215_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as in General
Procedure 10 to give the title compound. LCMS: m/z = 649.95 (M+H*); retention time = 1.00 minutes.
Example 326. 4-(3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoylamino)piperidine-l-carboxylic acid ethyl ester
Figure imgf000216_0001
(S-ll-fS-chloro^-Ctrifluoroniethy^benzylj-l^jS^-tetrahydropyridoP.S-bjpyrazin-V- yl}benzoic acid was reacted with 4-aininopiperidine-l-carboxylic acid ethyl ester as in General
Procedure 10 to give the title compound. LCMS: m/z = 601.99 (MH-H+); retention time = 0.86 minutes.
Example 327. N-(l-Benzylpiperidin-4-yl)-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]benzatnide
Figure imgf000216_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-amino-l-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 619.96 (M-HH+); retention time = 0.62 minutes. Example 328. 3- {l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide
Figure imgf000216_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2,2-diphenylethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 626.96 (M+HT); retention time = 1.06 minutes. Example 329. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(l-methylpiperidin-4-yl)benzamide
Figure imgf000217_0001
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-amino-l-methylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 543.99 (MH-H+); retention time = 0.53 minutes. Example 330. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-l-yl]methanone
Figure imgf000217_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljbenzoic acid was reacted with l-piperazinyl-2-(2-pyridinyl)ethane as in General Procedure 10 to give the title compound. LCMS: m/z = 620.99 (MH-H+); retention time = 0.55 minutes. Example 331. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzamide
Figure imgf000217_0003
(3- { l-[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-(trifluoromethoxy)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 620.94 (MH-H+); retention time = 1.04 minutes.
Example 332. N-[3,5-Bis(trifluoromethyl)benzyl]-3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000218_0001
(S-ll-fS-chloro^-Ctrifluoromethy^benzy^-l^.S^-tetrahydropyridofZ.S-bJpyrazin-?- yl}benzoic acid was reacted with 3,5-bis(trifiuoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 672.88 (M+HT1"); retention time = 1.11 minutes. Example 333. N-Benzhydryl-3-{l-[5-chloro-2-(tri£luoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000218_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with benzhydrylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 612.98 (M-I-H+); retention time = 1.06 minutes.
Example 334. 3- { 1 -[S-Chloro^-CtrifluoromethyObenzyl]-! ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-pyridin-4-ylmethylbenzamide
Figure imgf000218_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z = 537.96 (M+H*); retention time = 0.56 minutes. Example 335. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-pyridin-3-ylmethylbenzamide
Figure imgf000219_0001
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z = 538 (M+H*); retention time = 0.59 minutes. Example 336. 2-[4-(3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzoyl)piperazin- 1 -yl] -N-isopropylacetamide
Figure imgf000219_0002
(3 - { 1 - [5 -chloro-2-(trifluoromethyl)benzyl]- 1,2,3 ,4-tetrahydropyrido[2,3 -b]pyrazin-7- yl}benzoic acid was reacted with 2-piperazinyl-N-isopropylacetamide as in General Procedure 10 to give the title compound. LCMS: m/z = 615.01 (M+H"1}; retention time = 0.61 minutes. Example 337. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-[4-(2-methylquinolin-4-yl)piperazin- 1 -yl]methanone
Figure imgf000219_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-methyl-4-(l-piperazinyl)quinoline as in General Procedure 10 to give the title compound. LCMS: m/z = 656.99 (M+H*); retention time = 0.61 minutes. Example 338. 3- {l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide
Figure imgf000220_0001
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-(4-sulfamoylpheπyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 629.94 (M+H*); retention time = 0.77 minutes. Example 339. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(2,3,5 ,6-tetrahydro-[ 1 ,2']bipyrazinyl-4-yl)methanone
Figure imgf000220_0002
(3- { 1 [5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-(l-piperazinyl)pyrazine as in General Procedure 10 to give the title compound. LCMS: m/z = 593.97 (M+H4); retention time = 0.78 minutes. Example 340. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-lJ2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide
Figure imgf000220_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2)3>4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in General Procedure 10 to give the title compound. LCMS: m/z = 619.9 (M+H1); retention time = 0.99 minutes. Example 341. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)morpholin-4-ylmethanone
Figure imgf000221_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with morpholine as in General Procedure 10 to give the title compound. LCMS: m/z = 516.96 (MH-H+); retention time = 0.76 minutes. Example 342. 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} -N-naphthalen- 1 -ylmethylbenzamide
Figure imgf000221_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(aminomethyl)naphthalene as in General Procedure 10 to give the title compound. LCMS: m/z = 586.96 (M-I-H+); retention time = 1.02 minutes. Example 343. 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} -N-indan-1-ylbenzamide
Figure imgf000221_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-lJ2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z = 562.95 (MH-H+); retention time = 0.99 minutes. Example 344. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-[4-(3-methoxyphenyl)piperazin- 1 -yl]methanone
Figure imgf000222_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(3-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 622.01 (M-I-H+); retention time = 0.97 minutes. Example 345. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } phenyl)-[4-(4-methoxyphenyl)piperazin- 1 -yl]methanone
Figure imgf000222_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3)4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 621.98 (M+H*); retention time = 0.92 minutes. Example 346. 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-cyclohexylbenzamide
Figure imgf000222_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with cyclohexylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 529.01 (M-I-H+); retention time = 0.96 minutes.
Example 347. 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl] - 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(4-methanesulfonylbenzyl)benzamide
Figure imgf000223_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-methanesulfonylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 614.91 (M-I-H+); retention time = 0.81 minutes. Example 348. N-(2-Chlorobenzyl)-3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl } benzamide
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 570.9 (M+H*); retention time = 0.98 minutes. Example 349. N-(4-Chlorobenzyl)-3- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000223_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 570.9 (M+H*); retention time = 0.99 minutes.
Example 350. N-(3-Chlorobenzyl)-3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000224_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 570.99 (MR-H+); retention time = 0.99 minutes. Example 351. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-l-yl]methanone
Figure imgf000224_0002
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(tetrahydrofuran-2-carbonyl)piperazine as in General
Procedure 10 to give the title compound. LCMS: m/z = 613.98 (MH-H+); retention time = 0.73 minutes.
Example 352. 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 >2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(tetrahydrofuran-2-yuτiethyl)benzamide
Figure imgf000224_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2>3-b]pyrazin-7- yl}benzoic acid was reacted with 2-(aminomethyl)tetrahydrofuran as in General Procedure 10 to give the title compound. LCMS: m/z = 530.97 (M-I-H+); retention time = 0.81 minutes. Example 353. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(3-methoxybenzyl)benzamide
Figure imgf000225_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 566.99 (M+H+); retention time = 0.93 minutes. Example 354. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide
Figure imgf000225_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 566.93 (M-I-H+); retention time = 0.91 minutes. Example 355. 3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzarnide
Figure imgf000225_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 2-phenoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 566.93 (M+H*); retention time = 0.94 minutes.
Example 356. N-Benzyl-3- { 1 -[5-Chloro-2-(trifluorornethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000226_0001
(3-{l-[5-chloro-2-(tri£luoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 536.96 (M-J-H+); retention time = 0.92 minutes. Example 357. [4-(3-Chlorophenyl)piperazin- 1 -yl]-(3- { 1 -[5-chloro-2- (trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000226_0002
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(3-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 625.97 (M+H*); retention time = 1.05 minutes. Example 358. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } -N-indan-2-ylbenzamide
Figure imgf000226_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z = 562.95 (M^-H+); retention time = 0.98 minutes. Example 359. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-lJ2,3J4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-(4-phenethylpiperazin- 1 -yl)methanone
Figure imgf000227_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-phenethylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 618.98 (M+H*); retention time = 0.64 minutes. Example 360. [4-(2-Chlorophenyl)piperazin-l-yl]-(3-{l-[5-chloro-2- (trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000227_0002
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(2-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 625.96 (M+H*); retention time = 1.05 minutes. Example 361. N-(l-Benzylpyrrolidin-3-yl)-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzarnide
Figure imgf000227_0003
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-amino-l-benzylpyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 604.99 (M+H*); retention time = 0.63 minutes. Example 362. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2>3- b]pyrazin-7-yl}phenyl)-[4-(cyclohexylmethyl)piperazin-l-yl]methanone
Figure imgf000228_0001
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(cyclohexylmethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 611.96 (M+ET); retention time = 0.65 minutes. Example 363. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide
Figure imgf000228_0002
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 615.9 (M+ET); retention time = 0.77 minutes. Example 364. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3s4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-morpholin-4-ylpiperidin-l-yl)methanone
Figure imgf000228_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl3-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-(4-morpholinyl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 598.99 (M+H*); retention time = 0.52 minutes. Example 365. (3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-((S)-2-pyrrolidin- 1 -ylmethylpyrrolidin- 1 -yl)methanone
Figure imgf000229_0001
(3-{ 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with (S)-2-(l-pyrrolidinylmethyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 583.96 (M-I-H+); retention time = 0.58 minutes.
Example 366. (3- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-(2-pyridin-3-ylpyrrolidin- 1 -yl)methanone
Figure imgf000229_0002
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 577.95 (M+H^); retention time = 0.65 minutes.
Example 367. 3-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2-methoxybenzyl)-N-methylbenzamide
Figure imgf000229_0003
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with N-methyl-2-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 580.94 (M+H*); retention time = 0.96 minutes. Example 368. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-phenylpiperazin- 1 -yl)methanone
Figure imgf000230_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetτahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-phenylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 592.00 (MH-H+); retention time = 0.98 minutes. Example 369. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-pyrimidin-2-ylpiperazin-l-yl)methanone
Figure imgf000230_0002
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(2-pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 593.98 (MH-H+); retention time = 0.84 minutes. Example 370. [4-(4-Chlorophenyl)piperazin-l -yl] -(4- { 1 -[5-chloro-2- (trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyτido[2,3-b]pyrazin-7-yl} phenyl) methanone
Figure imgf000230_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with l-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 625.96 (M-I-H+); retention time = 1.06 minutes.
Example 371. [4-(4-Chlorophenyl)-4-hydroxypiperidin- 1 -yl]-(4- { 1 -[5-chloro-2-
(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000231_0001
(4- { 1 - [5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido [2,3 -b]pyrazin-7- yl}benzoic acid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as in General
Procedure 10 to give the title compound. LCMS: m/z = 640.96 (M+H*); retention time = 0.94 minutes.
