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WO2014160177A2 - Quinazoline inhibitors of pi3k - Google Patents

Quinazoline inhibitors of pi3k Download PDF

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Publication number
WO2014160177A2
WO2014160177A2 PCT/US2014/025980 US2014025980W WO2014160177A2 WO 2014160177 A2 WO2014160177 A2 WO 2014160177A2 US 2014025980 W US2014025980 W US 2014025980W WO 2014160177 A2 WO2014160177 A2 WO 2014160177A2
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WO
WIPO (PCT)
Prior art keywords
methyl
alkyl
alkylene
quinazolin
piperidin
Prior art date
Application number
PCT/US2014/025980
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French (fr)
Other versions
WO2014160177A3 (en
Inventor
Kenneth D. Rice
Paul Foster
Original Assignee
Exelixis, Inc.
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Filing date
Publication date
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Publication of WO2014160177A2 publication Critical patent/WO2014160177A2/en
Publication of WO2014160177A3 publication Critical patent/WO2014160177A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to the field of protein kinases and inhibitors thereof.
  • the invention relates to Phosphatidylinositol 3-kinase (PI3K) inhibitors, and methods of their use.
  • PI3K Phosphatidylinositol 3-kinase
  • the PI3K7 PTEN pathway regulates cellular survival, growth, and proliferation. Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is observed in various cancers and correlates with tumor growth and survival.
  • the catalytic subunit of P13 (pi 10a), encoded by the PIK3CA gene is mutated in approximately 13% of all human cancers.
  • the tumor suppressor PTEN which serves as a critical negative regulator of PI3 signaling, is frequently deleted or
  • PI3K inhibitors have therapeutic potential as single agents, as well as in combination with other therapies, for a variety of cancer indications. As a result, a need remains for compounds that inhibit PI3K.
  • Xi and X 2 are each independently N, C-H, C-Halo, C-(C C 6 )alkyl, C-(Ci-C 6 )alkoxy, or C-CN;
  • R x and R y are each independently H, (CpCeJalkyl, halo(Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, (C3-C6)heterocycloalkyl, (Cj-C6)alkylene-(C3-C6)cycloalkyl, (Ci-C6)alkylene- (C 3 -C 6 )heterocycloalkyI, (C
  • membered ring represented by , optionally containing an additional heteroatom selected from NH, N-(CpC6)alkyl, S, SO, or S0 2 , and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (Ci-C 6 )alkyl, (C
  • C 6 )haloalkoxy (CpC 6 )alkylene-NH 2 , (CpC 6 )alkylene-NH(CpC 6 )alkyl, (CpC 6 )alkylene- NH(C,-C 6 )haloalkyl, (CpC 5 )alkylene-N(CpC 6 )alkyl) 2 , NH 2 , NH(CpC 6 )alkyl, (Cp
  • R z is NR3R4, wherein R 3 and R4 are each independently H or (Ci-C 6 )alkyl optionally substituted with one , two, or three groups selected from halo, hydroxy, cyano, oxo, (Ci- C 6 )alkyl, (C,-C 6 )alkoxy, halo(C C 6 )alkyl, (C r C 6 )haloalkoxy, S(0)-(C r C 6 )alkyl, S0 2 -(C r C 6 )alkyl, (Ci-C 6 )alkylene-NH 2 , (C,-C6)alkylene-NH(C,-C 6 )alkyl, (CrC6)alkylene-NH(Ci- C 6 )haloalkyl, (C ,-C6)alkylene-N(C,-C 6 )alkyl) 2 ,NH 2 , NH(d-C 6 )alkyl, (
  • C6)alkylene-N(Ci-C 6 )alkyl)) 2 any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH 2 , NH(C,-C 6 )alkyl, N((C
  • R 3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from H, halo, hydroxy, cyano, oxo, (C
  • R 5 is H, halo, (Ci-C 6 )alkyl, halo(d-C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, or (C
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the invention also provides a method of inhibiting the in vivo activity of PI3K, comprising administering to a patient an effective PI3K-inhibiting amount of a compound of formula I or a pharmaceutical composition thereof.
  • the invention also provides a method for treating a disease, disorder, or syndrome comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the invention also provides a process for making a compound of formula I wherein R z is NR3R4, comprising reacting a compound of formula F with NHR3R4:
  • the invention also provides a process for making a compound of formula I wherein R z is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl comprising reacting a compound of formula F with X-R 2 wherein X is a leavin rou :
  • group "R” is depicted as "floating" on a ring system, as for example in the
  • a substituent "R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group may reside on either the 5-membered or the 6-membered ring of the fused or bridged ring system.
  • Acyl means a C(0)R radical where R is alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or
  • heterocycloalkylalkyl as defined herein, e.g., acetyl, trifluoromethylcarbonyl, 2- methoxyethylcarbonyl, and the like.
  • Acylamino means a NRR' radical where R is hydrogen, hydroxy, alkyl, or alkoxy, and R' is acyl, as defined herein.
  • Acyloxy means an OR radical where R is acyl, as defined herein, e.g.
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, etc.)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one double bond, e.g., ethenyl, propenyl, 1 -but-3-enyl, l-pent-3-enyl, and the like.
  • Alkoxy means an OR radical where R is alkyl group as defined herein, e.g., methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Alkoxyalkyl means an alkyl radical, as defined herein, substituted with at least one, specifically one, two, or three, alkoxy groups, as defined herein. Representative examples include methoxymethyl and the like.
  • Alkoxycarbonyl means a C(0)R radical where R is alkoxy, as defined herein.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric torms , pentyl (including all isomeric forms), and the like.
  • Alkylamino means an NHR radical where R is alkyl, as defined herein.
  • Alkylaminoalkyl means an alkyl radical substituted with one or two alkylamino groups, as defined herein.
  • Alkylaminoalkyloxy means an OR radical where R is alkylaminoalkyl, as defined herein.
  • Alkylcarbonyl means a C(0)R radical where R is alkyl, as defined herein.
  • Alkylsufonyl means an S(0) 2 R radical where R is alkyl, as defined herein.
  • Alkylsulfonylalkyl means an alkyl radical, as defined herein, substituted with at least one, specifically one or two, alkylsulfonyl groups, as defined herein.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms which radical contains at least one triple bond, e.g., ethynyl, propynyl, butynyl, pentyn-2-yl, and the like.
  • Amino means an NH 2 radical.
  • aminoalkyl means an alkyl radical substituted with at least one, specifically one, two, or three, amino groups, as defined herein.
  • aminoalkyloxy means an OR radical where R is aminoalkyl, as defined herein.
  • Aminocarbonyl means a C(0)NH 2 radical.
  • Alkylaminocarbonyl means a C(0)NHR radical where R is alkyl, as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic radical, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.
  • Arylalkyl means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl, phenethyl, and the like.
  • Arylalkyloxy means an OR radical where R is arylakyl, as defined herein.
  • Cyanoalkyl means an alkyl radical, as defined herein, substituted with one or two cyano groups.
  • Cycloalkylalkyl means an alkyl radical substituted with at least one, specifically one or two, cycloalkyl group(s), as defined herein.
  • Dialkylamino means a NRR' radical where R and R' are alkyl, as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino, N,N-methylethylamino, and the like.
  • Dialkylaminoalkyl means an alkyl radical substituted with one or two dialkylamino groups, as defined herein.
  • Dialkylaminoalkyloxy means an OR radical where R is dialkylaminoalkyl, as defined herein. Representative examples include 2-(N,N-diethylamino)-ethyloxy and the like.
  • Dialkylaminocarbonyl means a C(0)NRR' radical where R and R' are alkyl, as defined herein.
  • Halogen or "halo” means a fluorine, chlorine, bromine, and iodine radical.
  • Haloalkoxy means an OR' radical where R' is haloalkyl, as defined herein, e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Haloalkyl mean an alkyl group substituted with one or more halogens, specifically 1 , 2, 3, 4, 5, or 6 halo atoms, e.g., trifluoromethyl, 2-chloroethyl,
  • heteroaryl includes, but is not limited to, 1 ,2,4-triazolyl, 1 ,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (e.g., 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro- l H-indol-5-yl, and the like), isoindol l, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl
  • Heteroarylalkyl means an alky I radical, as defined herein, substituted with at least one, specifically one or two heteroaryl group(s), as defined herein.
  • the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, R y is absent.
  • heterocycloalkyi includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl,
  • tetrahydropyranyl 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,
  • Heterocycloalkylalkyl means an alkyl radical, as defined herein, substituted with one or two heterocycloalkyi groups, as defined herein, e.g., morpholinylmethyl, N-pyrrolidinylethyl, 3-(N-azetidinyl)propyl, and the like.
  • Heterocycloalkyloxy means an OR radical where R is heterocycloalkyl, as defined herein.
  • Hydroxyalkyl means an alkyl radical, as defined herein, substituted with at least one, preferably 1 , 2, 3, or 4, hydroxy groups.
  • Phenylalkyl means an alkyl radical, as defined herein, substituted with one or two phenyl groups.
  • Phenylalkyloxy means an OR radical where R is phenylalkyl, as defined herein.
  • Optionally substituted aryl means an aryl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl,
  • alkylaminocarbonyl dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, and aminoalkoxy; or aryl is pentafluorophenyl.
  • the alkyl and alkenyl either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted arylalkyl means an alkyl group, as defined herein, substituted with optionally substituted aryl, as defined herein.
  • Optionally substituted cycloalkyl means a cycloalkyl group, as defined herein, substituted with one, two, or three groups independently selected from acyl, acyloxy, acylamino, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl,
  • the alkyl and alkenyl either alone or as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, and haloalkylsulfonyl.
  • Optionally substituted cycloalkylalkyl means an alkyl group substituted with at least one, specifically one or two, optionally substituted cycloalkyl groups, as defined herein.
  • Optionally substituted heteroaryl means a heteroaryl group optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl,
  • alkylaminocarbonyl dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy.
  • alkyl and alkenyl either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted heteroarylalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heteroaryl group(s), as defined herein.
  • Optionally substituted heterocycloalkyl means a heterocycloalkyl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, haloalkyl, alkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, and phenylalkyl.
  • heterocycloalkyl the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted heterocycloalkylalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heterocycloalkyl group(s) as defined herein.
  • Optionally substituted phenyl means a phenyl group optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, and aminoalkoxy, or aryl is pentafluorophenyl.
  • phenyl the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted phenylalkyl means an alkyl group, as defined herein, substituted with one or two optionally substituted phenyl groups, as defined herein.
  • Optionally substituted phenylsulfonyl means an S(0) 2 R group where R is optionally substituted phenyl, as defined herein.
  • Oxo means an oxygen atom which is attached via a double bond.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule, such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously; that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. In a specific embodiment, the patient is a mammal, and in a more specific embodiment, the patient is human.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that it possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,
  • 2-hydroxyethanesulfonic acid 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Specific salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins.
  • organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine,
  • N-methylglucamine N-methylglucamine, polyamine resins, and the like.
  • exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, caffeine, and the like.
  • Platinum(s),” and “platin-containing agent(s)” include, for example, cisplatin, carboplatin, and oxaliplatin.
  • “Therapeutically effective amount” means an amount ot a compound of the invention that, when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • Preventing or "prevention” of a disease, disorder, or syndrome includes inhibiting the disease from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome.
  • Treating" or “treatment” of a disease, disorder, or syndrome includes (i) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (ii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • inhibiting i.e., arresting its development
  • relieving i.e., causing regression of the disease, disorder, or syndrome.
  • adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will be necessary, and such adjustments will
  • the compounds disclosed herein also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as l 3 C and l4 C; isotopes of nitrogen, such as l 5 N; isotopes of oxygen, such as , 7 0 and 18 0; isotopes of phosphorus, such as 31 P and 32 P; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18 F; and isotopes of chlorine, such as 36 CI.
  • isotopes of hydrogen such as 2 H and 3 H
  • isotopes of carbon such as l 3 C and l4 C
  • isotopes of nitrogen such as l 5 N
  • isotopes of oxygen such as , 7 0 and 18 0
  • isotopes of phosphorus such as 31 P and 32 P
  • isotopes of sulfur such as 35 S
  • isotopic variations e.g., deuterium, 2 H
  • isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, and 14 C), which may be useful in drug and/or substrate tissue distribution studies.
  • a radioactive isotope e.g., tritium, 3 H, and 14 C
  • the following paragraphs present a number of embodiments of compounds of the invention.
  • the embodiment includes the recited compounds, as well as single stereoisomers or mixture of stereoisomers thereof and pharmaceutically acceptable salts thereof.
  • the invention provides a compound of Formula I:
  • Xi is N, C-H, C-Halo, C-(C
  • X 2 is N, C-H, C-Halo, or C-(C,-C 6 )alkyl and X t is N or C-CN.
  • R 5 is (C r C6)alkyl, halo-(C r C 6 )alkyl, (C 2 -C 6 )alkenyl, halo-(C 2 -C6)alkenyl, or -(C
  • X is N or C-H
  • X 2 is C-H
  • R 5 is (d-C 6 )alkyl
  • the compound of formula I is a compound of formula IA:
  • a 6-membered saturated or partially saturated heterocycle optionally containing an additional heteroatom selected from NH, N-(Ci-C6)alkyl, S, SO, and S0 2 , and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (C
  • the compound of formula I is a compound of formula IA- 1 or IA-2:
  • R6 is H, halo, hydroxy, cyano, (C[-C6)alkyl, (Ci-C 6 )alkoxy, halo(Ci-C 6 )alkyI, (C
  • the compound of formula I is a compound of formula IA-3 or IA-4:
  • the compound of formula I is a compound of formula IA-5 or IA-6:
  • R z is halo, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, each of which may be optionally substituted with 1 , 2, or 3 groups selected from (C] -C6)alkyl, (Ci-C 6 )haloalkyl (C
  • X
  • R z is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
  • R z is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • R z is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
  • R z is isoxazolyl, pyrimidinyl, indazolyl optionally substituted with amino or methyl.
  • R z is benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, or triazolyl optionally substituted with methyl or amino.
  • R z is pyridazinyl optionally substituted with hydroxy!, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • R z is thienyl or furanyl optionally substituted with methyl.