Example 372. l-[l-(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzoyl)piperidin-4-yl]- 1 ,3-dihydrobenzoimidazol-2-one
Figure imgf000231_0002
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l,3-dihydro-l-(4-piperidinyl)benzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z = 647.03 (M+Hf*); retention time = 0.81 minutes.
Example 373. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-[4-(2-methoxyphenyl)piperazin- 1 -yl]methanone
Figure imgf000231_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 621.98 (M+H*); retention time = 0.95 minutes. Example 374. (4- { 1 -[5-Chloro-2-(tri£luoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}methanone
Figure imgf000232_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-[3-(tri£luoromethyl)phenyl]piperazine as in General
Procedure 10 to give the title compound. LCMS: m/z = 659.99 (M+H*); retention time = 1.08 minutes.
Example 375. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-phenylpiperidin- 1 -yl)methanone
Figure imgf000232_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3)4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-phenylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 590.99 (M-HH+); retention time = 1.04 minutes. Example 376. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(lH-indol-3-yl)piperidin-l-yl]methanone
Figure imgf000232_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-(lH-indol-3-yl)ρiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 630.92 (M+H*); retention time = 0.99 minutes. Example 377. (4-Benzhydrylpiperazin-l-yl)-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000233_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-benzhydrylρiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 680.99 (M-I-H+); retention time = 1.00 minutes. Example 378. (4-Benzylpiperidin- 1 -yl)-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000233_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 605.00 (M+H*); retention time = 1.09 minutes. Example 379. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-l-yl]methanone
Figure imgf000233_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(3,4-dichlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 659.92 (M+H*); retention time = 1.12 minutes. Example 380. 8-(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoyl)- 1 -phenyl- 1 ,3,8-triaza-spiro[4.5]decan-4-one
Figure imgf000234_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one as in General
Procedure 10 to give the title compound. LCMS: m/z = 661.03 (M-I-H-+); retention time = 0.86 minutes.
Example 381. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)- {4-[2-(trifluoromethyl)phenyl]piperazin- 1 -yl} methanone
Figure imgf000234_0002
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yljbenzoic acid was reacted with l-[2-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 659.99 (M-I-H+); retention time = 1.10 minutes.
Example 382. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-l-yl)methanone
Figure imgf000234_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-thieno[3,2-d]pyrimidinyl)piperazine as in General
Procedure 10 to give the title compound. LCMS: m/z = 648.99 (M-I-H+); retention time = 0.64 minutes.
Example 383. [4-(4-Chlorobenzyl)piperazin-l-yl]-(4- {l-[5-chloro-2-(trifluoromethyl)benzyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000235_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-chlorobenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 639.99 (IVH-H+); retention time = 0.69 minutes. Example 384. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(4-methoxybenzyl)piperazin-l-yl]methanone
Figure imgf000235_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-methoxybenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 636.02 (M+H1"); retention time = 0.61 minutes. Example 385. (4-Benzoylpiρerazin- 1 -yl)-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl] - 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000235_0003
(4- { l-[5-chloro-2-(trifluorornethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-benzoylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 619.98 (M-I-H+); retention time = 0.82 minutes. Example 386. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } phenyl)-(4-furo[3 ,2-c]p yridin-4-ylpiperazin- 1 -yl)methanone
Figure imgf000236_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(4-furo[3,2-c]pyridinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 633.03 (TVH-H+); retention time = 0.63 minutes. Example 387. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l^,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-l-yl]methanoήe
Figure imgf000236_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl] - 1 ,2,3,4-tetrahydropyrido[2,3 -b]pyrazin-7- yl}benzoic acid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as in General
Procedure 10 to give the title compound. LCMS: m/z = 649.96 (IVH-H+); retention time = 1.00 minutes.
Example 388. 4-{l-[5-Chloro-2-(tri£luoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2-pyridin-2-yl-ethyl)benzamide
Figure imgf000236_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 2-(2-pyridinyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z.= 551.01 (M-I-H+); retention time = 0.56 minutes. Example 389. 4-(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2J3- b]pyrazin-7-yl}benzoylamino)piperidine-l-carboxylic acid ethyl ester
Figure imgf000237_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-aminopiperidine-l-carboxylic acid ethyl ester as in General
Procedure 10 to give the title compound. LCMS: m/z = 601.99 (M+H*); retention time = 0.85 minutes.
Example 390. N-(I -Benzylpiperidin-4-yl)-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000237_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-amino-l-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 619.99 (M+H*); retention time = 0.61 minutes. Example 391. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2,2-diphenylethyl)benzamide
Figure imgf000237_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2,2-diphenylethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 626.99 QvRH+); retention time = 1.06 minutes. Example 392. 1 -[4-(4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoyl)piperazin-l-yl]ethanone
Figure imgf000238_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-acetylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 557.97 (M+H*); retention time = 0.68 minutes. Example 393. 4- { 1 -[5 -Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(l-methylpiperidin-4-yl)benzamide
Figure imgf000238_0002
(4-{l-[5-chloro-2-(1rifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-amino-l-methylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z = 543.96 (M+ET1"); retention time = 0.51 minutes. Example 394. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin- 1 -yljmethanone
Figure imgf000238_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-piperazinyl-2-(2-pyridinyl)ethane as in General Procedure 10 to give the title compound. LCMS: m/z = 620.98 (M+H*); retention time = 0.53 minutes. Example 395. 4- { 1 -[5-Chloro-2-(trifluorornethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-[4-(trifluoromethoxy)benzyl]benzarnide
Figure imgf000239_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl] - 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-(trifluoromethoxy)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 620.95 (M+H*); retention time = 1.03 minutes. Example 396. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-[4-(trifluoromethyl)benzyl]benzamide
Figure imgf000239_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 604.92 (MH-H+); retention time = 1.01 minutes. Example 397. N-[3,5-Bis(trifluoromethyl)benzyl]-4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000239_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 672.90 (M-HH+); retention time = 1.11 minutes. Example 398. 4-{l-[5-Chloro-2-(trifluoromethyl)ben2yl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2-thiophen-2-yl-ethyl)benzamide
Figure imgf000240_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3J4-tetrahydropyrido[2,3-b]pyrazin-7- yljbenzoic acid was reacted with 2-(2-aminoethyl)thiophene as in General Procedure 10 to give the title compound. LCMS: m/z = 556.91 (M+H4); retention time = 0.92 minutes. Example 399. N-Benzhydryl-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzarnide
Figure imgf000240_0002
(4- { l-[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with benzhydrylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 613.00 (M+H*); retention time = 1.06 minutes.
Example 400. 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-pyridin-4-yhnethylbenzamide
Figure imgf000240_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z = 537.98 (M+H*); retention time = 0.54 minutes. Example 401. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-pyridm-3-ylmethylbenzamide
Figure imgf000241_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z = 537.95 (IVH-H+); retention time = 0.57 minutes. Example 402. 2-[4-(4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoyl)piperazin-l-yl]-N-isopropylacetamide
Figure imgf000241_0002
(4- { 1 - [5 -chloro-2-(trifluoromethyl)benzyl] - 1 ,2,3 ,4-tetrahydropyrido [2,3 -b]pyrazin-7- yl}benzoic acid was reacted with 2-piperazinyl-N-isopropylacetamide as in General Procedure 10 to give the title compound. LCMS: m/z = 615.03 (M-J-H+); retention time = 0.58 minutes. Example 403. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzylj- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-l-yl]methanone
Figure imgf000241_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-methyl-4-(l-piperazinyl)quinoIine as in General Procedure 10 to give the title compound. LCMS: m/z = 656.96 (M-^H+); retention time = 0.62 minutes. Example 404. 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } -N-(2-methoxyethyl)benzamide
Figure imgf000242_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-methoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 504.97 (M+H*); retention time = 0.74 minutes. Example 405. 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide
Figure imgf000242_0002
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-(4-sulfamoylphenyl)ethylamϊne as in General Procedure 10 to give the title compound. LCMS: m/z = 629.94 (M+H4); retention time = 0.75 minutes. Example 406. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(2,3,5,6-tetrahydro[l,2l]bipyrazinyl-4-yl)methanone
Figure imgf000242_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-(l-piperazinyl)pyrazine as in General Procedure 10 to give the title compound. LCMS: m/z = 593.98 (M+H*); retention time = 0.79 minutes. Example 407. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2-phenylthiazol-4-yhnethyl)benzamide
Figure imgf000243_0001
(4-{l-[5-cWo«>-2-(trifluoiOmethyl)benzyl]-l,23,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in General Procedure 10 to give the title compound. LCMS: m/z = 619.9001+H+); retention time = 0.98 minutes. Example 408. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3a4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)moφholin-4-ylmethanone
Figure imgf000243_0002
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with morpholine as in General Procedure 10 to give the title compound. LCMS: m/z = 516.96 (M+H*); retention time = 0.74 minutes. Example 409. 4- { l-[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} -N-naphthalen- 1 -ylmethylbenzamide
Figure imgf000243_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(aminomethyl)naphthalene as in General Procedure 10 to give the title compound. LCMS: m/z = 586.95 (M+H*); retention time = 1.01 minutes. Example 410. 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} -N-indan- 1 -ylbenzamide
Figure imgf000244_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z = 562.95 (M+H*); retention time = 0.98 minutes. Example 411. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } phenyl)- [4-(4-methoxyphenyl)piperazin- 1 -yl]methanone
Figure imgf000244_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with l-(4-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 622.01 (M+JT*); retention time = 0.92 minutes.
Example 412. N-(2-Chlorobenzyl)-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000244_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 570.90 (M+H*); retention time = 0.98 minutes. Example 413. N-(4-Chlorobenzyl)-4-{l-[5-chloro-2-(trifluoromethyl)benzyl] -1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000245_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 570.90 QVB-H+); retention time = 0.98 minutes. Example 414. N-(3-Chloro-benzyl)-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000245_0002
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 570.90 (MH-H+); retention time = 0.98 minutes. Example 415. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-l-yl]methanone
Figure imgf000245_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(tetrahydrofuran-2-carbonyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 613.98 (M-I-H+); retention time = 0.72 minutes.
Example 416. ^{l-tS-Chloro^-CtrifluoromethyObenzylj-l^.S^-tetrahydropyrido^.S.- b]pyrazin-7-yl} -N-phenethylbenzamide
Figure imgf000246_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with phenethyl amine as in General Procedure 10 to give the title compound. LCMS: m/z = 550.96 (M+H4); retention time = 0.94 minutes. Example 417. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide
Figure imgf000246_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-(aminomethyl)tetrahydrofuran as in General Procedure 10 to give the title compound. LCMS: m/z = 530.96 (M+H*); retention time = 0.78 minutes. Example 418. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} -N-(3 -methoxybenzyl)benzamide
Figure imgf000246_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 566.97 (M+H*); retention time = 0.91 minutes. Example 419. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(4-methoxybenzyl)benzamide
Figure imgf000247_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyraziπ-7- yl}benzoic acid was reacted with 4-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 566.97 (M+H*); retention time = 0.90 minutes. Example 420. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(2-phenoxyethyl)benzamide
Figure imgf000247_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 2-phenoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 566.93 (M-I-H+); retention time = 0.93 minutes. Example 421. N-Benzyl-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000247_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 536.96 (M+H*); retention time = 0.91 minutes. Example 422. [4-(3-Chlorophenyl)piperazin- 1 -yl]-(4- { 1 -[5-chloro-2- (trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000248_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(3-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 625.96 (MMH+); retention time = 1.06 minutes. Example 423. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} -N-indan-2-ylbenzamide
Figure imgf000248_0002
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 2-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z = 562.96 (M+H*); retention time = 0.98 minutes.
Example 424. (4- { 1 - [5-Chloro-2-(trifluoromethyl)benzyl] - 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-(4-phenethylpiperazin-l-yl)methanone
Figure imgf000248_0003
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 1-phenethylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 620.02 01+H+); retention time = 0.63 minutes.
Example 425. N-Biphenyl-4-ylmethyl-4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide
Figure imgf000249_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with 4-(aminomethyl)biphenyl as in General Procedure 10 to give the title compound. LCMS: m/z = 613.00 (M-I-H+); retention time = 1.07 minutes.
Example 426. [4-(2-Chlorophenyl)piperazin- 1 -yl]-(4- { 1 -[5-chloro-2-
(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone
Figure imgf000249_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(2-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 625.96 (M+H*); retention time = 1.07 minutes. Example 427. N-(I -Benzylpyrrolidin-3-yl)-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido [2,3 -b]pyrazin-7-yl } benzamide
Figure imgf000249_0003
(4- { 1 - [5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 3-amino-l-benzylpyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 605.96 (M+H*); retention time = 0.62 minutes. Example 428. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-[4-(cyclohexylmethyl)piperazin- 1 -yl]methanone
Figure imgf000250_0001
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with l-(cyclohexylmethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z = 611.96 (M-HI+); retention time = 0.64 minutes. Example 429. 4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}-N-(4-sulfamoylbenzyl)benzamide
Figure imgf000250_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 615.91 (M+H+); retention time = 0.75 minutes. Example 430. (4-{l-[5-Chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}phenyl)-((S)-2-pyrrolidin-l-ylmethylpyrrolidin-l-yl)methanone
Figure imgf000250_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with (S)-2-(l-pyrrolidinylmethyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 583.95 (MH-H+); retention time = 0.58 minutes. Example 431. (^{l-tS-Chloro^-CtrifluoromethyObenzylj-l^^^-tetrahydropyrido^.S- b]pyrazin-7-yl}phenyl)-(2-pyridin-3-yl-pyrrolidin-l-yl)methanone
Figure imgf000251_0001
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l-2,3,4-tetrahydropyrido[2-3-b]pyrazin-7- yl} benzoic acid was reacted with 2-(3-pyridinyl)pyrτolidine as in General Procedure 10 to give the title compound. LCMS: m/z = 577.97 (IVH-H+); retention time = 0.63 minutes. Example 432. 4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} -N-(2-methoxybenzyl)-N-methylbenzamide
Figure imgf000251_0002
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with N-methyl-2-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z = 580.98 (M+H*); retention time = 0.96 minutes. Example 433. (4- { 1 -[5-Chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} phenyl)-( 1 ,3-dihydπ>isoindol-2-yl)methanone
Figure imgf000251_0003
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid was reacted with 1,3-dihydroisoindole as in General Procedure 10 to give the title compound. LCMS: m/z = 548.94 (M+H*); retention time = 0.94 minutes. Example 434. {4-[ 1 -(5-Chloro-2-trifluoromethyl-benzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]-phenyl}-(spiro[isobenzofuran-l(3H),41-piperidine]-l-yl)methanone
Figure imgf000252_0001
(4- { l-[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid was reacted with spiro(isobenzofuran-l(3H),4'-piperidine) as in General
Procedure 10 to give the title compound. LCMS: m/z = 618.98 (NH-H+); retention time = 1.00 minutes.
Example 435. 6-Bromo-3,4-dihydro-lH-quinoxalin-2-one
Figure imgf000252_0002
5-bromo-2,3-diaminopyridine (2.0 g, 10.6 mmol) and glyoxylic acid monohydrate (1.23 g, 13.4 mmol) were combined in water (55 mL), sonicated for 10 minutes and stirred overnight. The product was filtered, washed with water (5 * 100 mL) and dried under vacuum to afford 2.214 g of crude product. To a suspension of this material in methanol (100 mL) was added NaBEU (1.0 g, 26.3 mmol) with periodic cooling in an ice water bath to maintain reaction temperature below 35°C. After stirring for 4 hours, the reaction was quenched with 6N HCl (20 mL) and the resulting mixture stirred overnight. The mixture was warmed to 500C for 0.5 hour before removing volatile solvents by rotary evaporation. After adjusting the pH of the aqueous reside to 8 by the addition of ION NaOH, the product was removed by filtration and washed with water (5 x 50 mL) to give the title compound (1.985 g, 82%). m.p. 265 0C (dec), 1H-NMR (DMSO--/6, 400 MHz) δ 10.47 (s, IH), 7.65 (d, J= 2.1 Hz, IH), 7.01-6.99 (m, 2H), 3.94 (s, 2H).
Example 436. 7-Bromo- 1 -(2-chloro-3,6-difluorobenzyl)- 1 ,4-dihydro-2H-pyrido[2,3- b]pyrazin-3-one
Figure imgf000253_0001
To a solution of 6-bromo-3,4-dihydro-lH-quinoxalin-2-one (228 mg, 1.00 mmol) in DMF (10 mL) was added NaH (40 mg of a 60% dispersion in mineral oil, 1.00 mmol) and the resulting mixture sonicated for 5 minutes. After stirring at room temperature for 20 minutes, 2-chloro- 3,6-difluorobenzylbromide (242 mg, 1.00 mmol) was added and the mixture was stirred for 20 minutes. Solvent was reduced ~90% and the residue was triturated with ether (3 x 1 mL) and water (2 x 2 mL) to give the title compound (275 mg, 71%). m.p. 214 -216 0C (dec); LCMS: m/z = 388/390/392 (M-I-H+); 1H-NMR (DMSO-4 400 MHz) δ 7.73 (s, IH), 7.47-7.42 (m, IH), 7.35 (s, IH), 7.32-7.26 (m, IH), 7.11 (s, IH), 5.24, (s, 2H), 4.01 (s, 2H). Example 437. l-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]- l,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one
Figure imgf000253_0002
A mixture of 7-bromo-l-(2-chloro-3,6-difiuorobenzyl)-l,4-dihydro-2H-pyrido[2,3-b]pyrazin- 3-one (42 mg, 0.11 mmol), l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)pyridin-2-yl]piperazine (40 mg, 0.13 mmol), palladium (H) acetate (4 mg) and triphenylphosphine (14 mg) in n-propanol (1.0 mL) was degassed with argon while adding a 1.26 M aqueous solution OfNa2COs (0.12 mL) followed by water (0.38 mL). This mixture was heated in a microwave for 10 minutes at 1300C, cooled to room temperature and extracted into CH2Cb. The organic phase was passed through a plug OfNa2SO4, absorbed onto florisil and evaporated to dryness. This material was purified by silica gel chromatography by eluting with increasing amounts of 5% NHUOH/methanol in dichloromethane. The isolated material was recrystallized from methanol to give the title compound (15.4 mg, 29%). m.p. 235 -236 0C (dec); LCMS: m/z = 485/487 (M+H+); 1H-NMR (CDC13-rf6, 400 MHz) δ 8.22 (d, J= 2.4 Hz,
IH), 7.89 (d, 7= 2.4 Hz, IH), 7.49-7.46 (m, IH), 7.16 (s, IH), 7.15-7.06 (m, IH), 7.05-6.93 (m, IH), 6.69 (d, J=8.8, IH), 5.43, (s, 2H), 4.81 (s, IH), 4.24 (s, 2H), 3.61-3.59 (m, 4H), 2.55- 2.52 (m, 4H), 2.36 (s, 3H).