  • R z is bromo, chloro, or fluoro.
  • R 2 is NR3R4, wherein R 3 and R4 are each independently (Ci-CeJalkyl optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (C
  • -C 6 )alkyl)) 2 any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH 2 , NH(C,-C 6 )alkyl, N((C C 6 )alkyl) 2 , -OH, (C,-C 6 )alkyl, (C
  • R z is NR 3 R4, wherein R 3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (Ci-Ce)alkyl, (C
  • R z is
  • the compound of formula I is a compound of formula IA-7 or IA-8
  • Ria and Ri b are each independently H, (Ci-C 6 )alkyl, halo(C
  • Ri a is H or (C,-C 6 )alkyl
  • Rib is H, ( i- 6)alkyl, halo((J
  • R.5 is methyl
  • a is H, methyl, pyrrolidiny, piperidinyl, CH 2 - cyclopropyl, C b-pyrrolidinyl, or CH 2 -piperidinyl.
  • Ri a is H
  • Ri b is H
  • Ria is methyl, ethyl
  • Ri b is H, methyl, ethyl, or fluoroethyl.
  • R and Ri b are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH 2 , NH(C
  • R ) a i b N is or H 2 N
  • a Ri b N is
  • Ri a Ri b N is wherein:
  • Z is O, N, or C;
  • R 2a is absent when Z is O; or is H, OH, NH 2 , NH-(C 2 -C6)alkylene-0-(C r C 6 )alkyl, NH(C]-C 6 )haloalkyl, (C
  • -C 6 )alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C 3 -C 6 )heterocycloalkyl, or NH(C 0)NH-(C 2 -C 6 )alkylene-0-(Ci-C 6 )alkyl when Z is N or C;
  • R 2b is absent when Z is N or O; or is H, (Ci-C6)alkyl, or (C
  • each occurrence of R 2c is independently halo, (C
  • Z is N or C
  • R 2a is H, OH, NH 2 , NH-(C 2 -C 6 )alkylene-0-(C,-C 6 )alkyl, NH(C,-C 6 )haloalkyl, (Ci- C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C 6 )cycloalkyl, (C 3 -C6)heterocycloalkyl, or H(C-0)NH-(C 2 -C 6 )alkylene-0-(Ci-C 6 )alkyl;
  • R 2b is absent when Z is N; or is H, (Ci-C6)alkyl, or (C
  • the compound of formula I is a compound of formula IA-9 - 10:
  • Z is N or C
  • R 2b is absent when Z is N; or is H, (Ci-C f i)alkyl, or (C C 6 )haloalkyl when Z is C; each occurrence of R 2c is independently halo, (Ci-C 6 )alkyl, or (C
  • X t is N.
  • the compound of formula IA-9 or IA- 10 is a compound of formula IA-9a or IA- 10a:
  • R 2b is absent, H, (Ci-C 6 )alkyl, or (Ci-C 6 )haloalkyl;
  • each occurrence of R 2c is independently halo, (Ci-C 6 )alkyl, or (Ci-Cejhaloalkyl; and n is 0, 1 , or 2.
  • the compound of formula I is a compound of formula IA-9b - 10b:
  • Xi is N.
  • R 2a is H, methyl, ethyl, propyl, or butyl; R 2c is methyl; and n is 1 .
  • R 5 is methyl
  • the compound of formula I is a compound of formula IB-1 or IB-2:
  • R b is H, (C,-C 6 )alkyl, (C,-C6)alkylene-NH(C,-C 6 )haloalkyl, (C,-C 6 )aIkylene-N(C r C 6 )alkyl) 2 , (C
  • R, i is H, (Ci-C 6 )alkyl, halo(C,-C 6 )alkyl, (C,-C 6 )alkylene-NH 2 , (C,-C 6 )alkylene- NH(C,-C 6 )alkyl, (Ci-C 6 )alkylene-NH(Ci-C 6 )haloalkyl, (C
  • the compound of formula I is a compound of formula IB-3 or I -4:
  • X halo, cycloalkyl, aryl, heterocycl
  • R z is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
  • R z is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • R z is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
  • R z is isoxazolyl, pyrimidinyl, indazolyl optionally substituted with amino or methyl.
  • R z is benzimidazolyl, thiazolopyridin l, imidazolyl, thiazolyl, or triazolyl optionally substituted with methyl or amino.
  • R z is pyridazinyl optionally substituted with hydroxyl, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • R z is thienyl or furanyl optionally substituted with methyl.
  • R z is bromo, chloro, or fluoro.
  • R z is NR3R4, wherein R3 and R are each independently (Ci-C6)alkyl optionally substituted with one , two, or three groups selected from halo, hydroxy, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo(Ci- C 6 )alkyl, (C,-C 6 )haloalkoxy, (C,-C 6 )alkylene-NH 2 , (C
  • R z is NR 3 4
  • R3 is H
  • R z is NR3R4, wherein R 3 and R4 together with the atoms to which they are attached form a 3- to 7- membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (C
  • C 6 )alkylene-(Ci-C 6 )alkoxy NH(C,-C6)alkyleneNH2, NH(C, -C6)alkylene-NH(C
  • R z is
  • R 3 ⁇ 4 is methyl
  • the compound of formula I is a compound of formula IC:
  • R6c is halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C 6 )alkoxy, halo(C
  • R z is as previously defined in any of the other embodiments.
  • Xi is N.
  • R z is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
  • R z is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • R z is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
  • R z is isoxazolyl, pyrimidinyl, indazolyl optionally substituted with amino or methyl.
  • R z is benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, or triazolyl optionally substituted with methyl or amino.
  • R z is pyridazinyl optionally substituted with hydroxyl, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • R z is thienyl or furanyl optionally substituted with methyl.
  • R z is bromo, chloro, or fluoro.
  • R z is NR3R4, wherein R 3 and R4 are each independently (C
  • C 6 )alky lene-(C, -C 6 )alkoxy NH(C , -C 6 )alky leneNH 2 , NH(C , -C 6 )alkylene-NH(C , -C 6 )alkyl, NH(C , -C 6 )alkyleneN((C 1 -C 6 )alky l) 2 , NH(C , -C 6 )alkylene-cyloalkyl, NH(C
  • -C6)alkyl)) 2 any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH 2 , NH(C C 6 )alkyl, N((Ci-C 6 )alkyl) 2 , OH, (C r C 6 )alkyl, (C]-C 6 )alkoxy, or (C
  • R 2 is NR3R4, wherein R 3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo(Ci- C 6 )alkyl, (C,-C 6 )haloalkoxy, (C,-C 6 )alkylene-NH 2 , (C
  • C 6 )alkylene-NH(C , -C 6 )alky I, N H(C , -C 6 )alky leneN((C, -C 6 )alky l) 2 , NH(C , -C 6 )alkylene- cyloalkyl, NH(C C 6 )alkylene-heterocyloalkyl, N((Ci-C 6 )alkyl) 2 , (C C 6 )alkylene-NHS0 2 - (C,-C 6 )alkyl, (Ci-C 6 )alkylene-NH(C 0)-(C
  • -C 6 )alkyl, (C 0)-(C,-C 6 )alkyl, S(0)-(C,- C 6 )alkyl, S0 2 -(C,-C 6 )alkyl, -(C 4 -C 7 )heterocycloalkyl, (Ci
  • Re and R f are each independently H, (C r C 6 )alkyl), aryl, heteroaryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, (Ci-C 6 )alkylene-(C 3 - C 7 )cycloalkyl, (C
  • R z is
  • the compound of formula I is a compound listed in Table
  • Another embodiment is a pharmaceutical composition comprising a compound of
  • Compounds of the invention have activity for PI3 , particularly PI3K-alpha, and may be useful for treating diseases, particularly cancer in which activity against PI3 -alpha contributes to the pathology and/or symptomatology of the disease.
  • cancers in which activity against PI3 -alpha contributes to its pathology and/or symptomatology include breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NP /AL -transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, and head and neck cancer.
  • Compounds of the invention may also be used as inhibitors of PI3 in vivo for studying the in vivo role of PI3K in biological processes, including the diseases described herein. Accordingly, the invention also comprises a method of inhibiting P13 in vivo comprising administering a compound or composition of the invention to a mammal.
  • the invention provides a method of treating a disease, disorder, or syndrome wherein the disease is associated with uncontrolled, abnormal, and/or unwanted cellular activities effected directly or indirectly by PI3K comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula I, or a compound in Table 1 , or a pharmaceutically acceptable salt thereof, and admixed with a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • the disease is cancer.
  • the disease is cancer
  • the compound is a compound of formula I or of Table 1.
  • the invention provides a method of treating a disease, disorder, or syndrome comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a compound in Table 1 , or a pharmaceutically acceptable salt thereof, and admixed with a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • the disease is cancer.
  • the disease is cancer, and the compound is a compound of formula I or of Table 1.
  • the cancer is breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NPM/AL - transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma,
  • rhabdomyosarcoma ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, or head and neck cancer.
  • Embodiment 1 A compound of Formula I:
  • X, and X 2 are each independently N, C-H, C-Halo, C-(C
  • X 2 is N, C-H, C-Halo, C-(Ci-C 6 )alkyl, or C-(Ci-C 6 )alkoxy, C-CN;
  • R x and R y are each independently H, (Ci-Ce)alkyl, halo(C[-C6)alkyl, (C 3 - C 6 )cycloalkyI, (C 3 -C 6 )heterocycloalkyl, (Ci-C6)alkylene-(C 3 -C 6 )cycloalkyl, (C
  • ⁇ N ⁇ optionally containing an additional heteroatom selected from NH, N-(C
  • R 2 is NR3R4, wherein R 3 and R4 are each independently H or (C
  • -C 6 )alkyl, (C 0)-NRcR d, or S0 2 -NRcR d, wherein R
  • -C6)alkyl)) 2 any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH 2 , NH(C,-C 6 )alkyl, N((C, -C 6 )alkyl) 2 , OH, (C C 6 )alkyl, (C ( -C6)alkoxy, or (Ci-C6)haloalkoxy.
  • R 3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from H, halo, hydroxy, cyano, oxo, (Ci-C 6 )alkyl, (C
  • R 5 is H, halo, (C,-C 6 )alkyl, halo(C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyI, (C 2 - C 6 )alkynyl, or (CpC 6 )alkoxy.
  • Embodiment 2 The compound of embodiment 1 , wherein X is N, C-H, C-Halo, or C-(C
  • Embodiment 3 The compound of embodiment 1 -2, wherein X is N or C-H.
  • Embodiment 4 The compound of embodiment 1 -3, wherein R 5 is (C
  • Embodiment 5 The compound of embodiment 1-4, wherein X is N or C-H, and R 5 is (C r C 6 )alkyI.
  • Embodiment 6 The compound of embodiment 1 -5, wherein the compound of formula I is a compound of formula IA:
  • ring is a 6-membered saturated or partially saturated heterocycle optionally containing an additional heteroatom selected from NH, N-(C]-C6)alkyl, S, SO, and S0 2 , and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (Ci-C 6 )alkyl, (Cp C 6 )alkoxy, halo(C,-C 6 )alkyl, (CpC 6 )haloalkoxy, (C C 6 )alkylene-NH 2 , (C r C 6 )alkylene- NH(CpC 6 )alkyl, (CpC 6 )alkylene-NH(CpC 6 )haloalkyl, (CpC 6 )alkyiene-N(CpC 6 )alkyl) 2 ,
  • C 6 )alky lene-NH 2 NH(C , -C 6 )alky lene-NH(C , -C 6 )alky I, NH(C , -C 6 )alky leneN((C , -C 6 )alkyl) 2 , NH(CpC 6 )alkylene-(C3-C7)cyloalkyl, NH(CpC6)alkylene-(C3-C 7 )heterocyloalkyl, N((Cp C 6 )alkylene-(C 3 -C 7 )heterocycloalkyi) 2 , N((Ci-C 6 )alkyl)(C
  • Embodiment 7 The compound of embodiment 1 -6, wherein the compound of formula I is a compound of formula IA-1 or IA-2:
  • R6 is H, halo, hydroxy, cyano, (C
  • Embodiment 8 The compound of embodiment 1 -7, wherein the compound of formula I is a compound of formula IA-3 or IA-4:
  • Embodiment 9 The compound of embodiment 1 -8, wherein the compound of formula I is a compound of formula IA-5 or IA-6:
  • R z is halo, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from (Ci-C6)alkyl, (Ci -C6)haloalkyl (C
  • Embodiment 10 The compound of embodiment 1 -9, wherein R z is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
  • Embodiment 1 1. The compound of embodiment 1 -10, wherein R z is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • Embodiment 12 The compound of embodiment I - 1 1 , wherein R z is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
  • Embodiment 13 The compound of embodiment 1 -12, wherein R z is isoxazolyl, pyrimidinyl, or indazolyl, optionally substituted with amino or methyl.
  • Embodiment 15 The compound of embodiment 1 - 14, wherein R z is
  • benzimidazolyl thiazolopyridinyl, imidazolyl, thiazolyl, or triazolyl, optionally substituted with methyl or amino.
  • Embodiment 16 The compound of embodiment 1 -15, wherein R z is pyridazinyl optionally substituted with hydroxyl, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • Embodiment 17 The compound of embodiment 1 -16, wherein R z is thienyl or furanyl optionally substituted with methyl.
  • Embodiment 18 The compound of embodiment 1 -17, wherein R z is bromo, chloro, or fluoro.