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I
Figure imgf000255_0001
I or a pharmaceutically acceptable salt form thereof, wherein:
A is chosen from N and CH; X is chosen from -L2G1L3G2L4R7 and R8;
L1 is a bond, -C0-3-alkyl-C(=0)-Co-3-alkyl-, -Coo-alkyl-StK^-Co-s-alkyl-, -C0-3- alkyl-C(=0)NR10-Co-3-alkyl- -Co-3-alkyl-S(=0)2NR10-Co-3-alkyl- -Co-3-alkyl-
C(=0)0-Co-3-alkyl-, -Co-3-alkyl-OC(=0)NR10-Co-3-alkyl- -Co-3-alkyl-NR1 ^C0-3- alkyl-, -Coo-alkyl-O-Coo-alkyl-, -Q-β-alkyl-, -C2-6-alkenyl-, or -C2-6-alkynyl-; R1 is an optionally mono- or polysubstituted group chosen from aryl, C^io-cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, -OR20, -C(K))R20, -C(K))OR20, -C(K))NR20R21, -NR20R21, Cio-alkyl, Ci-3-haloalkyl, aryl, heteroaryl, Cs-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(=O)nR20, -S(=O)2NR20R21, -OCH2F, -OCHF2, -OCF3, - NHOH, -OC(O)R20, -OC(=O)NR20R21, -NR20C(=O)R21, -NR20C(KD)OR21, and -SCF3;
R2 and R3 are independently chosen from H, OH, and Ci^-alkyl, or R2 and R3 together form a carbonyl group; R4 and R5 are independently chosen from H and
Figure imgf000255_0002
or R4 and R5 together form a carbonyl group, or one of R4 and R5 forms a double bond with R6; R6 is chosen from H and C^-alkyl, or R6 forms a double bond with R4 or R5;
L2 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl- -Co-3-alkyl-S(=0)n-C0-3-alkyl-, -C0.3- alkyl-C(=0)NR30-Co.3-alkyl-, -C0-3-alkyl-S(K))2NR30-Co-3-alkyl-, -Co-3-alkyl-
C(=0)0-Co-3-alkyl-, -Co-3-alkyl-OC(=0)NR30-Co-3-alkyl- -Co-3-alkyl-NR3O-Co-3- alkyl-, -Co-s-alkyl-O-Co-s-alkyl-, -Ci_3-alkyl-, -C2-3-alkenyl-, or -C2-3-alkynyl-; G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C3-10- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, -OR40, -C(O)R40, -C(K))OR40, -C(O)NR40R41, -NR40R41, Cu-alkyl, Ci-3-haloalkyl, aryl, heteroaryl, Cs-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -SC=O)nR40, -S(=O)2NR40R41, -OCH2F, -OCHF2, -OCF3, - NHOH, -OC(O)R40, -OCC=O)NR40R41, -NR40C(=O)R41, -NR40C(K))OR41, and -SCF3;
L3 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl-, -Co-3-alkyl-S(=0)n-Co-3-alkyl-, -C0-3- alkyl-C(=0)NR50-Co-3-alkyl-, -Co.3-alkyl-S(=0)2NR50-Co-3-alkyl-, -C0-3-alkyl-
C(=0)0-Co-3-alkyl-, -C0-3-alkyl-OC(0)NR50-Co-3-alkyl-, -Co-3-alkyl-NR5<)-Co-3- alkyl-, -Co-s-alkyl-O-Coo-alkyl-, -Cu-alkyl-, -C2-3-alkenyl-, or -C2-3-alkynyl-; G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, C3-io- cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, -OR60, -C(O)R60, -C(O)OR60, -C(O)NR60R61, -NR60R61, Ci-3-alkyl, C1-3-haloalkyl, aryl, heteroaryl, C^io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(O)nR60, -SC=O)2NR60R61, -OCH2F, -OCHF2, -OCF3, - NHOH, -OC(O)R60, -OC(O)NR60R61, -NR60C(O)R61, -NR60C(K))OR61, and -SCF3;
L4 is a bond, -Co-3-alkyl-C(=0)-Co-3-alkyl-, -Co-3-alkyl-S(=0)n-Co-3-alkyl-, -Co-3- alkyl-C(=0)NR70-Co-3-alkyl-, -Co-3-alkyl-S(=0)2NR70-Co.3-alkyl-, -Co-3-alkyl- C(K))0-Co-3-alkyl-, -Co-3-alkyl-OC(=0)NR70-Co-3-alkyl-, -Co-3-alkyl-NR70-Co-3- alkyl-, -Coo-alkyl-O-Coo-alkyl-, -Cu-alkyl-, -C2-3-alkenyl-, or -C2-3-alkynyl-; R7 is an optionally mono- or polysubstituted group chosen from Ci-β-alkyl, C2-6- alkenyl, C2-6-alkynyl, aryl, C^io-cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the substituents may be identical or different and are chosen from halogen, -NO2, OR80, -C(KD)R80, -C(K))OR80, -C(K))NR80R81, -NR80R81, Ci-6-alkyl, Ci-β-haloalkyl, aryl, heteroaryl, Cs-io-cycloalkyl, heterocycloalkyl, pseudohalogen, -S(O)nR80, -S(O)2NR80R81, -OCH2F, -OCHF2, -OCF3, -
NHOH, -OC(O)R80, -OC(O)NR80R81, -NR80C(K))R81, -NR80C(K))OR81, - SiR80R81R82 and -SCF3;
R8 is chosen from H, halogen, CN3 and C(O)OH; R10, R20, R21, R30, R40, R41, R50, R60, R61, R70, R80, R81, and R82 at each occurrence are independently chosen from H, Ci-6-alkyl, C^-haloalkyl, aryl, heteroaryl, C3-io- cycloalkyl, and heterocycloalkyl; and n is 0, 1, or 2; provided that when L1 is — C(=O)— and R1 is phenyl, R8 is not H or Br.
2. A compound as defined in claim 1 , wherein A is N.
3. A compound as defined in claim 2, wherein L1 is -Co-3-alkyl-C(=0)-Co-3-alkyl-, -Co-3- alkyl-S(=0)n-Co-3-alkyl- -Co-3-alkyl-C(=0)NR10-Co-3-alkyl-, -Co-3-alkyl-S(-0)2NR10- Co-3-alkyl-, -C0-3-alkyl-C(=0)0-Co-3-alkyl-,
Figure imgf000257_0001
4. A compound as defined in claim 2, wherein L1 is -Co-3-alkyl-C(=0)-Co-3-alkyl— , -Co-3- alkyl-S(=0)2-Co-3-alkyl-, or -Ci-e-alkyl-.
5. A compound as defined in claim 1, wherein A is CH.
6. A compound as defined in claim 5, wherein L1 -R1 is -Ci-3-alkyl-C(=0)-Co-3-alkyl-R1, — Coo-alkyl-SCOVCo-s-alkyl-R1 , -C,.3-alkyl-C(=0)NR10-Co-3-alkyl-R1 , R^Co-s-alkyl- C(=0)NR10-Co-3-alkyl-, -C0-3-alkyl-S(=0)2NR10-Co-3-alkyl-R1, R1-C0.3-alkyl-
S(=0)2NR10-Co-3-alkyl- -C1-3-alkyl-C(=0)0-Co-3-alkyl-R1 J R1-Co-3-alkyl-C(=0)0-Co- 3-alkyl-, -Co-3-alkyl-OC(=0)NR10-Co-3-alkyl-R1 , R1 -Co-3-alkyl-OC(=0)NR10-Co-3- alkyl- -Co-s-alkyl-NR^-Qw-alkyl-R1, -C^-alkyl-O-Co-s-alkyl-R1, -C1-6-alkyl-R\ -
Figure imgf000257_0002
or -C2-6-alkynyl-R1.
7. A compound as defined in claim 5, wherein L1 is -Coo-alkyl-O-Coo-alkyl- or -CH2-.
8. A compound as defined in claim 1 , wherein R1 is an optionally mono- or polysubstituted group chosen from aryl and heteroaryl.
9. A compound as defined in claim 8, wherein each R1 substituent is independently chosen from halogen, -C(=O)-Ci-6-alkyl, Ci-3-haloalkyl, cyano, and -OCF3.
10. A compound as defined in any of claims 1-9, wherein R2 and R3 are independently chosen from H and Ci-6-alkyl, or R2 and R3 together form a carbonyl group.
11. A compound as defined in any of claims 1-9, wherein R4 and R5 are H.
12. A compound as defined in any of claims 1-9, wherein R6 is H.
13. A compound as defined in claim 1, wherein X is -L2G1L3G2L4R7.
14. A compound as defined in claim 13, wherein L2 is a bond, — Co-3-alkyl-C(=0)-Co-3- alkyl- -S(=0)n-Co-3-alkyl-, -C(=O)NR30-C0-3-alkyl- -S(=0)2NR30-Co-3-alkyl-, - C(=0)0-Co-3-alkyl-, -CH2-OC(=0)NR30-Co-3-alkyK -C0-3-alkyl-OC(=0)NR30-CH2-, -CH2-NR3O-Co-3-alkyl-, -CHj-O-Co-s-alkyl-, -CH2-OC(=O)-C0-3alkyl-, -CH2- NRI0C(=O)-C0-3-alkyl-, -CH2-NR10S(=0)2-Co-3-alkyl-, -C1-3-alkyl- -C2-3-alkenyl- or -C2-3-alkynyl-.
15. A compound as defined in claim 14, wherein L2 is a bond, -Co-3-alkyl-C(=0)-Co-3- alkyl-, -C(=O)NR30-C0-3-alkyl-, -C(O)O-C0-3- alkyl- or -Czo-alkynyl-.
16. A compound as defined in any of claims 1-9 or 13-15, wherein G1 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl.
17. A compound as defined in claim 16, wherein each G1 substituent is independently chosen from halogen and —OR40.
18. A compound as defined in any of claims 1-9 or 13-15, wherein L3 is a bond, -C0-3- alkyl-C(=0)-Co-3-alkyl-, -Co-3-alkyl-C(=0)NR50-Co-3-alkyl-, -Co-3-alkyl-S(=0)2NR50- Co-3-alkyl- -Co-s-alkyl-CC-OJO-Coo-alkyl-, -Co-3-alkyl-OC(=0)NR50-Co.3-alkyK - Co-s-alkyl-NR^-Coo-alkyl-, -Qw-alkyl-O-Co-s-alkyl-, or-Ci-3-alkyl-.
19. A compound as defined in any of claims 1-9 or 13-15, wherein G2 is a bond, or an optionally mono- or polysubstituted group chosen from aryl, heterocycloalkyl, and heteroaryl.
20. A compound as defined in claim 19, wherein each G2 substituent is independently chosen from halogen and -OR60.
21. A compound as defined in any of claims 1-9 or 13-15, wherein L4 is a bond, — C0-3- alkyl-C(=0)-Co-3-alkyl- -Co-3-alkyl-C(=0)NR70-C0-3-alkyl-, -C0-3-alkyl-C(=O)O-C0-3- alkyl— , or-Ci-3-alkyl— .
22. A compound as defined in any of claims 1-9 or 13-15, wherein R7 is an optionally mono- or polysubstituted group chosen from Ci^-alkyl, aryl, Cs-io-cycloalkyl, heterocycloalkyl, and heteroaryl.
23. A compound as defined in claim 22, wherein each R7 substituent is independently chosen from halogen, -OR80, -C(=O)R80, -C(=O)OR80, -C(=O)NR80R81, -NR80R81, C1- 6-alkyl, Ci-6-haloalkyl, aryl, heteroaryl, Cs-io-cycloalkyl, heterocycloalkyl, cyano, — SC=O)nR80, -S(=O)2NR80R81, -OCF3, and -SiR80R81R82.
24. A compound as defined in any of claims 1-9 or 13-15, wherein at least one of G1 and R7 is an optionally mono- or polysubstituted group chosen from aryl, C3-io-cycloalkyl, heterocycloalkyl, and heteroaryl.
25. A compound as defined in claim 24, wherein each G1 substituent is independently chosen from halogen and -OR40, and each R7 substituent is independently chosen from halogen, -OR80, -C(=O)R80, -C(=O)OR80, -C(=O)NR80R8i, -NR80R81, Cl-6-alkyl, C1^- haloalkyl, aryl, heteroaryl, Ca-io-cycloalkyl, heterocycloalkyl, cyano, -S(=O)nR80, - S(=O)2NR80R81, -OCF3, and -SiR80R81R82.
26. A compound as defined in any of claims 1-9 or 13-15, provided that when R7 is Ci-^- alkyl, at least one of L2, G1, L3, G2, or L4 is not a bond.
27. A compound as defined in any of claims 1-9 or 13-15, wherein R80 at each occurrence is independently chosen from H, Ci-β-alkyl, Ci-6-haloalkyl, and aryl.
28. A compound as defined in any of claims 1 to 9 or 13 to 15, wherein R80, R81, and R82 at each occurrence are independently chosen from H, Ci-β-alkyl, and
Figure imgf000259_0001
29. A compound as defined in any of claims 1-9 or 13-15, wherein R10, R20, R21, R30, R40, R41, R50, R51, R60, R61, R70, R80, R81, and R82 at each occurrence are independently chosen from H and Ci-β-alkyl.
30. A compound as defined in claim 29, wherein R10, R20, R21, R30, R40, R41, R50, R51, R60, R61, R70, R80, R81, and R82 at each occurrence are H.
31. A compound as defined in any of claims 1-9 or 13-15, wherein X is R8.
32. A compound as defined in any of claims 1-9 or 13-15, wherein n is 2.
33. A compound as defined in claim 1 , wherein said compound is l^-chloro-S.ό-difluorobenzyO-T-pyridin-S-yl-S^-dihydro-lH-pyridoP^-bJpyrazin^- one; 4-[l-(2τchloro-3,6-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]benzoic acid ethyl ester;
4-[l-(2-chloro-3,6-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]benzoic acid; l-(2-chloro-3,6-difluorobenzyl)-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4- dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one;
4-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester;
4-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid; l-benzyl-7-pyridin-3-yl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
4-( 1 -benzyl-2-oxo- 1 ,2 ,3 ,4-tetrahydropyrido [2,3 -b]pyrazin-7-yl)-N-(2-pyrrolidin- 1 -yl- ethyl)benzamide;
-?-l-benzyl-7-[4-(2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carbonyl)phenyl]-3,4- dihydro-lH-pyrido[2,3-b]pyrazin-2-one; 4-(l -benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-morpholin-4-yl- propyl)benzamide;
4-(l -benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(4- dimethylaminobutyl)benzamide; 4-( 1 -benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3 -b]pyrazin-7-yl)-N-(6- dimethylaminohexyl)benzamide; l-benzyl-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-lH-pyrido[2,3- b]pyrazin-2-one;
S-l-benzyl-7-[3-(2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carbonyl)phenyl]-3,4- dihydro-1 H-pyrido [2,3-b]pyrazin-2-one;
3-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylainino- ethyl)benzamide; l-benzyl-7-[3-φyrrolidine-l-carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one; 7-(4-acetylphenyl)- 1 -benzyl-3 ,4-dihydro- 1 H-pyrido [2,3-b]pyrazin-2-one;
3-(l -benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzamide;
4-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyτazin-7-yl)benzamide;
1 -benzyl-7-(4-methanesulfonyl-phenyl)-3,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one; l-benzyl-7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3J4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one;
1 -benzyl-7-[4-(4-(pyrrolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl]-3 ,4-dihydro- 1 H- pyrido[2,3-b]pyrazin-2-one;
4-(l -benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-ethyl-benzainide;
5-(l -benzyl-2-oxo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile; 5-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carboxylic acid ethyl ester;
3-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid methyl ester;
3-(l-benzyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid; l-benzyl-7-pyridin-3-yl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
4-(l-benzyl-l,2,3,4-tetτahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester;
4-(l-benzyl-l ,2,3,4-tetrahydropyτido[2,3-b]ρyrazin-7-yl)benzoic acid; [4-(l-benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-(4-methylpiperazin-
1 -yl)methanone;
[4-(l-benzyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]-((S)-2- pyrrolidinylmethylpyrrolidin- 1 -yl)methanone; [4-( 1 -benzyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyra2in-7-yl)phenyl]-(4-(pyrrolidin- 1 - yl)piperidin- 1 -yl)methanone; phenyl-(7-pyridin-3-yl-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)methanone;
4-(l-benzoyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid ethyl ester;
2-pyrrolidin- 1 -yl-ethanesulfonic acid [4-( 1 -benzyl-2-oxo- 1 ,2 ,3 ,4-tetrahydropyrido [2,3 - b]pyrazin-7-yl)phenyl]amide;
2-pyrrolidin- 1 -yl-ethanesulfonic acid [4-( 1 -benzoyl- 1 ,2 ,3,4-tetrahydropyrido [2,3 - b]pyrazin-7-yl)phenyl]amide;
2-(4-methylpiperazin-l-yl)-ethanesulfonic acid [4-( 1 -benzoyl- 1, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl]amide; 2-pyrrolidin- 1 -yl-ethanesulfonic acid {4-[ 1 -(2,5-difluorobenzyl)-2-oxo- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl } -amide;
2-[ethyl-((S)- 1 -pyrrolidin- 1 -ylmethyl-propyl)-amino]-ethanesulfonic acid {4-[ 1 -(2,5- difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;
2-moφholin-4-yl-ethanesulfonic acid {4-[l-(2,5-difluorobenzyl)-2-oxo-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -amide;
2-pyrrolidin- 1 -yl-ethanesulfonic acid {4-[l-(2,5-difluorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-amide;
4-(l-benzoyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(2-dimethylamino- ethyl)benzamide; 4-(l-benzoyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)-N-(3-dimethylamino- propyl)benzamide;
{7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l- y 1 } phenyhnethanone ;
4-[l-(2,5-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester;
4-[l-(2,5-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid; 1 -(2,5 -difluorobenzyl)-7-[4-((S)-2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 - carbonyl)phenyl]-3,4-dihydro-lH-pyrido[2J3-b]pyrazin-2-one;
4-[l-(2,5-difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2- pyrrolidin- 1 -yl-ethyl)benzamide; 1 -(2,5-difluorobenzyl)-7-[4-(4-methylpiperazine-l -carbonyl)phenyl]-3,4-dihydro-lH- pyrido[2,3-b]pyrazin-2-one; l-(2,5-difluorobenzyl)-7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-3,4- dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one;
(S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carboxylic acid {4-[l-(2,5- difluorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-ainide;
4-[l-(2,5-difluorobenzyl)-l>2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester;
4-[ 1 -(2,5-difluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid;
{4-[l-(2,5-difluorobenzyl)-l,2,3,4-tetτahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-((S)-2- ((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone;
{4-[l-(2,5-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4-
(pyrrolidin-1 -yl)piperidin- 1 -yl)methanone;
{4-[l-(2,5-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4- methylpiperazin- 1 -yl)methanone; {4-[l-(2,5-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}- morpholin-4-yl-methanone;
1 -(2,5-difluorobenzyl)-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3 -yl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazine; l-(2,5-difluorobenzyl)-7-(6-moφholin-4-yl-pyridin-3-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine;
5-[l-(2,5-difluorobenzyl)-l,2,3)4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2- carbonitrile;
5-[l-(2,5-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2- carboxylic acid; 5-[l-(2,5-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic acid ethyl ester;
5-[l-(2,5-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-nicotinic acid; 1 -(2,5-difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3 -bjpyrazine^-carboxylic acid ethyl ester;
{5-[ 1 -(2,5-difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridin-2- yl} moφholin-4-yl-methanoπe; [l-(2,5-difluorobenzyl)-l,2J3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- methylpiperazin- 1 -yl)methanone;
1 -(2,5-difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [2(4- methylpiperazin-l-yl)ethyl]amide;
7-[4-((S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l-carbonyl)phenyl]-l-(2,4,5- trifluorobenzyl)-3 ,4-dihydro- 1 H-pyrido [2,3 -b]pyrazin-2-one;
((S)-2-((pyrrolidin-l -yl)methyl)pyrrolidin- 1 -yl)- {4-[ 1 -(2,4,5-trifluorobenzyl)- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-methanone;
7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-l-(2,4,5-trifluorobenzyl)-3,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one; (4-methylpiperazin-l -yl)- {4-[ l-(2,4,5-trifluorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]phenyl} -methanone;
(2,5-difluorophenyl)-{7-[4-(4-methylpiperazine-l-carbonyl)phenyl]-3J4-dihydro-2H- pyrido[2,3-b]pyrazin-l-yl}-methanone;
(2,5-difluorophenyl)-{7-[4-((S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l- carbonyl)phenyl]-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl} -methanone; l-(2,5-difluorobenzyl)-3,3-dimethyl-7-[4-((S)-2-[(pyrrolidin-l-yl)methyl]pyrrolidine-l- carbonyl)phenyl]-3 ,4-dihydro- 1 H-pyrido [2,3 -b]pyrazin-2-one;
1 -(2,5-difluorobenzyl)-3 ,3-dimethyl-7-[4-(4-methylpiperazine- 1 -carbonyl)phenyl]-3 ,4- dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one; {4-[l-(2,5-difluorobenzyl)-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl}-((S)-2-((pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)methanone;
{4-[l-(2,5-difluorobenzyl)-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl}-(4-methylpiperazin-l-yl)methanone;
{4-[ 1 -(2-chloro-3,6-difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl } -(4-(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone;
{4-[l-(2-chloro-3,6-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -((S)-2-((pyrrolidin- 1 -yl)methyl)pyrrolidin- 1 -yl)methanone; 1 -(2-chloro-3,6-difluorobenzyl)-7-(3-chloro-2-moφholin-4-yl-pyridin-4-yl)- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-(3-fluoro-2-morpholin-4-yl-pyridin-4-yl)-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazine; 1 -(2-chloro-3,6-difluorobenzyl)-7-(3,5-dimethyl-isoxazol-4-yl)- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
{4-[ 1 -(2-chloro-3,6-difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -(4-methylpiperazin-l -yl)methanone; l-(2-chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-l-yl)-pyrimidin-5-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-(2-morpholin-4-yl-pyrimidin-5-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-(4-moφholin-4-yl-phenyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
2-phenyl- 1 - {7-[4-(4-(pyrrolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl]-3,4-dihydro-2H- pyrido[2,3-b]pyrazin- 1 -yl} -ethanone; 2-(2,5-difluorophenyl)-l-{7-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]-3,4-dihydro-2H- pyrido[2,3-b]pyrazin- 1 -yl} ethanone;