  • Embodiment 21 The compound of embodiment 1 -20, wherein R 3 and R 4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (C r C 6 )alkoxy, halo(C r C 6 )alkyl, (Ci -C 6 )haloalkoxy, (C C 6 )alkylene-NH 2 , (Ci-C 6 )alkylene- H(C , -C 6 )alky 1, (C , -C 6 )alky lene- H(C , -C 5 )haloalky 1, (C , -C 6 )alky lene-N(C , -C 6 )alkyl) 2 , NH 2 , NH(C,-C 6 )alkyl, (C,-C 6 )alkyl
  • Embodiment 22 The compound of embodiment 1 -21 , wherein R z is
  • Embodiment 23 The compound of embodiment 1 -22 and embodiments 10-22, wherein the compound of formula I is a compound of formula IA-7 or IA-8:
  • Ria and R ⁇ are each independently H, (Ci-Cejalkyl, halo(Ci-C6)alkyl, (C] -C6)alkylene-NH 2 , (C , -C 6 )alky lene-NH(C , -C 6 )alky I, (C , -C 6 )alkylene-NH(C, -C 6 )haloalky 1, (C , -C 6 )alkylene- N(C,-C 6 )alkyl) 2 , (C
  • Embodiment 24 The compound of embodiment 1 -23, wherein:
  • Ria is H or (C, -C 6 )alkyl
  • Ri b is H, (C, -C 6 )alkyl, halo(Ci-C 6 )aIkyl, (Ci -C 6 )alkylene-NH 2 , (C,-C 6 )alkylene- NH(C, -C 6 )alkyl, (C, -C 6 )alkylene-NH(C]-C6)haloalkyl, (C 1 -C 6 )alkylene-N(Ci-C 6 )alkyl) 2 , (C r C 6 )alkylene-OC(0)-(CrC6)alkyl, aryl, heteroaryl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci -C6)alkylene-heteroaryl, (C
  • Embodiment 26 The compound of embodiment 1 -25, wherein R ]b is H, methyl, ethyl, or fluoroethyl.
  • Embodiment 27 The compound of embodiment 1 -26, wherein Ri a is H, and Ri b is H.
  • Embodiment 28 The compound of embodiment 1-27, wherein R is methyl,
  • R lb is H, methyl, ethyl, or fluoroethyl.
  • Embodiment 29 The compound of embodiment 1 -28, wherein Ri a and R
  • Embodiment 30 The com ound of embodiment 1-29 wherein in a further step
  • Embodiment 31 The compound of embodiment 1 -30, wherein in a further step
  • Ri a Ri b N is wherein:
  • Z is O, or C
  • each occurrence of R 2c is independently halo, (C
  • Embodiment 32 The compound ot embodiment 1-3 1 , wherein in a turtner
  • Z is N or C
  • R 2b is absent when Z is N; or is H, (Ci-C 6 )alkyl, or (Ci-C 6 )haloalkyl when Z is C; each occurrence of R 2c is independently halo, (Ci-C6)alkyl, or (Ci-C6)haloalkyl; and n is 0, 1 , or 2.
  • Embodiment 33 The compound of embodiment 1 -32, wherein the compound of formula I is a compound of formula IA-9 or IA-10:
  • Z is N or C
  • R 2b is absent when Z is N; or is H, (d-C 6 )alkyl, or (C
  • Embodiment 34 The compound of embodiment 1 -33, wherein the compound of formula IA-9 or IA-10 is a compound of formula IA-9a or IA- 10a:
  • Embodiment 35 The compound of embodiment 1 -34, wherein:
  • R 2a is OH, NH 2 , NH-(C 2 -C 6 )alkylene-0-(C,-C 6 )alkyl, NH(C,-C 6 )haloalkyl, (C, -
  • C6alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C 6 )cycloalkyl, (C3-C 6 )heterocycloalkyl, or NH(C 0)NH-(C 2 -C 6 )alkylene-0-(C,-C 6 )alkyl;
  • R 2b is absent H, (C
  • each occurrence of R 2c is independently halo, (Ci-Cejalkyl, or (Ci-C6)haloalkyl; and n is 0, I , or 2.
  • Embodiment 37 The compound of embodiment 1 -36, wherein the compound of formula I is a compound of formula IA-9b or !A- l Ob:
  • Embodiment 38 The compound of embodiment 1 -37, wherein R 2a is H, methyl, ethyl, propyl, or butyl; R 2c is methyl; and n is 1.
  • Embodiment 39 The compound of embodiment 1 -38, wherein R5 is methyl.
  • Embodiment 40 The compound of embodiments 1 -39, wherein the compound of formula 1 is a compound of formula IB- 1 or IB-2:
  • R b is H, (C,-C 6 )alkyl, (C,-C 6 )alkylene-NH(C
  • Ri is H, (Ci-C 6 )alkyl, halo(C r C 6 )alkyl, (C
  • Embodiment 41 The compound of embodiment 1 -40, wherein the compound of formula 1 is a compound of formula 1B-3 or IB-4:
  • R z is halo, cycloalkyi, aryl, heterocycloalkyi, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from (C
  • Embodiment 43 The compound of embodiment 1 -42, wherein R 5 is methyl.
  • Embodiment 44 The compound of embodiments 1 -43, wherein the compound of formula 1 is a compound of formul
  • R 3 ⁇ 4c is halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C 6 )alkoxy, halo(Ci-Ce)alkyl, (Ci- C 6 )haloalkoxy, (C,-C 6 )alkylene-NH 2 , (C
  • C6)alkylene-N(Ci-C6)alkyl)) 2 any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH 2 , NH(C,-C 6 )alkyl, N((C,-C 6 )alkyl) 2 , OH, (C C 6 )alkyl, (C
  • Embodiment 45 A compound selected from Table 1.
  • Embodiment 46 A pharmaceutical composition comprising a compound of embodiments 1 -45 admixed with a pharmaceutical carrier, excipient, or diluent.
  • Embodiment 47 A method for treating a disease, disorder, or syndrome which method comprises administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of embodiments 1 -46.
  • Embodiment 48 The method of embodiment 1 -47, wherein the disease is cancer.
  • Embodiment 49 The method of embodiment 1 -48, wherein the cancer is breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NPM/AL -transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, or head and neck cancer.
  • Embodiment 50 A process for making a compound of formula I, comprising process for making a compound of formula 1 or of embodiments 1 -49, comprising reacting a compound of formula F with NHR3R to provide a compound of formula I:
  • NR x R y is as defined in embodiment I ;
  • X, R3, R4, and R 5 are as defined in embodiment 1.
  • the invention provides pharmaceutical compositions comprising an inhibitor of PI3 according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • administration is by the oral route.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesical ly, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, and the like, specifically in unit dosage forms suitable for simple administration of precise dosages.
  • the compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include carriers, adjuvants, and the like.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, and the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, and the like.
  • the choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4, 107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5, 145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (such as propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • polyols such as propyleneglycol, polyethyleneglycol, glycerol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient or carrier, such as sodium citrate or dicalcium phosphate; or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate; (e) solution retarders, such as, for example paraffin; (f) inert customary excip
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like;
  • solubilizing agents and emulsifiers as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol,
  • oils in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
  • polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
  • Suspensions in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, and the like
  • compositions will contain about 1 % to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1 ,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • Compounds of this invention can be made by the synthetic procedures described below.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wis.) or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 -17 (John Wiley and Sons, 1991 ); Rodd's Chemistry of Carbon Compounds, Volumes 1 -5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1 -40 (John Wiley and Sons, 1991 ); March's Advanced Organic Chemistry, (John Wiley and Sons, 4 th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), each of which is incorporated herein by reference.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.
  • the compounds of formula I, or their pharmaceutically acceptable salts may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure.
  • Compounds of the Invention that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
  • Some of the compounds of the invention contain an active ketone C(0)CF 3 and may exist in part or in whole as the C(OH 2 )CF 3 form. Regardless of whether the compound is drawn as the C(0)CF 3 or C(OH 2 )CF 3 form, both are included within the scope of the invention. Although an individual compound may be drawn as the C(0)CF form, one of ordinary skill in the art would understand that the compound may exist in part or in whole as the C(OH 2 )CF 3 form and that the ratio of the two forms may vary depending on the compound and the conditions in which it exists.
  • Some of the compounds of the invention may exist as tautomers.
  • the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention.
  • the present invention also includes N-oxide derivatives and protected derivatives of compounds of the invention. For example, when compounds of the invention contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art.
  • optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.
  • Enantiomers ((R)- and (S)-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid
  • enantiomeric form Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomers enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the chemistry for the preparation of the compounds of this invention is known to those skilled in the art. In fact, there may be more than one process to prepare the compounds of the invention. The following examples illustrate but do not limit the invention. All references cited herein are incorporated by reference in their entirety.
  • compounds of the invention can be prepared by reacting a compound of formula F with NHR3R4 to provide a compound of formula I:
  • NR x R y is defined above and X, R 3 , R4, and R 5 are also as defined above.
  • This transformation can be performed using palladium-catalyzed coupling chemistry according to Suzuki-type or Buchwald-type methods, which is readily available to the skilled artisan, using a primary or secondary alkyl amine or a cyclic amine such as NHR 3 R4.
  • the amine can be optionally substituted pyrrolidine, piperidine, piperizine, or the like.
  • the compound of formula F can be prepared by reacting a compound of formula E with NHR x R y :
  • NR x R y is as defined above and X and R5 are also as defined above.
  • Benzyl piperidin-4-ylcarbamate hydrochloride salt [00248] To a mixture of ter/-butyl 4-aminopiperidine-l -carbox late (2.20 g, 10.98 mmol) and triethyl amine (TEA) ( 1.9 mL, 14.3 mmol) in dichloromethane ( 15 mL) was added a benzyl chloroformate (2.24 g, 13.2 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 hours (h) and diluted with water. The mixture was partioned with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated, and the aqueous layer was further extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure, and the residue was purified by silca gel
  • Step 2 Benzyl l-(l,2,3,4-tetrahydroisoquinoline-7-carbonyl)piperidin-4-ylcarbamate hydrochloride salt
  • 6-Bromo-8-methylquinazolin-4(3H)-one (887 mg, 3.71 mmol) was taken into thionyl chloride (20 mL), followed by addition of catalytic DMF, and the solution was brought to reflux for 2 hours. The solution was concentrated, and the solid residue was digested into a mixture of ethyl acetate and hexanes. The slurry was filtered, and the filter cake was air dried to give 6-bromo-4-chloro-8-methylquinazoline (418 mg) as a tan solid.
  • Step 6 Phenylmethyl (l- ⁇ [2-(6-bromo-8-methylquinazoIin-4-yl)-l,2,3,4- tetrahydroisoquinolin-7-yl
  • Step 7 l-( ⁇ 2-[6-(3,3-Difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-yl ⁇ carbonyl)piperidin-4-amine
  • Phenylmethyl ( l - ⁇ [2 -(6-bromo-8-methylquinazolin-4-yl)- 1 ,2,3,4- tetrahydroisoquinolin-7-yl]carbonyl ⁇ piperidin-4-yl)carbamate 38.9 mg, 0.063 mmol
  • XANTPHOS (10.7 mg
  • tribasic potassium phosphate ( 80 mg) were placed in a sealable glass vessel, followed by addition of anhydrous toluene (1 mL), and the mixture was heated at 1 15 °C for 12 hours.
  • Phenylmethyl [ l -( ⁇ 2-[6-(3,3-difluoropyrrolidin- l -yl)-8-methylquinazolin-4-yl]- l ,2,3,4-tetrahydroisoquinolin-7-yl ⁇ carbonyl)piperidin-4-yl]carbamate (13.6 mg, 0.021 mmol) was taken into hydrogen bromide in acetic acid (30 weight percent, 1 mL), and the resulting solution was stirred for 30 minutes at room temperature. The mixture was then concentrated, and the residue was purified by preparative reverse phase HPLC using ammonium acetate buffered aqueous acetonitrile mobile phase.
  • Table 2 lists the compounds, as well as supporting characterization data that were prepared similarly to Example 1.
  • “Compound Number” refers to the compound numbering provided in Table 1.

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Abstract

The invention is directed to compounds of formula I: and pharmaceutically acceptable salts as well as methods of making and using the compounds to inhibit PI3K.

Description

QUINAZOLI E INHIBITORS OF PI3K
Priority Claim
[0001] This application claims priority to United States Application Serial No.
61 779,679, filed March 13, 2013. The entire contents of the aforementioned application are incorporated herein by reference.
Field
[0002] This invention relates to the field of protein kinases and inhibitors thereof. In particular, the invention relates to Phosphatidylinositol 3-kinase (PI3K) inhibitors, and methods of their use.
Background
[0003] The PI3K7 PTEN pathway regulates cellular survival, growth, and proliferation. Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is observed in various cancers and correlates with tumor growth and survival. For example, the catalytic subunit of P13 (pi 10a), encoded by the PIK3CA gene, is mutated in approximately 13% of all human cancers. In addition, the tumor suppressor PTEN, which serves as a critical negative regulator of PI3 signaling, is frequently deleted or
downregulated in human tumors. Moreover, resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and genotoxic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/ PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents, as well as in combination with other therapies, for a variety of cancer indications. As a result, a need remains for compounds that inhibit PI3K.
Summary
[0004] These and other needs are met by the present invention, which is directed to a compound of formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
Xi and X2 are each independently N, C-H, C-Halo, C-(C C6)alkyl, C-(Ci-C6)alkoxy, or C-CN;
Rx and Ry are each independently H, (CpCeJalkyl, halo(Ci-C6)alkyl, (C3- C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Cj-C6)alkylene-(C3-C6)cycloalkyl, (Ci-C6)alkylene- (C3-C6)heterocycloalkyI, (C|-C6)aIkylene-(C3-C6)heteroaryI, (C|-C6)alkylene-(C3-C6)aryl, (CrC6)haloalkoxy, (Ci-C6)alkylene-NH2, (C|-C6)alkylene-NH(Ci-C6)alkyl, (C,-C6)alkylene- NH(Ci-C6)haloalkyl, (C,-C6)alkylene-N((C,-C6)alkyl)2, (C,-C6)alkylene-OH, (C,- C6)alky lene-(C , -C6)alkoxy, (C , -C6)alky lene-NHS02-(C ( -C6)alky 1, (C i -C6)alky lene- NH(C=0)-(C|-C6)alkyl, or (Ci-C6)alkylene-(C=0)-(Ci-C6)alkyl, any of which may be optionally substituted; or
Rx and Ry taken togethe the atom to which they are attached form a 4-6
membered ring represented by
Figure imgf000003_0002
, optionally containing an additional heteroatom selected from NH, N-(CpC6)alkyl, S, SO, or S02, and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (C|-C6)alkoxy, halo(Ci-C6)alkyl, (Cp
C6)haloalkoxy, (CpC6)alkylene-NH2, (CpC6)alkylene-NH(CpC6)alkyl, (CpC6)alkylene- NH(C,-C6)haloalkyl, (CpC5)alkylene-N(CpC6)alkyl)2, NH2, NH(CpC6)alkyl, (Cp
C6)alkylene-OH, (CpC6)alkylene-(CrC6)alkoxy, NH(C C6)alkylene-NH2, NH(C,- C6)alkylene-NH(C , -C6)alkyl, NH(C , -C6)alky lene-N((CpC6)alkyl)2, NH(C rC6)alkylene-(C3- C7)cyloalkyl, NH(CpC6)alkylene-(C3-C7)heterocyloalkyl, N((CpC6)alkylene-(C3- C7)heterocycloalky 1)2, N((C , -C6)alky 1)-(C i -C6)alky lene-(C3-C7)cy loalkyl, N((C i - C6)alky l)(C , -C6)alkylene-(C3-C7)heteroc loalkyl, N((C i -C6)alky l)2, (C , -C6)alkylene-NHS02- (CpC6)alkyl, (CpC6)alkylene-NH(C=0)-(CrC6)alkyl, (C=0)-(CrC6)alkyl, S(0)-(Cp C6)alkyl, S02-(CrC6)alkyl, aryl, hetreroaryl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (CrC6)alkylene-(C3-C7)heterocycloalkyl, nitro, (CrC6)alkylene-CN, (CrC6)alkylene- OC(0)-(C,-C6)alkyl, (C=0)-NRaRb, NH(C=0)-(C,-C6)alkylene-NH2, NH(C=0)-(C3- C7)cycloalkyIene, NH(C=0)-(C3-C7)heterocyc]oalkylene, N((CrC6)alkyl)(C=0)-(Ci- C6)alkylene-NH2, N((C,-C6)alkyl)(C=0)-(C3-C7)cycloalkylene, N((C,-C6)alkyl)(C=0)-(C3- C7)heterocycloalkylene, NH-S02-NRaRb, or S02-NRaRb, wherein Ra and Rb are each independently H, (Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C i -C6)alky lene-(C3-C7)cycloalkyl, (C i -C6)alky lene-(C3-C7)heterocycloalkyl, -(C, - C6)alkylene-NH2, (C|-C6)alkylene-NH(C|-C6)alkyl), or (Ci-C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, NH(C,-C6)alkoxy, NH(C,-C6)haloalkyl, N((C,-C6)alkyI)2, (C=0)- ORa, -OH, (C,-C6)alkyl, (C,-C6)haloalkyl, (Ci-C6)alkylene-(C3-C7)cycIoalkyl, or (C
C6)alkylene-(C3-C7)heterocycloalkyl optionally substituted with 1 -3 halo, (C3- C7)heterocycloalkyl optionally substituted with 1 -3 halo, (Ci-C6)alkoxy, or (Cj- Cejhaloalkoxy;
Rz is halo, cyano, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from halo, hydroxy, (Ci-C6)alkyl, (Ci-Cejhaloalkyl, (CrC6)alkoxy, halo(C,-C6)alkyl> (C,-C6)haloalkoxy, (C=0)-NH2, NH(C=0)-(C,-C6)alk l, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)- N((C,-C6)alkyl)2; or
Rz is NR3R4, wherein R3 and R4 are each independently H or (Ci-C6)alkyl optionally substituted with one , two, or three groups selected from halo, hydroxy, cyano, oxo, (Ci- C6)alkyl, (C,-C6)alkoxy, halo(C C6)alkyl, (CrC6)haloalkoxy, S(0)-(CrC6)alkyl, S02-(Cr C6)alkyl, (Ci-C6)alkylene-NH2, (C,-C6)alkylene-NH(C,-C6)alkyl, (CrC6)alkylene-NH(Ci- C6)haloalkyl, (C ,-C6)alkylene-N(C,-C6)alkyl)2,NH2, NH(d-C6)alkyl, (C,-C6)alkylene-OH, (C 1 -C6)alkylene-(C, -C6)alkoxy, NH(C 1 -C6)alkyleneNH2, NH(Ci -C6)alkylene-NH(C, - C6)alkyl, NH(C,-C6)alkyleneN((Ci-C6)alkyl)2, NH(C,-C6)alkylene-cyloalkyl, NH(C,- C6)alkylene-heterocyloalkyl, N((Ci-C6)alkyl)2, (Ci-C6)alkylene-NHS02-(Ci-C6)alkyl, (C C6)alkylene-NH(C=0)-(C,-C6)alkyl, (C=0)-(C|-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(C,- C6)alkyl, (C4-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci- C6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(Ci-C6)alkyl,
Figure imgf000004_0001
or S02-NRcRd> wherein Rc and R<j are each independently are H, (Ci -C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C 1 -C6)alky lene-(C3-C7)cycloalky 1, (C 1 -C6)alkylene-(C3- C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (C|-C6)alkylene-NH(Ci-C6)alky]), or (C
C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C|-C6)alkyl)2, OH, (Ci-C6)alkyl, (C|-C6)alkoxy, or (C| -C6)haloalkoxy; or
R3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from H, halo, hydroxy, cyano, oxo, (C|-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkyl, (Ci-C6)haloalkoxy, (Q- C6)alkylene-NH2, (Ci-C6)alkylene-NH(C,-C6)alkyl, (Ci-C6)alkylene-NH(Ci-C6)haloalkyl, (C,-C6)alkylene-N(C,-C6)alkyl)2, S(0)-(Ci-C6)alkyl, S02-(C,-C6)alkyl, NH2, NH(C,- C6)alkyl, (C,-C6)alkylene-OH, (CrC6)alkylene-(Ci-C6)alkoxy, NH(Ci-C6)alkyleneNH2, NH(C , -C6)alky lene-NH(C , -C6)alky 1, NH(Ci -C6)alky leneN((C , -C6)alkyl)2, NH(C ,- C6)alkylene-cyloalkyl, NH(Ci-C6)alkylene-heterocyloalkyl, N((C|-C6)alkyl)2, (C,- C6)alkylene-NHS02-(C,-C6)alkyl, (C,-C6)alkylene-NH(C=0)-(Ci-C6)alkyl, (C=0)-(C,- C6)alkyl, S(0)-(C,-C6)alkyl, S02-(C,-C6)alkyl, (C4-C7)heterocycloalkyl, (C,-C6)alkylene-(C3- C7)heterocycloalkyl, nitro, (d-C6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(Ci-C6)alkyl, (C=0)-NReRf, or S02-NReRf, wherein Re and Rf are each independently H, (d-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)cycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (C
C6)alkylene-NH(Ci-C6)alkyl), or (C|-C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)aIkyl, N((C|-C6)alkyl)2, OH, (CrC6)alkyl, (C|-C6)alkoxy, or (Q-C6)haloalkoxy; and
R5 is H, halo, (Ci-C6)alkyl, halo(d-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2- C6)alkynyl, or (C|-C6)alkoxy.
[0005] The invention also provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, excipient, or diluent.
[0006] The invention also provides a method of inhibiting the in vivo activity of PI3K, comprising administering to a patient an effective PI3K-inhibiting amount of a compound of formula I or a pharmaceutical composition thereof.
[0007] The invention also provides a method for treating a disease, disorder, or syndrome comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, excipient, or diluent. [0008] The invention also provides a process for making a compound of formula I wherein Rz is NR3R4, comprising reacting a compound of formula F with NHR3R4:
Figure imgf000006_0001
wherein X|, X2, NRxRy, R3, R4, and R5 are as defined above.
[0009] The invention also provides a process for making a compound of formula I wherein Rz is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl comprising reacting a compound of formula F with X-R2 wherein X is a leavin rou :
Figure imgf000006_0002
wherein Xi, X2, NRxRy, Rz, and R5 are as defined above.
Detailed Description
Abbreviations and Definitions
[0010] The following abbreviations and terms have the indicated meanings throughout:
Abbreviation Meaning
AcOH acetic acid
br broad
°C degrees Celsius
cone concentrated
d doublet
dd doublet of doublet
dt doublet of triplet
DC dichloromethane
DIEA or DIPEA N.N-di-isopropyl-N-ethylamine
DMA N,N-dimethylacetamide
DME 1 ,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
dppf 1 , 1 '-bis(diphenylphosphano)ferrocene
EI Electron Impact ionization
equiv equivalents
Figure imgf000007_0001
[00111 The symbol "-" means a single bond, "=" means a double bond, "s" means a triple bond, and " " means a single or double bond. The symbol "ΛΛΛ/ " refers to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous. When a group is depicted removed from its parent Formula, the "~" symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
[0012] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, -CH2CH2-. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.
Figure imgf000008_0001
group "R" is depicted as "floating" on a ring system, as for example in the
Figure imgf000008_0002
then, unless otherwise defined, a substituent "R" may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
[0014] If a group "R" is depicted as floating on a fused or bridged ring system, as for example in the formulae:
Figure imgf000008_0003
then, unless otherwise defined, a substituent "R" may reside on any atom of the fused or bridged ring system, assuming replacement of a depicted hydrogen (for example the -NH- in the Formula above), implied hydrogen (for example as in the Formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the Formula above, "Z" equals =CH-) from one of the ring atoms, so long as a stable structure is formed. In the examples depicted, the "R" group may reside on either the 5-membered or the 6-membered ring of the fused or bridged ring system.
[0015] When a group "R" is depicted as existing on a ring system containing saturated carbons, as for example in the formula:
Figure imgf000008_0004
where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" may reside on the same carbon. In another example, two R's on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring structure with the depicted ring as for example in the formula:
Figure imgf000009_0001
[0016] "Acyl" means a C(0)R radical where R is alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or
heterocycloalkylalkyl, as defined herein, e.g., acetyl, trifluoromethylcarbonyl, 2- methoxyethylcarbonyl, and the like.
[0017] "Acylamino" means a NRR' radical where R is hydrogen, hydroxy, alkyl, or alkoxy, and R' is acyl, as defined herein.
[0018] "Acyloxy" means an OR radical where R is acyl, as defined herein, e.g.
cyanomethylcarbonyloxy and the like.
[0019] "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
[0020] "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one double bond, e.g., ethenyl, propenyl, 1 -but-3-enyl, l-pent-3-enyl, and the like.
[0021 ] "Alkoxy" means an OR radical where R is alkyl group as defined herein, e.g., methoxy, ethoxy, propoxy, isopropoxy, and the like.
[0022] "Alkoxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, specifically one, two, or three, alkoxy groups, as defined herein. Representative examples include methoxymethyl and the like.
[0023] "Alkoxycarbonyl" means a C(0)R radical where R is alkoxy, as defined herein.
[0024] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric torms , pentyl (including all isomeric forms), and the like.
[0025] "Alkylamino" means an NHR radical where R is alkyl, as defined herein.
[0026] "Alkylaminoalkyl" means an alkyl radical substituted with one or two alkylamino groups, as defined herein.
[0027] "Alkylaminoalkyloxy" means an OR radical where R is alkylaminoalkyl, as defined herein.
[0028] "Alkylcarbonyl" means a C(0)R radical where R is alkyl, as defined herein.
[0029] "Alkylsufonyl" means an S(0)2R radical where R is alkyl, as defined herein.
[0030] "Alkylsulfonylalkyl" means an alkyl radical, as defined herein, substituted with at least one, specifically one or two, alkylsulfonyl groups, as defined herein.
[0031] "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms which radical contains at least one triple bond, e.g., ethynyl, propynyl, butynyl, pentyn-2-yl, and the like.
[0032] "Amino" means an NH2 radical.
[0033] "Aminoalkyl" means an alkyl radical substituted with at least one, specifically one, two, or three, amino groups, as defined herein.
[0034] "Aminoalkyloxy" means an OR radical where R is aminoalkyl, as defined herein.
[0035] "Aminocarbonyl" means a C(0)NH2 radical.
[0036] "Alkylaminocarbonyl" means a C(0)NHR radical where R is alkyl, as defined herein.
[0037] "Aryl" means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic radical, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.
[0038] "Arylalkyl" means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl, phenethyl, and the like.
[0039] "Arylalkyloxy" means an OR radical where R is arylakyl, as defined herein.
[0040] "Cyanoalkyl" means an alkyl radical, as defined herein, substituted with one or two cyano groups.
[0041] "Cycloalkyl" means a monocyclic or fused or bridged bicyclic or tricyclic, saturated or partially unsaturated (but not aromatic), monovalent hydrocarbon radical of three to fourteen carbon ring atoms. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. More specifically, the term cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
3 7
cyclohexyl, cyclohexyl, cyclohex-3-enyl, (l r,3r,5/?,7/?)-tricyclo[3.3.1.1 · ]decan-2-yl, and the like.
[0042] "Cycloalkylalkyl" means an alkyl radical substituted with at least one, specifically one or two, cycloalkyl group(s), as defined herein.
[0043] "Dialkylamino" means a NRR' radical where R and R' are alkyl, as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino, N,N-methylethylamino, and the like.
[0044] •'Dialkylaminoalkyl" means an alkyl radical substituted with one or two dialkylamino groups, as defined herein.
[0045] "Dialkylaminoalkyloxy" means an OR radical where R is dialkylaminoalkyl, as defined herein. Representative examples include 2-(N,N-diethylamino)-ethyloxy and the like.
[0046] "Dialkylaminocarbonyl" means a C(0)NRR' radical where R and R' are alkyl, as defined herein.
[0047] "Halogen" or "halo" means a fluorine, chlorine, bromine, and iodine radical.
[0048] "Haloalkoxy" means an OR' radical where R' is haloalkyl, as defined herein, e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
[0049] "Haloalkyl" mean an alkyl group substituted with one or more halogens, specifically 1 , 2, 3, 4, 5, or 6 halo atoms, e.g., trifluoromethyl, 2-chloroethyl,
2,2-difluoroethyl, and the like.
[0050] "Heteroaryl" means a monocyclic or fused or bridged bicyclic monovalent radical of 5 to 14 ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms, where each heteroatom is independently -0-, -S(0)n- (n is 0, 1 , or 2), -NH-, -N=, or N-oxide, with the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising the bicyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group.
Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. More specifically, the term heteroaryl includes, but is not limited to, 1 ,2,4-triazolyl, 1 ,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (e.g., 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro- l H-indol-5-yl, and the like), isoindol l, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (e.g., tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-6-yi, and the like), pyrrolo[3,2-c]pyridinyl (e.g., pyrrolo[3,2-c]pyridin- 2-yl, pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, 2,3-dihydrobenzofuranyl, benzo[i/][l ,3]dioxolyl, 2,3-dihydrobenzo[Z>][l ,4]dioxinyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof, and the like. The term "5- or 6-membered heteroaryl" describes a subset of the term "heteroaryl."
[0051 ] "Heteroarylalkyl" means an alky I radical, as defined herein, substituted with at least one, specifically one or two heteroaryl group(s), as defined herein.
[0052] "Heterocycloalkyi" means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic radical of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused or bridged, bicyclic or tricyclic group of 5 to 12 ring atoms in which one or more, specifically one, two, three, or four ring heteroatoms where each heteroatom is independently -0-, -S(0)n- (n is 0, 1 , or 2), -N=, or -NH-, the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or - C(=NH)- group. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, Ry is absent. More specifically the term heterocycloalkyi includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl,
tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,
isothiazolidinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, tetrahydropyranyl, (3a/?,6aS)-5- methyloctahydrocyclopenta[c]pyrrolyl, and (3 a£,6afl)-5 -methyl- 1 ,2,3,3a,4,6a- hexahydrocyclopenta[c]pyrrolyl, and the derivatives thereof and N-oxide or a protected derivative thereof, and the like.
[0053] "Heterocycloalkylalkyl" means an alkyl radical, as defined herein, substituted with one or two heterocycloalkyi groups, as defined herein, e.g., morpholinylmethyl, N-pyrrolidinylethyl, 3-(N-azetidinyl)propyl, and the like.
[0054] "Heterocycloalkyloxy" means an OR radical where R is heterocycloalkyl, as defined herein.
[0055] "Hydroxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, preferably 1 , 2, 3, or 4, hydroxy groups.
[0056] "Phenylalkyl" means an alkyl radical, as defined herein, substituted with one or two phenyl groups.
[0057] "Phenylalkyloxy" means an OR radical where R is phenylalkyl, as defined herein.
[0058] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted" refers to all subsequent modifiers in a term, unless stated otherwise. A list of exemplary optional substitutions is presented below in the definitions for "optionally substituted" groups.
[0059] "Optionally substituted aryl" means an aryl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, and aminoalkoxy; or aryl is pentafluorophenyl. Within the optional substituents on "aryl," the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[0060] "Optionally substituted arylalkyl" means an alkyl group, as defined herein, substituted with optionally substituted aryl, as defined herein.
[0061 ] "Optionally substituted cycloalkyl" means a cycloalkyl group, as defined herein, substituted with one, two, or three groups independently selected from acyl, acyloxy, acylamino, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl,
alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,
alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, carboxy, and cyano. Within the above optional substitutents on "cycloalkyl," the alkyl and alkenyl, either alone or as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, and haloalkylsulfonyl.
[0062] "Optionally substituted cycloalkylalkyl" means an alkyl group substituted with at least one, specifically one or two, optionally substituted cycloalkyl groups, as defined herein.
[0063] "Optionally substituted heteroaryl" means a heteroaryl group optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy. Within the optional substituents on "heteroaryl," the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[0064] "Optionally substituted heteroarylalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heteroaryl group(s), as defined herein.
[0065] "Optionally substituted heterocycloalkyl" means a heterocycloalkyl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, haloalkyl, alkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, and phenylalkyl. Within the optional substituents on "heterocycloalkyl," the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[0066] "Optionally substituted heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heterocycloalkyl group(s) as defined herein. [0067] "Optionally substituted phenyl" means a phenyl group optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, and aminoalkoxy, or aryl is pentafluorophenyl. Within the optional substituents on "phenyl," the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[0068] "Optionally substituted phenylalkyl" means an alkyl group, as defined herein, substituted with one or two optionally substituted phenyl groups, as defined herein.
[0069] "Optionally substituted phenylsulfonyl" means an S(0)2R group where R is optionally substituted phenyl, as defined herein.
[0070] "Oxo" means an oxygen atom which is attached via a double bond.
[0071] "Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.
[0072] "Metabolite" refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule, such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of
biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously; that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
[0073] "Patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. In a specific embodiment, the patient is a mammal, and in a more specific embodiment, the patient is human.
[0074] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that it possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in
Remington 's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, PA, 1985) or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19, both of which are incorporated herein by reference.
[0075] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid, and the like.
[0076] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Specific salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine,
N-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, caffeine, and the like.
[0077] "Platin(s)," and "platin-containing agent(s)" include, for example, cisplatin, carboplatin, and oxaliplatin. [0078] "Therapeutically effective amount" means an amount ot a compound of the invention that, when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
[0079] "Preventing" or "prevention" of a disease, disorder, or syndrome includes inhibiting the disease from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome.
[0080] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (ii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and such adjustments will be
ascertainable with routine experimentation by one of ordinary skill in the art.
[0081 ] The compounds disclosed herein also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
Examples of isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as 2H and 3H; isotopes of carbon, such as l 3C and l4C; isotopes of nitrogen, such as l 5N; isotopes of oxygen, such as , 70 and 180; isotopes of phosphorus, such as 31 P and 32P; isotopes of sulfur, such as 35S; isotopes of fluorine, such as 18F; and isotopes of chlorine, such as 36CI. Use of isotopic variations (e.g., deuterium, 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Additionally, certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3H, and 14C), which may be useful in drug and/or substrate tissue distribution studies. Embodiments of the Invention
[0082] The following paragraphs present a number of embodiments of compounds of the invention. In each instance, the embodiment includes the recited compounds, as well as single stereoisomers or mixture of stereoisomers thereof and pharmaceutically acceptable salts thereof.
[0083] In one aspect, the invention provides a compound of Formula I:
Figure imgf000018_0001
1
wherein the variables are as previously defined.
[0084] In one embodiment of the compound of formula I, Xi is N, C-H, C-Halo, C-(C|- C6)alkyl. In another embodiment, Xi is N or C-H.
[0085] In another embodiment of the compound of formula I, X2 is N, C-H, C-Halo, or C-(C,-C6)alkyl and Xt is N or C-CN.
[0086] In another embodiment, R5 is (CrC6)alkyl, halo-(CrC6)alkyl, (C2-C6)alkenyl, halo-(C2-C6)alkenyl, or -(C|-C6)alkoxy.
[0087] In another embodiment, X, is N or C-H, X2 is C-H, and R5 is (d-C6)alkyl.
[0088] In another embodiment, the compound of formula I is a compound of formula IA:
Figure imgf000018_0002
1A
wherein
Figure imgf000018_0003
is a 6-membered saturated or partially saturated heterocycle optionally containing an additional heteroatom selected from NH, N-(Ci-C6)alkyl, S, SO, and S02, and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (C|-C6)alkyl, (C|- C6)alkoxy, halo(C,-C6)alkyl, (C,-C6)haloalkoxy, (CrC6)alkylene-NH2, (C,-C6)alkylene- NH(C ,-C6)alkyl, (Ci -C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C, -C6)alkyl, (CrC6)alkylene-OH, (C,-C6)alkylene-(C,-C6)alkoxy, NH(C,- C6)alky lene-NH2, NH(C , -C6)alkylene-NH(C , -C6)alkyl, NH(C , -C6)alky leneN((C , -C6)alkyl)2, NHid-CeJalkylene-iCj-CyJcyloalkyK NHCC^alkylene-CCs-CTjheterocyloalkyl, N((Cr C6)alkylene-(C3-C7)heterocycloalkyl)2, N((Ci-C6)alkyl)(C|-C6)aikylene-(C3-C7)cyloalkyl, N((C , -C6)alkyl)(C , -C6)alkylene-(C3-C7)heterocyloalkyl, N((C , -C6)alky 1)2, (C , -C6)alky lene- NHS02-(C,-C6)alkyl, (CrdJalkylene-NH^OMQ-CeJalkyl, (C=0)-(C,-C6)alkyl, S(O)- (C|-C6)alkyl, S02-(C| -C6)alkyl, aryl, hetreroaryl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (C|-C6)alkylene-CN, (CrC6)aIkylene- OC(0)-(C,-C6)alkyl, (C=0)-NRaRb, NH(C=0)-(C,-C6)alkylene-NH2, NH(C=0)-(C3- C7)cycloalkylene, NH(C=0)-(C3-C7)heterocycloalkylene, N((CrC6)alkyl)(C=0)-(Ci- C6)alkylene-NH2, N((C,-C6)alkyl)(C=0)-(C3-C7)cycloalkylene, N((C,-C6)alkyl)(C=0)-(C3- C7)heterocycloalkylene, NH-S02-NRaRb, or S02-NRaRb, wherein Ra and R¾ are each independently H, (Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C i -C6)alky lene-(C3-C7)cycloalkyl, (C , -C6)alkylene-(C3-C7)heterocycloalky I, (C i - C6)alkylene-NH2) (Ci -C6)alkylene-NH(C,-C6)alkyl), or (C,-C6)alkylene-N(C,-C6)alkyl))2, any of which may be optionally substituted; or any of which taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, NH(C,-C6)alkoxy, NH(C C6)haloalkyl, N((CrC6)alkyl)2, (C=0)-ORa, OH, (C,-C6)alkyl, (C,-C6)haloalkyl, (C,-C6)alkylene-(C3-C7)cycloalkyl, (Ci-C6)alkylene-(C3- C7)heterocycloalkyl optionally substituted with 1 -3 halo, (C -C7)heterocycloalkyI optionally substituted with 1 -3 halo, (C C6)alkoxy, or (C|-C6)haloalkoxy.
[0089] In a further embodiment, the compound of formula I is a compound of formula IA- 1 or IA-2:
Figure imgf000019_0001
IA- 1 IA-2 wherein R6 is H, halo, hydroxy, cyano, (C[-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkyI, (C|- C6)alkylene-NH2, (Ci -C6)alkylene-NH(Ci-C6)alkyl, (Ci-C6)alkylene-NH(C,-C6)haloalkyl, (C-CeJalkylene-NiC-CeJalky z, (Ci-C6)alkylene-NHS02Me,NH2, NH(C C6)alkyl, hydroxyalkyl, (Ci-C6)alkylene-0(C,-C6)alkyl, NH(Ci-C6)alkylene-NH2, NH(C C6)alkylene- cyloalkyl, NH(C|-C6)alkylene-heterocyloalkyI, N((C,-C6)alkyl)2, (C,-C6)alkyIene-NHS02- (C , -C6)alky I, (C , -C6)alky lene-NH(C=0)-(C , -C6)alkyl, NH(C=0)-(C , -C6)alkylene-NH2,
Figure imgf000020_0001
NH(C=0)-(C3-C7)heterocycloalkyIene, (C=0)-(CrC6)alkyl, NHS02-(C,-C6)alkyl, N((Ci-C6)alkyl)S02-(Ci-C6)alkyl, S(0)-(C|-C6)alkyl, S02-(Ci- C6)alkyl, (C3-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci- C6)alkylene-CN, NH(C , -C6)alky lene-NH(C , -C6)alkyl, NH(C , -C6)alky lene-N((C , -C6)alky 1)2, (C,-C6)alkylene-OC(0)-(C |-C6)alkyl, (C=0)-NR6aR6b, or S02-NR6aR6b, wherein Rea and Reb are each independently H, (C i-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (Ci-C6)alkylene-(C3-C6)cycloalkyl, (Ci-C6)alkylene-(C3- C6)heterocycloalkyl, (C,-C6)alkylene-NH2, (Ci-C6)alkylene-NH(Ci-C6)alkyl), or (C,- C6)alkylene-N(Ci-C6)alkyI))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2> NH(d-C6)alkyl, N((Ci-C6)alkyl)2, OH, (C,-C6)alkyl, (Ci-C6)alkoxy, or (Ci-C6)haloalkoxy. In a particular embodiment of the compound of formula IA-1 or 1A-2, Xt is N.
[0090] In a further embodiment, the compound of formula I is a compound of formula IA-3 or IA-4:
Figure imgf000020_0002
IA-3 IA-4
wherein Q is C=0, S=0, or S02 and R| is OH or R6aR6b, Rea and R6b are each
independently H, (Ci-C6)alkyl, halo(C,-C6)alkyl, (C,-C6)alkylene-NH2, (C,-C6)alkylene- NH(C, -C6)alkyl, (C,-C6)alkylene-NH(Ci-C6)haloalkyl, (C,-C6)alkylene-N(C|-C6)alkyl)2, (C,- C6)alkylene-OC(0)-(C| -C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-
Figure imgf000021_0001
(Ui-U6)alkylene-heteroaryl, (Ui-L6)alkylene-(<J3- C6)cycloalkyl, or (Ci-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|-Ce)alkyl, N((Cr C6)alkyl)2, OH, (C|-C6)alkyl, (CrC6)alkoxy, or (Ci-C6)haloalkoxy. In a particular embodiment of the compound of formula IA-3 or IA-4, Xi is N.
[0091] In a further embodiment, the compound of formula I is a compound of formula IA-5 or IA-6:
Figure imgf000021_0002
IA-5 IA-6
wherein Rz is halo, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, each of which may be optionally substituted with 1 , 2, or 3 groups selected from (C] -C6)alkyl, (Ci-C6)haloalkyl (C|- C6)alkoxy, halo(C,-C6)alkyl, (Ci-C6)haloalkoxy, (C=0)-NH2, NH(C=0)-(Ci-C6)alkyl, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)-N((C,- C6)alkyl)2. In a particular embodiment of the compound of formula IA-5 or IA-6, X| is N.
[0092] In this and other embodiments, Rz is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
[0093] In particular, Rz is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
[0094] In particular, Rz is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
[0095] In particular, Rz is isoxazolyl, pyrimidinyl, indazolyl optionally substituted with amino or methyl.
[0096] In particular Rz is pyridinyl optionally substituted with fluoro, chloro, amino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, or (C=0)- NHMe.
[0097] In particular Rz is benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, or triazolyl optionally substituted with methyl or amino. [0098] In particular, Rz is pyridazinyl optionally substituted with hydroxy!, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
[0099] In particular, Rz is thienyl or furanyl optionally substituted with methyl.