2-(2,5-difluorophenyl)-l-{7-[4-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)phenyl]-3,4- dihydro-2H-pyrido[2,3-b]pyrazin-l -yl} ethanone;
{4-[l-(5-chloro-2-trifluoromethylbenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl } -(4-(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone;
1 -(5-chloro-2-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -(2-chloro-5-trifluoromethylbenzyl)-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-difluorobenzenesulfonyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
1 -benzenesulfonyl-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine; 1 -(2-chlorob enzenesulfonyl)-7- [6-(4-methylpiperazin- 1 -yl)pyridin-3 -yl]- 1 ,2,3 ,4 tetrahydropyrido[2, 3 -b]pyrazine; l-(2,5-dichlorobenzyl)-7-(2-methoxypyrimidin-5-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine; 4-[l-(2,5-dichlorobenzyl)-l>2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-
2H-pyridine-l-carboxylic acid tert-butyl ester; l-(2,5-dichlorobenzyl)-7-(l,2,3,6-tetrahydropyridin-4-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine;
{4-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-(4- methylpiperazin-l-yl)methanone; l-(2,6-dichlorobenzyl)-7-pyridin-3-yl-3,4-dihydτo-lH-pyrido[2,3-b]pyrazin-2-one; l-(2,6-dichlorobenzyl)-7-pyridin-3-yl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
4-[l-(2,6-dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester; 4-[l-(2,6-dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid;
5-1 -(2,6-dichlorobenzyl)-7-[4-((2-pyrrolidin- 1 -yl)methylpyrrolidine- 1 - carbonyl)phenyl]-3,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one;
4-[l-(2,6-dichlorobenzyl)-2-oxo-l,2,334-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(2- pyrrolidin-l-yl-ethyl)benzamide;
4-[l-(2,6-dichlorobenzyl)-2-oxo-l,2)3J4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(6- dimethylaminohexyl)benzaniide;
4-[l-(2,6-dichlorobenzyl)-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-N-(4- dimethylaminobutyl)benzamide; 7-[4-(4-methylpiperazine- 1 -carbonyl)phenyl]- 1 -[ 1 -(2,4,5-trifluorophenyl)ethyl]-3,4- dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one;
S- {2-[(pyrrolidin- 1 -yl)methyl]pyrrolidin-l -yl} -(4- { 1 -[ 1 -(2,4,5-trifluorophenyl)ethyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4-methylpiperazin-l -yl)-(4- { 1 -[ 1 -(2,4,5-tri£luorophenyl)ethyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
5-(4-{l-[l-(2,5-difluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- {2-[(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl } methanone; l-[l-(2,5-difluorophenyl)ethyl]-7-[4-(4-methylpiperazine-i-carbonyl)phenyl]-3,4- dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
5-(4- { 1 -[ 1 -(2,5-difluorophenyl)ethyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)- {2-[(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl } methanone; 1 -(2,5-dichlorobenzyl)-7-[4-(4-(pyrrolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl]-3,4- dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
S- 1 -(2,5-dichlorobenzyl)-7-[4-(2-[(pyrrolidin- 1 -yl)methyl]pyrrolidine- 1 - carbonyl)phenyl] -3 ,4-dihydro- 1 H-pyrido [2,3-b]pyrazin-2-one;
S-{4-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl}-{2- [(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl } methanone;
{4-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -(4-
(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone;
1 -(2,6-dichlorobenzyl)-7-[4-(4-(pyrrolidin- 1 -yl)piperidine- 1 -carbonyl)phenyl]-3 ,4- dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one; {4-[ 1 -(2,6-dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} -(4-
(pyrrolidin- 1 -yl)piperidin- 1 -yl)methanone;
{4-[ 1 -(2,6-dichlorobenzyl)- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]phenyl} - {2-
[(pyrrolidin- 1 -yl)methyl]pyrrolidin- 1 -yl} methanone;
7-(6-chloropyridin-3-yl)-l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- bjpyrazine; l-(2,5-dichlorobenzyl)-7-(6-pyrrolidin-l-yl-pyridin-3-yl)-l,2,3,4-tetrahydropyrido[2,3- bjpyrazine;
7-(2-chloropyridm-4-yl)-l-(2,6-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- bjpyrazine; {3-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynyl}carbamic acid tert-butyl ester;
3-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynylamine;
{3-[l-(2,6-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynyl}carbamic acid tert-butyl ester;
3-[l-(2,6-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynylamine; N- {3-[ 1 -(2,6-dichlorobenzyl)- 1 ,2,3>4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2- ynyl} -2-dimethylamino-acetamide;
{3-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl> - dimethylamine; 1 -(2,5-dichlorobenzyl)-7-[3-(l , 1 -dioxo- 1 λ6-thiomorpholin-4-yl)prop- 1 -ynyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
1 -[ 1 -(2-chloro-3,6-difluorophenyl)ethyl]-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-dichlorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l>2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-[3-fluoro-2-(trifluoromethyl)benzyl]-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-(2-pyrrolidin-l-yl-pyridin-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
5-[ 1 -(2-chloro-3,6-difluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- pyridin-2-ylamine; l-(2-chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-(2-moipholin-4-yl-pyridin-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
1 -(2,5-dichlorobenzyl)-4-methyl-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine; 1 -(2-chloro-3,6-difluorobenzyl)-7-(3-moφholin-4-yl-phenyl)- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-[l-(3-methylbutyl)-lH-pyrazol-4-yl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-(lH-pyrazol-4-yl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine; 4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid ethyl ester;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid ethyl ester; 4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid;
3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tefrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid;
(2-{4-[l-(2-chloro-3,6-difluorobenzyl)-l,2,3J4-tetrahydropyrido[2,3-b]pyrazin-7-yl]- pyrazol-l-yl}ethyl)dimethylamine; l-[5-chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-l-yl-pyridin-4-yl)-l, 2,3,4- tetrahydro-pyrido[2,3-b]pyrazine; l-[4.(4-{l-[5-chloro-2-(rrifluoromethyl)benzyl]-l,2,3,4-tetrahydro-pyrido[2,3- b]pyrazin-7-yl}pyridin-2-yl)piperazin-l-yl]ethanone; l-[5-chloro-2-(trifluoromethyl)benzyl]-7-(lH-pyrazol-4-yl)-l,2,3,4-tetrahydro- pyrido[2,3-b]pyrazine; l-[5-chloro-2-(trifluoromethyl)benzyl]-7-(l-triisopropylsilanyl-lH-pyrrol-3-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine; l-[5-chloro-2-(trifluoromethyl)benzyl]-7-(lH-pyrτol-3-yl)-l,2,3,4-tetrahydro- pyrido[2,3-b]pyrazine; l-[5-chloro-2-(trifluoromethyl)benzyl]-7-(l-methyl-lH-pyrazol-4-yl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazine;
{l-[(5-chloro-2-trifluoromethyl)benzyl]-l,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7- yl } piperidin- 1 -yl-methanone; {l-[(5-chloro-2-trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}-
(4-methoxy-piperidin- 1 -yl)methanone;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- phenylpiperazin- 1 -yl)-methanone;
[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-pyrimidin-2- yl-piperazin-l-yl)-methanone;
[4-(4-chloroρhenyl)-4-hydroxypiperidin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone; 1 - { 1 -[I -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]piperidin-4-yl}-l,3-dihydrobenzoimidazol-2-one;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2- methoxyphenyl)piperazin- 1 -yl]methanone; [l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyiido[2,3-b]pyrazin-7-yl]-{4-[3-
(trifluoromethyl)phenyl]piperazin- 1 -yl} methanone;
[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4- phenylpϊperidin- 1 -yl)methanone;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(3,4- dichlorophenyl)-piperazin- 1 -yl]methanone;
(4-benzhydrylpiperazin-l-yl)-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]methanone;
(4-benzylpiperidin-l-yl)-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl]methanone; 8-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonyl]-l- phenyl-l,3,8-triaza-spiro[4.5]decan-4-one;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-thieno[3,2- d]pyrimidin-4-yl-piperazin- 1 -yl)methanone;
[l-(2,5-dichlorobenzyl)-l,2s3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4- methoxybenzyl)piperazin- 1 -yl]methanone;
(4-benzoylpiperazin- 1 -yl)-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl] methanone;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-furo[3,2- c]pyridin-4-yl-piperazin- 1 -yl)methanone; [l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(6- fluorobenzo[d]isoxazol-3-yl)piperidin- 1 -yl]methanone;
[4-(3-chlorophenyl)piperazin- 1 -yl]- [ 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;
1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2- pyridin-2-yl-ethyl)amide;
4-{[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]amino}piperidine-l-carboxylic acid ethyl ester; 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (1 - benzyl-piperidin-4-yl)amide; l-(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2,2- diphenylethyl)amide; l-{4-[l-(2J5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]piperazin-l -yl} ethanone; l-(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 3- chlorobenzylamide;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl] -[4-(2-pyridin-2-yl-ethyl)piperazin- 1 -yl]methanone; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4-
(trifluoromethoxy)benzylamide;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(4-morpholin-4- yl-piperidin- 1 -yl)methanone; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2- thiophen-2-yl-ethyl)amide;
1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3 -b]pyrazine-7-carboxylic acid benzhydrylamide; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyτazine-7-carboxylic acid (pyridin-4-ylmethyl)amide; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid
(pyridin-3-ylmethyl)amide;
2-{4-[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carbonyl]piperazin- 1 -yl} -N-isopropylacetamide; [l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(2- methylquinolin-4-yl)piperazin-l-yl]methanone;
[l-(2,5-dichlorobenzyl)-l,2>3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-((S)-2-pyrrolidin-
1 -ylmethyl-pyrrolidin- 1 -yl)methanone; l-(2,5-dichlorobenzyl)-l,2J3,4-tetrahydropyrido[2>3-b]pyrazine-7-carboxylic acid 3,5- bis-(trifluoromethyl)benzylamide; l-(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [2-
(4-sulfamoylphenyl)ethyl]amide; [l-(2>5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2,3,5,6- tetrahydro-[ 1 ,2']bipyrazinyl-4-yl)methanone;
1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2- phenylthiazol-4-yl-methyl)amide; [l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]moφholin-4-yl- methanone;
1 -(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid
(naphthalen- 1 -yl-methyl)amide; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid indan-1-ylamide; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid benzylamide;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-(4- methoxyphenyl)piperazin-l-yl]methanone; 1 -(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide;
1 -(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid
(biphenyl-4-ylmethyl)amide;
[4-(4-chlorophenyl)piperazin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (2- phenoxyethyl)amide;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-[4-
(tetrahydrofuran-2-carbonyl)piperazin- 1 -yl]methanone; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid phenethyl-amide;
1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid
(tetrahydroflιran-2-yl-methyl)ainide;
[4-(4-chlorobenzyl)piperazin-l -yl]-[ 1 -(2,5-dichlorobenzyl)-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;
1 -(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 2- chloro-benzylamide; [ l-(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyiazin-7-yl]-[4-(2-
(trifluoromethyl)phenyl)piperazin- 1 -yl]methanone; l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4- methoxybenzylamide; 1 -(2,5-dichlorobenzyl)-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid indan-2-ylamide;
[l-(2,5-dichlorobenzyl)-l,2,3,4-tetrahydropyrido[2J3-b]pyrazin-7-yl]-(4-phenethyl- piperazin- 1 -yl)methanone;
[4-(2-chlorophenyl)piperazin-l -yl]-[ 1 -(2,5-dichlorobenzyl)- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone;
[(4-cyclohexylmethyl)piperazin-l-yl]-[l-(2,5-dichlorobenzyl)-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]methanone; l-(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid 4- sulfamoyl-benzylamide; [1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-(2-pyridin-3-yl- pyrrolidin- 1 -yl)methanone;
{4-[5-(2,5-dichlorophenoxy)-5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-3-yl]phenyl} -4- methyl-piperazin- 1 -yl)methanone;
4-(2-chloro-3,6-difluorophenoxy)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3>4- tetrahydro-[l,8]naphthyridine;
{4-[5-(3-chlorophenoxy)-5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-3-yl] -phenyl} -4- methylpiperazin- 1 -yl)methanone;
{4-[5-(3,5-dichlorophenoxy)-5,6,7,8-tetrahydro-[l,8]naphthyridin-3-yl]phenyl}-4- methylpiperazin- 1 -yl)methanone; (4-methylpiperazin- 1 -yl)- {4-[5-(pyridine-3-yloxy)-5,6,7,8-tetrahydro-
[l,8]naphthyridin-3-yl]phenyl}methanone;
1 -(4-fluoro-2- {6-[4-(4-methylpiperazine- 1 -carbonyl)phenyl]- 1 ,2,3,4-tetrahydro-
[ 1 ,8]naphthyridin-4-yloxy}phenyl)ethanone;
4-(3-chlorophenoxy)-6-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]-l,2,3,4-tetrahydro- [l,8]naphthyridine;
4-(3-chlorophenoxy)-6-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-
[ 1 ,8]naphthyridine; 4-(3-chlorophenoxy)-6-(4-moipholin-4-yl-phenyl)-l,2,3,4-tetrahydro-
[ 1 ,8]naphthyridine;
4-(3-chlorophenoxy)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3»4-tetrahydro-
[1 ,8]naphthyridine; 4-(2,5-difluorobenzyl)-6-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]-l ,2,3,4-tetrahydro-
[ 1 , 8]naphthyridine;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-moφholin-4-yl-piperidin-l-yl)methanone;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-thiazol-2-yl-piperazin-l-yl)methanone;
3,6-difluoro-2-[7-(6-morpholiπ-4-yl-pyridin-3-yl)-3,4-dihydro-2H-pyrido[2,3- b]pyrazin- 1 -ylmethyl]benzonitrile;
7-(6-moφholin-4-yl-pyridin-3-yl)-l-[5-(trifluoromethyl)furan-2-ylmethyl]-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazine; 7-[2-(4-methylpiperazin-l-yl)pyridin-4-yl]-l-[5-(trifluoromethyl)furan-2-ylmethyl]- l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- carboxylic acid [4-(dimethylamino)butyl] amide;
4-{l-[2-(trifluoromethoxy)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} benzoic acid ethyl ester;
4-{l-[2-(trifluoromethoxy)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoic acid;
4-[ 1 -(2-chloropyridin-3-ylmethyl)- 1 J2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid ethyl ester; 4-[ 1 -(2-chloropyridin-3-ylmethyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid;
{4-[ 1 -(2-chloropyridin-3-ylmethyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl]phenyl} -(4-pyrrolidin- 1 -yl-piperidin- 1 -yl)methanone;
N-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 7-yl}phenyl)acetamide;
(4-pyrrolidin- 1 -yl-piperidin- 1 -yl)-(4- { 1 -[2-(trifluoromethoxy)benzyl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone; (3-{l-[5-chloro-2-(trifluoromethyl)ben2yl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-phenylpiperazin- 1 -yl)methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-pyrimidin-2-ylpiperazin- 1 -yl)methanone; [4-(4-chlorophenyl)-piperazin-l-yl]-(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
[4-(4-chlorophenyl)-4-hydroxypiperidin- 1 -yl]-(3- { 1 -[5-chloro-2-
(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } pheny l)methanone; l-[l-(3-{l -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-l,3-dihydrobenzoimidazol-2-one;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-(2-methoxyphenyl)piperazin- 1 -yl]methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)- {4-[3-(trifluoromethyl)phenyl]piperazin-l -yl} methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-phenylpiperidin-l-yl)methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-( lH-indol-3-yl)piperidin- 1 -yl]methanone; (4-benzhydrylpiperazin-l -yl)-(3- { 1 -[5-chloro-2-(tri£luoromethyl)benzyl] - 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4-benzylpiperidin-l-yl)-(3-{l-[5-chloro-2-(trifluoroniethyl)benzyl]-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(3,4-dichlorophenyl)piperazin-l-yl]methanone;
8-(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2>3-b]pyrazin-7- yl}benzoyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)- {4-[2-(trifluoromethyl)phenyl]piperazin-l -yl} methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-thieno[3,2-d]pyrimidin-4-ylpiperazin-l-yl)methanone; [^(^chlorobenzyOpiperazin-l-ylj-ζS-ll-fS-chloro^-Ctrifluoromethy^benzyl]-!, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2J3-b]pyrazin-7- yl}phenyl)-[4-(4-methoxybenzyl)piperazin-l-yl]methanone; (4-benzoylpiperazin-l -yl)-(3- {1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-(4-furo[3 ,2-c]pyridin-4-ylpiperazin- 1 -yl)methanone;
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2>3-b]pyrazin-7- yl}phenyl)-[4-(6-£luorobenzo[d]isoxazol-3-yl)piperidin-l-yl]methanone;
4-(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoylamino)piperidine-l-carboxylic acid ethyl ester;
N-(l-ben2ylpiperidin-4-yl)-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl]benzamide; 3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-(2,2-diphenylethyl)benzamide;
3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(I -methylpiperidin-4-yl)benzamide;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin- 1 -yl]methanone;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-[4-(trifluoromethoxy)benzyl]benzamide;
N-[3,5-bis(trifluoromethyl)benzyl]-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzaπiide; N-benzhydryl-3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3 - b]pyrazin-7-yl}benzamide;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-pyridin-4-ylmethylbenzamide;
3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-pyridin-3-ylmethylbenzamide;
2-[4-(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoyl)piperazin-l-yl]-N-isopropylacetamide; (3 - { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(2-methylquinolin-4-yl)piperazin-l-yl]methanone;
3- { l-[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3.4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide; (3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyra2in-7- yl}phenyl)-(2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-yl)methanone;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-(2-phenylthiazol-4-ylmethyl)benzamide;
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)morpholin-4-y lmethanone;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-naphthalen- 1 -ylmethylbenzamide;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-indan- 1 -ylbenzamide; (3- { l-[5-chloro-2-(trifluorornethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(3-methoxyphenyl)piperazin-l-yl]methanone;
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-(4-methoxyphenyl)piperazin- 1 -yljmethanone;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-cyclohexylbenzamide;
3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- y 1 } -N-(4-methanesulfonylbenzyl)benzamide;
N-(2-chlorobenzyl)-3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide; N-(4-chlorobenzyl)-3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
N-(3-chlorobenzyl)-3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
(3- { l-[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin- 1 -yl]methanone;
3- { l-[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-(tetrahydrofuran-2-ylmethyl)benzamide; 3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(3-methoxybenzyl)benzamide;
3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(4-methoxybenzyl)benzamide; 3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(2-phenoxyethyl)benzamide;
N-benzyl-3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzamide;
[4-(3-chlorophenyl)piperazin- 1 -yl]-(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl }phenyl)methanone;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-indan-2-ylbenzamide;
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-phenethylpiperazin- 1 -yl)methanone; [4-(2-chlorophenyl)piperazin-l -yl] -(3- { 1 -[S-chloro^-CtrifluoromethyObenzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
N-(l-benzylpyrrolidin-3-yl)-3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
(3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(cyclohexylmethyl)piperazin- 1 -yl]methanone;
3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-(4-sulfamoylbenzyl)benzamide;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-morpholin-4-ylpiperidin-l-yl)methanone; (3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-((S)-2-pyrrolidin-l-ylmethylpyrrolidin-l-yl)methanone;
(3-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(2-pyridin-3-ylpyrrolidin- 1 -yl)methanone;
3- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(2-methoxybenzyl)-N-methylbenzamide;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-phenylpiperazin- 1 -yl)methanone; (4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(4-pyrimidin-2-ylpiperazin-l-yl)methanone;
[4-(4-chlorophenyl)piperazin-l-yl]-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone; [4-(4-chlorophenyl)-4-hydroxypiperidin- 1 -yl]-(4- { 1 -[5-chloro-2-
(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)methanone; l-[l-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzoyl)piperidin-4-yl]-l,3-dihydrobenzoimidazol-2-one; (4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l^,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-[4-(2-methoxyphenyl)piperazin- 1 -yl]methanone;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-{4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}methanone;
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-phenylpiperidin- 1 -yl)methanone;
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-[4-( 1 H-indol-3-yl)piperidin- 1 -yl]methanone;
(4-benzhydrylpiperazin- 1 -yl)-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone; (4-benzylpiperidin- 1 -yl)-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido [2,3-b]pyrazin-7- yl} phenyl)-[4-(3 ,4-dichlorophenyl)piperazin- 1 -yl]methanone;
8-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoyl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4-one;
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-{4-[2-(trifluoromethyl)phenyl]piperazin-l-yl}methanone;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} phenyl)-(4-thieno [3,2-d]pyrimidin-4-yl-piperazin- 1 -yl)methanone; [4-(4-chlorobenzyl)piperazin-l-yl]-(4- { l-[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(4-methoxybenzyl)piperazin-l-yl]methanone; (4-benzoylpiperazin-l -yl)-(4- { I -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3 -b]pyrazin-7-yl } phenyl)methanone;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- y 1 } pheny l)-(4-furo [3 ,2-c]pyridin-4-ylpiperazin- 1 -yl)methanone; (4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-l-yl]methanone;
4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-(2-pyridin-2-yl-ethyl)benzamide;
4-(4.{l.[5-chloro-2-(tri£luoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}benzoylamino)piperidine-l-carboxylic acid ethyl ester;
N-(I -benzylpiperidin-4-yl)-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(2,2-diphenylethyl)benzamide; 1 -[4-(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl } benzoyl)piperazin- 1 -yl] ethanone;
4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-(l-methylpiperidin-4-yl)benzamide;
(4-{l-[5-chloro-2-(trifluoromethyl)ben2yl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(2-pyridin-2-yl-ethyl)piperazin-l-yl]methanone;
4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-[4-(trifluoromethoxy)benzyl]benzainide;
4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-[4-(trifluoromethyl)beπzyl]benzamide; N-[3,5-bis(trifluoromethyl)benzyl]-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzaniide;
4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-(2-thiophen-2-yl-ethyl)benzamide;
N-benzhydryl-4- { l-[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzamide;
4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-pyridin-4-ylmethylbenzamide; 4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-pyridin-3-ylmethylbenzamide;
2-[4-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl} benzoyl)piperazin- 1 -yl]-N-isopropylacetamide; (4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-(2-methylquinolin-4-yl)piperazin- 1 -yl]methanone;
4-{ 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(2-methoxyethyl)benzamide;
4-{l-[5-chloro-2-(trifluoroniethyl)benzyl]-l,2,3,4-tetrahydropyrido[2>3-b]pyrazin-7- yl} -N-[2-(4-sulfamoylphenyl)ethyl]benzamide;
(4-{l-[5-chloro-2-(tri£luoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(2,3,5,6-tetrahydro[l,2']bipyrazinyl-4-yl)methanone;
4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-(2-phenylthiazol-4-ylmethyl)benzamide; (4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)morpholin-4-ylmethanone;
4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-naphthalen-l-ylmethylbenzamide;
4- { 1 -[5-chloro-2-(tri£luoromethyl)benzyl]- 1 ,2,3.4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-indan- 1 -ylbenzamide;
(4- { l-[5-chloro-2-(tτifluoromethyl)benzyl]-l ,2,3J4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(4-methoxyphenyl)piperazin- 1 -yl]methanone;
N-(2-chlorobenzyl)-4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide; N-(4-chlorobenzyl)-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
N-(3-chloro-benzyl)-4- { l-[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3 ,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-[4-(tetrahydrofuran-2-carbonyl)piperazin-l-yl]methanone;
4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-phenethylbenzamide; 4- { 1 -[5-chloro-2-(trifluoromethyi)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-(tetrahydrofuran-2-ylmethyl)benzamide;
4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(3-methoxybenzyl)benzamide; 4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-(4-methoxybenzyl)benzamide;
4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}-N-(2-phenoxyethyl)benzamide;
N-benzyl-4- { l-[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-yl}benzamide;
[4-(3-chlorophenyl)piperazin-l-yl]-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-indan-2-ylbenzamide; (4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)-(4-phenethylpiperazin- 1 -yl)methanone;
N-biphenyl-4-ylmethyl-4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}benzamide;
[4-(2-chlorophenyl)piperazin-l-yl]-(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l, 2,3,4- tetrahydropyrido[2,3-b]pyrazin-7-yl}phenyl)methanone;
N-(l-benzylpyrrolidin-3-yl)-4-{l-[5-chloro-2-(trifluoroniethyl)benzyl]-l,2,3,4- tetrahydropyrido[2s3-b]pyrazin-7-yl}benzaniide;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } phenyl)- [4-(cyclohexylmethyl)piperazin- 1 -yl]methanone; 4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl} -N-(4-sulfamoylbenzyl)benzamide;
(4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-((S)-2-pyrrolidin-l-ylmethylpyrrolidin-l-yl)methanone;
(4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(2-pyridin-3-yl-pyrrolidin-l-yl)methanone;
4-{l-[5-chloro-2-(trifluoromethyl)benzyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl } -N-(2-methoxybenzyl)-N-methylbenzamide; (4- { 1 -[5-chloro-2-(trifluoromethyl)benzyl]-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl}phenyl)-(l,3-dihydroisoindol-2-yl)methanone;
{4-[l-(5-chloro-2-trifluoromethyl-benzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7- yl] -phenyl} -(spiro[isobenzofuran- 1 (3H),4'-piperidine]- 1 -yl)methanone; or 1 -(2-chloro-3 ,6-difluorobenzyl)-7-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl] - 1 ,4- dihydro-2H-pyrido[2,3-b]pyrazin-3-one; or a pharmaceutically acceptable salt form thereof.
34. A compound as defined in claim 1, wherein said compound is l-(2-chloro-3,6-difluoroben2yl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; 1 -benzyl-7-iodo-3,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2-one;
1 -benzyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -benzyl-7-iodo-l ,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
(3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenylmethanone;
(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-l-yl)phenyhτiethanone; 1 -(2,5-difluorobenzyl)-7-iodo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-difluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile; l-(2,5-di£luorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid;
7-iodo-l-(2,4,5-trifluorobenzyl)-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
7-iodo- 1 -(2,4,5-trifluorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; (2,5-difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyiido[2,3-b]pyrazin-l-yl)methanone; l-(2,5-difluorobenzyl)-7-iodo-3,3-dimethyl-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one; l-(2,5-difluorobenzyl)-7-iodo-3,3-dimethyl-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-3,6-difluorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; 1 -(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl)-2-phenylethanone;
2-(2,5-difluorophenyl)- 1 -(7-iodo-3 ,4-dihydro-2H-pyrido[2,3-b]pyrazin- 1 -yl)ethanone; l-(5-chloro-2-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2-chloro-5-trifluoromethylbenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one; l-(2-chloro-5-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-difluorobenzenesulfonyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -benzenesulfonyl-7-iodo-l ,2,3>4-tetrahydropyrido[2,3-b]pyrazine; l-(2-chlorobenzenesulfonyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; 1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile;
1 -(2,5-dichlorobenzyl)- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid;
1 -(5-fluoro-2-trifluoromethylbenzyl)-7-iodo-3 ,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-2- one; l-(5-fluoro-2-trifluoromethylbenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-2- ol; l-(2,6-dichlorobenzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
7-iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
7-iodo-l-[l-(2,4,5-trifluorophenyl)ethyl]-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine; 1 -[ 1 -(2,5-difluorophenyl)ethyl]-7-iodo-3,4-dihydro- lH-pyrido[2,3-b]pyrazin-2-one;
1 -[ 1 -(2,5-difluorophenyl)ethyl]-7-iodo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2,5-dichlorobeπzyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; l-(2,5-dichlorobenzyl)-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -(2,6-dichlorobenzyl)-7-iodo- 1 ,2,3.4-tetrahydropyrido[2,3-b]pyrazine; 1 -[ 1 -(2-chloro-3,6-difluorophenyl)ethyl]-7-iodo-3,4-dihydro- 1 H-pyrido[2,3-b]pyrazin-
2-one; l-[l-(2-chloro-3,6-difluorophenyl)ethyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3- b]pyrazine; l-[3-fluoro-2-(trifluoromethyl)benzyl]-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2- one; l-[3-fluoro-2-(trifluoromethyl)benzyl]-7-iodo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
1 -(2,5-dichlorobenzyl)-7-iodo-4-methyl- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine;
6-bromo-4-(3-chlorophenoxy)- 1 ,2,3,4-tetrahydro-[l ,8]naphthyridine;
4-(2,5-difluorobenzyl)-l ,2,3,4-tetrahydro-[l ,8]naphthyridine; 6-bromo-4-(2,5-difluorobenzyl)-l,2,3,4-tetrahydro-[l,8]naphthyridine;
7-iodo-l-[5-(trifluoromethyl)furan-2-ylmethyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-
2-one;
7-iodo- 1 -[5-(trifluoromethyl)fiiran-2-ylmethyl]- 1 ,2,3 ,4-tetrahydropyrido[2,3- b]pyrazine; 7-iodo-l-[2-(trifluoromethoxy)benzyl]-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one;
7-iodo- 1 -[2-(trifluoromethoxy)benzyl] - 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; l-(2-chloropyridin-3-ylmethyl)-7-iodo-3,4-dihydro-lH-pyrido[2,3-b]pyrazin-2-one; or
1 -(2-chloropyridin-3-ylmethyl)-7-iodo- 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazine; or a pharmaceutically acceptable salt form thereof.
35. A pharmaceutical composition comprising a compound as defined in any of claims 1-9, 13-15, 33 or 34.
36. Use of a compound as defined in any of claims 1-9, 13-15, 33 or 34 in the manufacture of a medicament for the treatment of an ALK or c-Met mediated disorder or condition.
PCT/US2007/010656 2006-05-01 2007-05-01 Pyrido [2, 3-b] pyrazine and [1, 8] -naphthyridine derivatives as alk and c-met inhibitors WO2007130468A2 (en)

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AU2007248603A AU2007248603B8 (en) 2006-05-01 2007-05-01 Pyrido [2, 3-B] pyrazine and [1, 8] -naphthyridine derivatives as ALK and c-Met inhibitors
EP07776633.5A EP2091951B1 (en) 2006-05-01 2007-05-01 Pyrido[2,3-b]pyrazine and [1,8]-naphthyridine derivatives as alk and c-met inhibitors
MX2008013942A MX2008013942A (en) 2006-05-01 2007-05-01 Pyrido [2, 3-b] pyrazine and [1, 8] -naphthyridine derivatives as alk and c-met inhibitors.
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