[00100] In another embodiment, Rz is bromo, chloro, or fluoro.
[00101 ] In another embodiment, R2 is NR3R4, wherein R3 and R4 are each independently (Ci-CeJalkyl optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (C| -C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkyl, (Ci-C6)haloalkoxy, (Cj- C6)alkylene-NH2, (Ci-CeJalkylene-NHCC-CeJalkyl, (C,-C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)all ylene-N(Ci -C6)alkyl)2, NH2) NH(Ci-C6)alkyl, (C,-C6)alkylene-OH, (C,- C6)alky lene-(C 1 -C6)alkoxy, NH(C , -C6)alky leneNH2, NH(C 1 -C6)alky lene-NH(C , -C6)alkyl, NH(C I -C6)alky leneN((C , -C6)alky 1)2, NH(C, -C6)alkylene-cy loalkyl, NH(C { -C6)alkylene- heterocyloalkyl, N((Ci-C6)alkyl)2, (C,-C6)alkylene-NHS02-(C|-C6)alkyl, (C, -C6)alkylene- NH(C=0)-(C, -C6)alkyl, (C=0)-(C,-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(C|-C6)alkyl, (C4- C7)heterocycloalkyl, (Ci -C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (C] -C6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(C|-C6)alkyl, (C=0)-NRcRd, or S02-NRcRd, wherein Rc and Rd are each independently are H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocyc loalkyl, (C 1 -C6)alkylene-(C3-C7)cycloalky I, (C 1 -C6)alky lene-(C3- C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (Ci-C6)alkylene-NH(Ci-C6)alkyl), or (C
C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C C6)alkyl)2, -OH, (C,-C6)alkyl, (C| -C6)alkoxy, or (Ci-C6)haloalkoxy.
[00102] In particular, when Rz is NR3R4, R3 is H, and R4 is methyl, ethyl, propyl, butyl, pentyl, CH2CH2-OCH3, or -(C=0)-CH2-OH.
[00103] In another embodiment, Rz is NR3R4, wherein R3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (Ci-Ce)alkyl, (C|-C6)alkoxy, halo(Ci- C6)alkyl, (C,-C6)haloalkoxy, (CrC6)alkylene-NH2, (C1-C6)alkylene-NH(C,-C6)alkyl, (Cr C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C|-C6)alkyl, (Ci-C6)alkylene-OH, (C,-C6)alkylene-(Ci-C6)aikoxy, NH(CrC6)alkyleneNH2, NH(C,- C6)alky lene-NH(C , -C6)alkyl, NH(C , -C6)alkyleneN((C , -C6)alkyl)2, NH(C , -C6)alky lene- cyloalkyl, NH(CrC6)alkylene-heterocyloalkyl, N((C,-C6)alkyl)2, (C|-C6)alkylene-NHS02- (C,-C6)alkyl, (C -Ceialkylene-NH^OHC-CeJalkyl, (C=0)-(C,-C6)alkyl, S(0)-(C,- C6)alkyl, S02-(C C6)alkyl, (C4-C7)heterocycloalkyl, (CrC6)alkylene-(C3- C7)heterocycloalkyl, nitro, (CrC6)alkylene-CN, (C|-C6)alkylene-OC(0)-(Ci-C6)alkyl,
Figure imgf000023_0001
or S02-NReRf, wherein Re and Rf are each independently H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)cycloalkyl, (C,-C6)alkylene-(C3-C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (C
C6)alkylene-NH(C,-C6)alkyl), or (Ci-C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)alkyl, N((C, -C6)alkyl)2, OH, (Ci-C6)alkyl, (Ci-C6)alkoxy, or (C|-C6)haloalkoxy.
[00104] In a particular embodiment, Rz is
Figure imgf000023_0002
[00105] In a further embodiment, the compound of formula I is a compound of formula IA-7 or IA-8
Figure imgf000023_0003
IA-7 IA-8
wherein Q is C=0 or S02; and
Ria and Rib are each independently H, (Ci-C6)alkyl, halo(C|-C6)alkyl, (Cp
C6)alkylene-NH2, (C|-C6)alkylene-NH(C, -C6)alkyl, (C,-C6)alkylene-NH(Ci-C6)haloalkyl, (CrC6)alkylene-N(C,-C6)alkyl)2, (C,-C6)alkylene-OC(0)-(C|-C6)alkyl, aryl, heteroaryl, (C3- C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci-C6)alkylene-heteroaryl, (C|-C6)alkylene-(C3-C6)cycloalkyl, or (Ci-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|- C6)alkyl, N((CrC6)alkyl)2, OH, (C,-C6)alkyl, (d-C6)alkoxy, or (C,-C6)haloaikoxy. In a particular embodiment of the compound of formula IA-7 or IA-8, Xi is N.
[00106] In a further embodiment, in a compound of formula IA-7 or IA-8:
Ria is H or (C,-C6)alkyl; Rib is H, ( i- 6)alkyl, halo((J|-C6)alkyI, (C|-C6}alkylene-NH2, (Ci-C6)alkylene-
NH(C,-C6)alkyl, (C,-C6)alkylene-NH(C,-C6)haloalkyl, (C1-C6)alkylene-N(C1-C6)alkyl)2, (C
C6)alkylene-OC(0)-(C, -C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-
C6)heterocycloalkyl, (C|-C6)alkylene-aryl, (C] -C6)alkylene-heteroaryl, (C|-C6)alkylene-(C3-
C6)cycloalkyl, or (Ci-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; and
R.5 is methyl.
[00107] In this and other embodiments, R|a is H, methyl, pyrrolidiny, piperidinyl, CH2- cyclopropyl, C b-pyrrolidinyl, or CH2-piperidinyl.
[00108] In this and other embodiments, is H, methyl, ethyl, or fluoroethyl.
[00109] In a further embodiment, Ria is H, and Rib is H.
In a further embodiment, Ria is methyl, ethyl,
Figure imgf000024_0001
Figure imgf000024_0002
and Rib is H, methyl, ethyl, or fluoroethyl.
[00111] In a further embodiment, R and Rib are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|- C6)alkyl, N((C,-C6)alkyl)2, OH, (C, -C6)alkyl, (C,-C6)alkoxy, or (C,-C6)haloalkoxy.
[00112] In a further embodiment, R) a ibN is or H2N
In a further embodiment, R|aRibN is
Figure imgf000024_0003
Figure imgf000024_0004
[00114] In a further embodiment, RiaRibN is
Figure imgf000024_0005
wherein:
Z is O, N, or C; R2a is absent when Z is O; or is H, OH, NH2, NH-(C2-C6)alkylene-0-(CrC6)alkyl, NH(C]-C6)haloalkyl, (C|-C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(Ci-C6)alkyl when Z is N or C;
R2b is absent when Z is N or O; or is H, (Ci-C6)alkyl, or (C|-C6)haloalkyl when Z is
C;
each occurrence of R2c is independently halo, (C|-C6)alkyl, or (Ci-C6)haloalkyl; and n is 0, 1 , or 2.
Figure imgf000025_0001
Z is N or C;
R2a is H, OH, NH2, NH-(C2-C6)alkylene-0-(C,-C6)alkyl, NH(C,-C6)haloalkyl, (Ci- C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or H(C-0)NH-(C2-C6)alkylene-0-(Ci-C6)alkyl;
R2b is absent when Z is N; or is H, (Ci-C6)alkyl, or (C|-C6)haloalkyl when Z is C; each occurrence of R2c is independently halo, (Ci-C6)alkyl, or (Ci-Cejhaloalkyl; and n is 0, 1 , or 2.
[00116] In a further embodiment, the compound of formula I is a compound of formula IA-9 - 10:
Figure imgf000025_0002
IA-9 IA-10 wherein Q is C=0 or S02;
Z is N or C;
R2a is H, OH, NH2, NH-(C2-C6)alkylene-0-(C,-C6)alkyl, NH(Ci-C6)haloalkyl, (C,- C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(C| -C6)alkyl;
R2b is absent when Z is N; or is H, (Ci-Cfi)alkyl, or (C C6)haloalkyl when Z is C; each occurrence of R2c is independently halo, (Ci-C6)alkyl, or (C|-C6)haloalkyl; and n is 0, 1 , or 2.
[00117] In a particular embodiment of the compound of formula IA-9 or IA-10, Xt is N.
[00118] In a further embodiment, the compound of formula IA-9 or IA- 10 is a compound of formula IA-9a or IA- 10a:
Figure imgf000026_0001
IA-9a !A-l Oa
[00119] In this and other embodiments:
R2a is OH, NH2, NH-(C2-C6)alkylene-0-(Ci-C6)alkyl, NH(Ci-C6)haloalkyl, (d- C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(C,-C6)alkyl;
R2b is absent, H, (Ci-C6)alkyl, or (Ci-C6)haloalkyl;
each occurrence of R2c is independently halo, (Ci-C6)alkyl, or (Ci-Cejhaloalkyl; and n is 0, 1 , or 2.
00120] In a particular embodiment of the compound of formula IA-9a or IA-10a, Xi is N.
Figure imgf000026_0002
Figure imgf000027_0001
[00122] In a further embodiment, the compound of formula I is a compound of formula IA-9b - 10b:
Figure imgf000027_0002
IA-9b IA-10b
[00123] In a particular embodiment of the compound of formula IA-9b or IA-10b, Xi is N.
[00124] In this and other embodiments, R2a is H, methyl, ethyl, propyl, or butyl; R2c is methyl; and n is 1 .
[00125] In this and other embodiments, R5 is methyl.
[00126] In a further embodiment, the compound of formula I is a compound of formula IB-1 or IB-2:
Figure imgf000027_0003
IB-1 IB-2
wherein Q is CH2, C=0, S=0, or S02; Rb is H, (C,-C6)alkyl, (C,-C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)aIkylene-N(Cr C6)alkyl)2, (C|-C6)alkylene-OC(0)-(C,-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (CrC6)alkylene-aryl, (C,-C6)alkylene-heteroaryl, (CrC6)alkylene-(C3- C6)cycloalkyl, (C|-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, -OH, (C,-C6)alkyl, (C,- C6)alkoxy, or (C]-C6)haloalkoxy; and
R, i is H, (Ci-C6)alkyl, halo(C,-C6)alkyl, (C,-C6)alkylene-NH2, (C,-C6)alkylene- NH(C,-C6)alkyl, (Ci-C6)alkylene-NH(Ci-C6)haloalkyl, (C|-C6)alkylene-N(C|-C6)alkyl)2, (C C6)alkylene-OC(0)-(Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (C|-C6)alkylene-heteroaryl, (Ci-C6)alkylene-(C3- C6)cycloalkyl, (Ci-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted with halo, NH2, NH(C|-C6)alkyl, N((C|-C6)alkyl)2, OH, (Ci-C6)alkyl, (C
C6)alkoxy, or (C]-C6)haloalkoxy.
[00127] In a particular embodiment of the compound of formula IB-1 or IB-2, Xi is N.
[00128] In a further embodiment, the compound of formula I is a compound of formula IB-3 or I -4:
Figure imgf000028_0001
IB-3 IB-4
wherein Rz is halo, cycloalkyl, aryl, heterocycloalk l, or heteroaryl, each of which is optionally substituted with 1 , 2, or 3 groups selected from (CrC6)alkyl, (C C6)haloalkyl (Cr C6)alkoxy, halo(C,-C6)alkyl, (C,-C6)haloalkoxy, (C=0)-NH2, NH(C=0)-(CrC6)alkyl, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)-N((C,- C6)alkyl)2. In a particular embodiment of the compound of formula IB-3 or IB-4, Xi is N.
[00129] In this and other embodiments, Rz is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
[00130] In particular, Rz is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy. [00131] In particular, Rz is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
[00132] In particular, Rz is isoxazolyl, pyrimidinyl, indazolyl optionally substituted with amino or methyl.
[00133] In particular, Rz is pyridinyl optionally substituted with fluoro, chloro, amino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, or (C=0)- NHMe.
[00134] In particular Rz is benzimidazolyl, thiazolopyridin l, imidazolyl, thiazolyl, or triazolyl optionally substituted with methyl or amino.
[00135] In particular, Rz is pyridazinyl optionally substituted with hydroxyl, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
[00136] In particular, Rz is thienyl or furanyl optionally substituted with methyl.
[00137] In another embodiment, Rz is bromo, chloro, or fluoro.
[00138] In another embodiment of the compound of formula IB-3 or IB-4, Rz is NR3R4, wherein R3 and R are each independently (Ci-C6)alkyl optionally substituted with one , two, or three groups selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci- C6)alkyl, (C,-C6)haloalkoxy, (C,-C6)alkylene-NH2, (C|-C6)alkylene-NH(C,-C6)alkyl, (C,- C6)aikylene-NH(Ci-C6)haloalkyl, (C,-C6)alkylene-N(C|-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (Ci-C6)alkylene-OH, (C,-C6)alkylene-(C,-C6)alkoxy, NHid-CeialkyleneNH;,, NH(C,- C6)alkylene-NH(C,-C6)alkyl, NH(Ci-C6)alkyleneN((C ,-C6)alkyl)2, NH(C,-C6)alkylene- cyloalkyl, NH(C, -C6)alkylene-heterocyloalkyl, N((CrC6)alkyl)2, (C,-C6)alkylene-NHS02- (C,-C6)alkyl, (C,-C6)alkylene-NH(C=0)-(Ci-C6)alkyl, (C=0)-(CrC6)alkyl, S(0)-(C,- C6)alkyl, S02-(Ci-C6)aIkyl, (C4-C7)heterocycloaIkyl, (C,-C6)alky[ene-(C3- C7)heterocycloalkyl, nitro, (Ci-C6)alkylene-CN, (CrCeialkylene-OCtOMCi-CeJalkyl,
Figure imgf000029_0001
or S02-NRcRd, wherein Rc and Rd are each independently are H, (C|-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)cycloalkyl, (C|-C6)alkylene-(C3-C7)heterocycloalkyl, (d-C6)alkylene-NH2, (C
C6)alkylene-NH(CrC6)alkyl), or (Ci -C6)alkylene-N(C|-C6)aIkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)alkyl, N((C|-C6)alkyl)2, OH, (C,-C6)alkyl, (Ci-C6)alkoxy, or (C,-C6)haloalkoxy.
[00139] In particular, Rz is NR3 4, R3 is H, and R4 is methyl, ethyl, propyl, butyl, pentyl, CH2CH2-OCH3, or (C=0)-CH2-OH.
[00140] In another embodiment of the compound of formula IB-3 or IB-4, Rz is NR3R4, wherein R3 and R4 together with the atoms to which they are attached form a 3- to 7- membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (C|-C6)alkyl, (C|-C6)alkoxy, halo(Ci-C6)alkyl, (Ci-C6)haloalkoxy, (Q- C6)alkylene-NH2, (Ci-C6)alkylene-NH(C,-C6)alkyl, (Ci-C6)alkylene-NH(Ci-C6)haloalkyl, (C,-C6)alkylene-N(C, -C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,-C6)alkylene-OH, (C
C6)alkylene-(Ci-C6)alkoxy, NH(C,-C6)alkyleneNH2, NH(C, -C6)alkylene-NH(C|-C6)alkyl, NH(C , -C6)alkyleneN((C i -C6)alky l)2, NH(C, -C6)alkylene-cyloalkyl, NH(C , -C6)alky lene- heterocyloalkyl, N((Ci-C6)alkyl)2, (Ci-C6)alkylene-NHS02-(Ci-C6)alkyl, (C|-C6)alkylene- NH(C=0)-(C,-C6)alkyl, (C=0)-(CrC6)alkyl, S(0)-(C,-C6)alkyl, S02-(C C6)alkyl, (C4- C7)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci-C6)alkylene-CN, (C|-C6)alkylene-OC(0)-(Ci-C6)alkyl, (C=0)-NReRf, or S02-NReRf, wherein Re and Rf are each independently H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)cycloalkyl, (C|-C6)alkylene-(C3- C7)heterocycloalkyl, (C |-C6)alkylene-NH2,
Figure imgf000030_0001
or (C,- C6)alkylene-N(C |-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C]-C6)alkyl)2, OH, (Ci-C6)alkyl, (C|-C6)alkoxy, or (C|-C6)haloalkoxy.
[00141] In a particular embodiment, Rz is
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000031_0001
[00143] In some embodiments, R¾ is methyl.
[00144] In another embodiment, the compound of formula I is a compound of formula IC:
Figure imgf000031_0002
IC
wherein R6c is halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(C|-Ce)alkyl, (C|- C6)haloalkoxy, (C|-C6)alkylene-NH2, (C|-C6)alkylene-NH(Ci-C6)alkyl, (C,-C6)alkylene- NH(C,-C6)haloalkyI, (C|-C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (Ct- C6)alkylene-OH, (C, -C6)alkylene-(C,-C6)alkoxy, NH(C,-C6)alkylene-NH2, NH(C,- C6)alkylene-NH(Cl-C6)alkyl, NH(C,-C6)alkyleneN((C,-C6)alkyl)2, NH(d-C6)alkylene-(C3- C7)cy loalkyl, NH(C , -C6)alky lene-(C3-C7)heterocyloalkyl, N((C , -C6)alky l)(C , -C6)alkylene- (C3-C7)cyloalkyl, N((C, -C6)alkyl)(C,-C6)alkylene-(C3-C7)heterocyloalkyl, N((C,-C6)alkyl)2) (C , -C6)alkylene-NHS02-(C , -C6)alky 1, (C , -C6)alky lene-NH(C=0)-(C , -C6)alkyl, (C=0)-(C r C6)alkyl, S(0)-(Ci-C6)alkyl, S02-(C C6)alkyl, aryl, hetreroaryl, (C3-C7)cycloalkyl, (C3- C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci-C6)alkylene-CN, (Ci-C6)alkylene-0C(0)-(C|-C6)alkyl, (C=0)-NRaRb, or S02-NRaRb, wherein Ra and Rb are each independently H, (d-CeJalkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)cycloalkyl, (C|-C6)alkylene-(C3- C7)heterocycloalkyl, (C,-C6)alkylene-NH2, (C,-C6)alkylene-NH(C|-C6)alkyl), or (C C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)alkyl, N((C,-C6)alkyl)2, OH, (Ci-C6)alkyl, (Ci-C6)alkoxy, or (C|-C6)haloalkoxy; and
Rz is as previously defined in any of the other embodiments. [00145] In a particular embodiment of the compound of formula IC, Xi is N.
[00146] In this and other embodiments, Rz is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
[00147] In particular, Rz is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
[00148] In particular, Rz is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
[00149] In particular, Rz is isoxazolyl, pyrimidinyl, indazolyl optionally substituted with amino or methyl.
[00150] In particular, Rz is pyridinyl optionally substituted with fluoro, chloro, amino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, or (C=0)- NHMe.
[00151] In particular Rz is benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, or triazolyl optionally substituted with methyl or amino.
[00152] In particular, Rz is pyridazinyl optionally substituted with hydroxyl, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
[00153] In particular, Rz is thienyl or furanyl optionally substituted with methyl.
[00154] In another embodiment, Rz is bromo, chloro, or fluoro.
[00155] In another embodiment, Rz is NR3R4, wherein R3 and R4 are each independently (C| -C6)alkyl optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(C|-C6)alkyl, (d-C6)haloalkoxy, (Cr C6)al ky lene-NH2, (C , -C6)alky lene-NH(C , -C6)al ky I, (C , -C6)alky lene-NH(C , -C6)haloalky I, (C,-C6)alkylene-N(Ci-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,-C6)alkylene-OH, (C
C6)alky lene-(C, -C6)alkoxy, NH(C , -C6)alky leneNH2, NH(C , -C6)alkylene-NH(C , -C6)alkyl, NH(C , -C6)alkyleneN((C 1 -C6)alky l)2, NH(C , -C6)alkylene-cyloalkyl, NH(C| -C6)alkylene- heterocyloalkyl, N((C,-C6)alkyl)2, (Ci-C6)alkylene-NHS02-(C,-C6)alkyl, (d-C6)aIkylene- NH(C=0)-(C,-C6)alkyl, (C=0)-(C,-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(C,-C6)alkyl, -(C4- C7)heterocycloalkyl, (Ci -C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci-C6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(C|-C6)alkyl, (C=0)-NRcRd, or SO NRcR^, wherein Rc and Rj are each independently are H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloaIkyl, (C3- C6)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)cycloalkyl, (C|-C6)alkylene-(C3- C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (C,-C6)alkylene-NH(C,-C6)alkyl), (Cr
C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C C6)alkyl, N((Ci-C6)alkyl)2, OH, (CrC6)alkyl, (C]-C6)alkoxy, or (C|-C6)haloalkoxy.
[00156] In particular, when Rz is NR3R4, wherein R3 is H and R4 is methyl, ethyl, propyl, butyl, pentyl, CH2CH2-OCH3, or (C=0)-CH2-OH.
[00157] In another embodiment, R2 is NR3R4, wherein R3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci- C6)alkyl, (C,-C6)haloalkoxy, (C,-C6)alkylene-NH2, (C|-C6)alkylene-NH(C|-C6)alkyl, (Cr C6)alkylene-NH(Ci-C6)haloalkyl, (Ci-C6)alkylene-N(Ci-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,-C6)alkylene-OH, (C,-C6)alkylene-(Ci-C6)alkoxy, NH(C|-C6)alkyleneNH2, NH(C
C6)alkylene-NH(C , -C6)alky I, N H(C , -C6)alky leneN((C, -C6)alky l)2, NH(C , -C6)alkylene- cyloalkyl, NH(C C6)alkylene-heterocyloalkyl, N((Ci-C6)alkyl)2, (C C6)alkylene-NHS02- (C,-C6)alkyl, (Ci-C6)alkylene-NH(C=0)-(C|-C6)alkyl, (C=0)-(C,-C6)alkyl, S(0)-(C,- C6)alkyl, S02-(C,-C6)alkyl, -(C4-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)heterocycloalkyl, nitro, (C,-C6)alkylene-CN, (C|-C6)alkylene-0C(0)-(C|-C6)alkyl,
(C=0)-NReRf, or S02-NReRf, wherein Re and Rf are each independently H, (CrC6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)cycloalkyl, (C|-C6)alkylene-(C3-C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (Ct- C6)alkylene-NH(CrC6)alkyl), (Ci-C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)alkyl, N((C,-C6)alkyl)2, OH, (C, -C6)alkyl, (C,-C6)alkoxy, or (C,-C6)haloalkoxy.
[00158] In a particular embodiment, Rz is
Figure imgf000033_0001
[00159] In another embodiment, the compound of formula I is a compound listed in Table
Table 1
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
CMPD STRUCTURE NAME
34 o 0 2-[6-(2-aminopyrimidin-5-yl)-
V 8-methylquinazolin-4-yl]-N- methy l-N-(piperidin-4- ylmethy 1)- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
35 0 l -[(2-{6-[5-fluoro-6- (methyloxy)pyridin-3-yl]-8- methylquinazolin-4-yl}- 1 ,2,3,4-tetrahydroisoquinolin- 7-yl)carbonyl]piperidin-4-
Γ T amine
36 0 4-{7-[(4-aminopiperidin-l- yl)carbonyl]-3,4- dihydroisoquinolin-2(l H)-yl}-
8-methyl-N-[2-
N (methyloxy)ethyl]quinazolin- 6-amine
37 0 1 -( {2-[8-methyl-6-(2-methyl-
1 H-benzimidazol-5-
Η;ΝΧ Ν ICL yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7- y 1 } carbony l)piperidin-4-am ine
38 2-[6-(2- amino[l,3]thiazolo[5,4- b]pyridin-6-yl)-8- methylquinazolin-4-yl]-N- methyl-N-(piperidin-4- ylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
CMPD STRUCTURE NAME
69 ° o N-methyl-2-(8-methyl-6- pyridin-3-ylquinazolin-4-yl)- N-(piperidin-4-ylmethyl)-
1,2,3,4- tetrahydroisoquinoline-7- sulfonamide
70 2-[6-(3,5-dimethylisoxazol-4- yl)-8-methylquinazolin-4-yl]- N-methyl-N-(piperidin-4- ylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
71 5 -(4- { 7-[(4-aminopiperidin- 1 - yl)carbonyl]-3,4- dihydroisoquinolin-2(l H)-yl}- 8-methylquinazoIin-6- yl)pyridin-2 -amine
72 l-[(2-{8-methyl-6-[6- (methyloxy)pyridin-3- y l]quinazolin-4-yl} - 1 ,2,3,4- tetrahydroisoquinoIin-7- yl)carbonyl]piperidin-4-amine
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
CMPD STRUCTURE Γ ΑΜΕ
81 4-[4-(l H-benzimidazol-2- yl)piperazin-l-yl]-6-bromo-8- methylquinazoline
82 4-[4-( 1 H-benzimidazol-2- yl)piperazin-l-yl]-6-(3,3- difluoropyrrolidin-1 -yl)-8- methylquinazoline
Figure imgf000051_0001
83 N-methyl-N-[(l - methylpiperidin-4-yl)methyl]- 2-(8-methyl-6-pyridin-4- ylquinazolin-4-yl)-l , 2,3,4- tetrahydroisoquinoline-7- sulfonamide
84 N-methyl-N-[(l- methylpiperidin-4-yl)methyl]- 2-[8-methyl-6-(l ,3-thiazol-2- y l)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide CMFD STRUCTURE
85 5 -(4- { 7-[(4-aminopiperidin- 1 - yl)carbonyl]-3,4- dihydroisoquinolin-2(l H)-yl}- 8-methylquinazolin-6- yl)pyridin-3 -amine
86 0 o N-methyl-N-[(l - methylpiperidin-4-yl)methyl]- 2-(8-methyl-6-pyridazin-3- ylquinazolin-4-yl)-l,2,3,4- tetrahydroisoquinoline-7- sulfonamide
Figure imgf000052_0001
87 N-methyI-N-[(l- methylpiperidin-4-yl)methyl]- 2-(8-methyl-6-pyridin-3- ylquinazolin-4-yl)-l , 2,3,4- tetrahydroisoquinoIine-7- sulfonamide
88 N-methyl-N-[(l- methylpiperidin-4-yl)methyl]- 2-[8-methyl-6-(l H-pyrazol-4- yl)quinazolin-4-ylj- 1 ,2,3,4- tetrahydroisoquinoline-7-
1 L NH sulfonamide
89 N-methyl-N-[(l - methylpiperidin-4-yl)methyl]- 2-(8-methyl-6-pyrimidin-5- yIquinazoIin-4-yI)-l , 2,3,4- tetrahydroisoquinoline-7- sulfonamide CMPD STRUCTURE I AME
90 l -({2-[8-methyl-6-(5- methylpyridin-3- yl)quinazolin-4-yl]- 1,2,3,4- tetrahydroisoquinolin-7- y 1 } carbony Opiperid in-4-am ine
Figure imgf000053_0001
91 2-[6-(l ,5-dimethyl-lH- pyrazol-4-yl)-8- methylquinazolin-4-yl]-N- methyl-N-(piperidin-4- ylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
92 2-[6-( l ,5-dimethyl-l H- pyrazol-4-yl)-8- methylquinazolin-4-yl]-N- methyl-N-[( 1 -methy Ipiperidin- 4-yl)methyl]- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
93 N-methyl-N-[(l - methylpiperidin-4-yl)methyl]- 2-[8-methyl-6-( 1 ,3-thiazol-5- yl)quinazolin-4-yl]-l,2,3,4- tetrahydroisoquinoline-7- sulfonamide
Figure imgf000053_0002
CMPD STRUCTURE NAME
94 0 o 2-[6-(4-fluoro-3- hydroxyphenyl)-8- methylquinazolin-4-yl]-N- methyl-N-(piperidin-4- ylmethy 1)- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
95 N-methyl-2-{8-methyl-6-[3- (trifluoromethyl)phenyl]quina zolin-4-yl}-N-(piperidin-4- ylmethyl)- 1 ,2,3,4- tetrahydroisoqu ino 1 ine-7- sulfonamide
96 0 O N-methyl-2-(8-methyl-6-{3- [(trifluoromethyl)oxy]phenyl} quinazolin-4-yl)-N-(piperidin- 4-ylmethyl)- 1 ,2,3,4- tetrahydro isoquinol ine-7- sulfonamide
97 N-methyl-3-{8-methyl-4-[7-
{ [methyl(piperidin-4- y lmethyl)amino]sulfonyl } -3,4- dihydroisoquinolin-2(l H)- yl]quinazolin-6-yl}benzamide
98 N-methyl-2-{8-methyl-6-[6- (trifluoromethyl)pyridin-3- y l]quinazolin-4-yl } -N- (piperidin-4-ylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
vy CMPD STRUCTURE NAME
99 V N-methy 1-2- { 8-methyl-6-[5- (trifluoromethyl)pyridin-3- yl]quinazolin-4-yl}-N- (piperidin-4-ylmethyl)-l,2,3,4- tetrahydro i soquinol ine-7- sulfonamide
100 O 0 N-methy 1-2- [8-(methyloxy)-6- (2-methylpyridin-4- yI)quinazolin-4-yl]-N- (piperidin-4-ylmethyl)-l ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
101 l-{ l -[6-(3,3- difluoropyrrolidin-1 -yl)-8- methylquinazolin-4- yI]piperidin-4-yl}-l ,3- dihydro-2H-imidazo[4,5- b]pyridin-2-one
102 H 1 - { 1 -[8-methyl-6-( 1 ,3-thiazol- 2-yl)quinazolin-4-yl]piperidin-
4-yl}-l ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one
CMPD STRUCTURE NAME
103 N-methyl-N-[(l - methylpiperidin-4-yl)methyl]- 2-[8-methyl-6-( 1 ,3-thiazol-5- yl)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinoline-7-
I _ I carboxamide
N
104 N-methyl-2-[8-methyl-6-(5- methylpyridin-3- yl)quinazolin-4-yl]-N-[(l- methylpiperidin-4-yl)methyl]- 1 ,2,3,4- tetrahydroisoquinoline-7- carboxamide
105 2-[6-(5-fluoropyridin-3-yl)-8- methylquinazolin-4-yl]-N- methyl-N-[(l -methylpiperidin- 4-yl)methyl]-l,2,3,4- tetrahydroisoquinoline-7- carboxamide
106 N-{[ l -(6-bromo-8- methylquinazolin-4- yl)piperidin-4- yl]methyl}benzenesulfonamid e
Figure imgf000057_0001
CMPD STRUCTURE NAME
111 o° 2-(8-methyI-6-pyridin-3- ylquinazolin-4-yl)- 1,2,3,4- tetrahydroisoquinoline-7- sulfonamide
112 N-({l-[6-(3,3- difluoropyrrolidin- 1 -y l)-8- methylquinazolin-4- yl]piperidin-4- y 1 } methy I)benzenesulfonam id e
113 00 l-{[2-(8-methyl-6-pyridin-3- s'' ylquinazolin-4-yl)- 1,2,3,4- tetrahydroisoquinolin-7- yl]suIfonyl}piperidin-4-amine
114 2-(8-methyl-6-pyridin-3- ylquinazolin-4-yl)- 1,2,3,4- tetrahydroisoquinoline-7- carboxylic acid
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
CMPD STRUCTURE NAME
129 H N-({ l -[6-(3,3- difluoropyrrolidin-l-yl)-8- methylquinazolin-4- yl]piperidin-4- y 1 } methy l)methanesulfonam id e
130 N-(2-fluoroethyl)-l -{[2-(8- methyl-6-pyridin-3- ylquinazolin-4-yl)-l , 2,3,4- tetrahydroisoquinolin-7- yl]sulfonyl}piperidin-4-amine
Figure imgf000062_0001
131 8-methyl-6-[6- (methyloxy)pyridin-3-yl]-4-[7- (pyrrolidin- 1 -ylcarbonyl)-3,4- dihydroisoquinolin-2( 1 H)- yl]quinazoline
132 8-methyl-6-(l H-pyrazol-4-yl)- 4-[7-(pyrrolidin- 1 -ylcarbonyl)- 3,4-dihydroisoquinolin-2(lH)- yl]quinazoline
Figure imgf000063_0001
CMPD STRUCTURE NAME
137 F N-(2-fluoroethyl)-l-[(2-{8- methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7- yl)sulfonyl]piperidin-4-amine
138 N-(2-fluoroethyl)-l-[(2-{8- methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7- yl)carbonyl]piperidin-4-amine
139 N,N,8-trimethyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-amine
140 N-methyl-N-[2-(8-methyl-6- pyridin-3-ylquinazolin-4-yl)- 1 ,2,3,4-tetrahydroisoquinolin- 7-yl]acetamide
Figure imgf000064_0001
141 N-methyl-N-[2-(8-methyl-6- pyridin-3-ylquinazolin-4-yl)- 1 ,2,3,4-tetrahydroisoquinolin- 7-yl]methanesulfonamide STRUCTURE 1 AME
142 2-[2-(8-methyl-6-pyridin-3- ylquinazolin-4-yl)- 1 ,2,3,4- tetrahydroisoquinolin-7- yl]propan-2-ol
Figure imgf000065_0001
143 8-methy l-4-[7-(pyrrol idin- 1 - ylcarbonyl)-3,4-
GNXTQ dihydroisoquinolin-2(l H)-yl]- 6-( 1 ,3-thiazol-5-yl)quinazoline
144 5 - { 8-methy l-4-[7-(pyrrolidin- l -ylcarbonyl)-3,4-
CN dihydroisoquinolin-2(l H)- yl]quinazolin-6-yl}pyrimidin- 2-amine
Figure imgf000065_0002
145 6-[5-fluoro-6- (methyloxy)pyridin-3-yl]-8- methy I-4-[7-(pyrrolidin- 1 - ylcarbonyl)-3,4- dihydroisoquinolin-2(lH)- yl]quinazoline
Figure imgf000066_0001
CMPD STRUCTURE NAME
1 50 N- { [ 1 -(8-methyl-6-pyridin-3- ylquinazolin-4-yl)piperidin-4- y l]methy 1 } benzam ide
151 H N-[(l-{8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}piperidin- 4- yl)methyl]methanesulfonamid e
152 N-[(l -{8-methyl-6-[6- (methy loxy)pyrid in-3 - yl]quinazolin-4-yl}piperidin- 4- yl)methyl]benzenesulfonamide
153 o 0 l -{ [2-(8-fluoro-6-pyridin-3- s ylquinazolin-4-yl)- 1 ,2,3,4- tetrahydroisoquinolin-7-
H;N ' XX yl]sulfonyl}piperidin-4-amine
F
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
CMPD STRUCTURE NAME
192 o N-(cyclopropy lmethyl)- 1 -[(2- {8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7- yl)carbonyI]piperidin-4-amine
193 N-{2-[8-methyl-6-(l H- pyrazol-4-yl)quinazolin-4-yl]- 1 ,2,3,4-tetrahydroisoquinolin-
7-y 1 } -5 -oxoprol inamide
194 l -amino-N-{2-[8-methyl-6- (l H-pyrazol-4-yl)quinazolin- 4-yl]-l ,2,3,4- tetrahydroisoquinolin-7- y 1 } cyclopropanecarboxam ide
195 N-[2-(3,3-difluoropyrrolidin- 1 -yl)ethyl]-2-{8-methyI-6-[6-
(methyloxy)pyridin-3- yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinol ίη-7-am ine
196 0 N-(2,2-difluoroethyI)-l -[(2- {8-methyl-6-[6- (methyloxy)pyridin-3- y l]quinazolin-4-y 1}- 1 ,2,3,4- tetrahydroisoquinolin-7- yI)carbonyl]piperidin-4-amine CMPD STRUCTURE NAME
197 8-methyl-6-[6- (methyloxy)pyridazin-3-yl]-4- { -[(4-methy lpiperazin- 1 - yl)carbonyl]-3,4- dihydroisoquinolin-2( 1 H)- yl}quinazoline
198 phenylmethyl {[(3S)- l -{8- methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}piperidin- 3-yl]methyl}carbamate
Figure imgf000077_0001
199 l -[(3S)-l -{8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}piperidin- 3 hanamine " T -yl]met
200 3-chloro-N- { [ 1 -(8-methy 1-6- pyridin-3-ylquinazolin-4- yl)piperidin-4- y IJmethyl} benzenesulfonamid e
CMPD STRUCTURE NAME
201 l -methyl-3-{[(3S)-l-{8- methyl-6-[6- (methy loxy)pyridin-3 - yl]quinazolin-4-yl}piperidin- 3-yl]methyl}urea
202 2- methyl-N-{[(3S)-l -{8- methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}piperidin-
3- yl]methyl}alaninamide
Figure imgf000078_0001
203 6-[6-(ethyloxy)pyridin-3-yl]- 8-methyI-4-{7-[(4- methy lpiperazin- 1 - yl)carbonyl]-3,4- dihydroisoquinolin-2( 1 H)- yl}quinazoline
204 N-[3-chloro-4- (methy loxy)pheny l]-4- { 8- methyl-6-[6- (methyloxy)pyridin-3- fNT°" yl]quinazolin-4-yl}piperazine- 1 -carboxamide
205 N,N-diethyl-N'-(2-{8-methyl- 6-[6-(methyloxy)pyridazin-3- yl]quinazolin-4-yl}- 1 ,2,3,4- tetrahydroisoquinolin-7- yl)ethane-l ,2-diamine
Figure imgf000078_0002
CMPD STRUCTURE NAME
206 N-(2-fluoroethyl)-2-{8- methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-N- piperidin-4-yl-l , 2,3,4- tetrahydroisoquinoline-7- carboxamide
Figure imgf000079_0001
207 0 8-methyl-4-[7-{[4-(l- methy lethy l)p iperazin- 1 - yl]carbonyl} -3,4- dihydroisoquinolin-2(l H)-yl]- 6-[6-(methyloxy)pyridin-3- yl]quinazoline
208 4-[7-{[(3R)-3,4- dimethylpiperazin-1 - yl]carbonyl}-3,4- dihydroisoquinolin-2(l H)-yl]- ι 8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazoline
209 4-[7-{[(3S)-3,4- dimethylpiperazin-1- yl]carbonyl}-3,4- dihydroisoquinolin-2(l H)-yl]- 8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazoline
210 8-methyl-6-[6- (m ethy loxy)py rid i n-3 -y 1] -4- [7- (piperazin-l -ylcarbonyl)-3,4- dihydroisoquinolin-2(l H)- yl]quinazoline
Figure imgf000079_0002
CMPD STRUCTURE NAME
21 1 N,N-diethyl-N'-{2-[8-methyI-
6-(l H-pyrazol-5- yl)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7- yl} ethane- 1 ,2-diamine
212 N,N-diethyl-N'-[2-(6- isothiazol-4-yl-8- methylquinazolin-4-yl)- 1 ,2,3,4-tetrahydroisoquinolin- 7-yl]ethane-l ,2-diamine
213 2-methyl-N-(2-{8-methyl-6- [6-(methy loxy)pyrid in-3 - yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7- yl)alaninamide
Figure imgf000080_0001
214 2-methyl-N-{2-[8-methyl-6- ( 1 -methyl- 1 H-pyrazol-4- yl)quinazolin-4-yl]-l, 2,3,4- tetrahydroisoquinolin-7- yljalaninamide
215 N,N-diethyl-N'-[2-(8-methyl- 6-pyridin-4-ylquinazolin-4- yl)-l , 2,3,4- tetrahydroisoquinolin-7- y ljethane- 1 ,2-diam ine
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
CMPD STRUCTURE NAME
234 1 -amino-N-{2-[8-methy!-6-(5- methy 1- 1 H-pyrazol-4- yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7- y 1 } cyclopentanecarboxamide
235 N-[2-(6-isoxazol-4-yl-8- methylquinazolin-4-yl)- 1 ,2,3,4-tetrahydroisoquinolin- 7-yl]-2-methylalaninamide
236 2-methyl-N-{2-[8-methyl-6- ( 1 -methyl- 1 H-pyrazol-5- yI)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7- yl}alaninamide
Figure imgf000085_0001
237 2-methy l-N-(2- { 8-methyl-6- [6-(methyloxy)pyridazin-3- yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7- yl)alaninamide
238 l -{ [2-(6-bromo-8- methylquinazolin-4-yl)- 1 ,2,3,4-tetrahydroisoquinolin-
7-yl]carbonyl}-N-(2- fluoroethyl)piperidin-4-amine
Figure imgf000085_0002
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
CMPD STRUCTURE NAME
259 0 4-[7-{[4-(3,3- difluoropyrrolidin-1 - yl)piperidin-l -yl]carbonyl}- 3,4-dihydroisoquinolin-2( 1 H)- yl]-8-methyl-6-[6-
Γ li (methyloxy)pyridin-3- yl]quinazoline
260 (3R)-N-(2-{8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7- yl)pyrrolidine-3-carboxamide
261 N-(2-fluoroethyI)-l -({2-[8- methyl-6-(6-methylpyridazin- 3-yl)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7- yl}carbonyl)piperidin-4-amine
262 N-(2-fluoroethyl)-l -({2-[8- methyl-6-(5-methylpyridazin- 3-yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7- yl}carbonyl)piperidin-4-amine
263 2-{8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-N-(2- morpholin-4-ylethyl)-l, 2,3,4- tetrahydroisoquinolin-7-amine
Figure imgf000090_0001
CMPD STRUCTURE NAME
264 (2S)-N-(2-{8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7- yl)piperidine-2-carboxamide
265 2-{8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7-amine
266 2-{8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7-amine
Figure imgf000091_0001
267 N-(2-fluoroethyl)-l-{[2-(8- methyl-6-pyridazin-3- ylquinazolin-4-yl)-l,2,3,4- tetrahydroisoquinolin-7- y l]carbonyl } piperidin-4-am ine
268 0 l -({2-[6-(6-chloropyridazin-3- yl)-8-methylquinazolin-4-yl]- 1 ,2,3,4-tetrahydroisoquinolin-
7-y 1 } carbony l)-N-(2- fluoroethyl)piperidin-4-amine CMPD STRUCTURE NAME
269 N-(2-fluoroethy 1)- 1 - { [2-(8- methyl-6-pyrimidin-5- ylquinazolin-4-yl)-l , 2,3,4- tetrahydroisoquinolin-7- y ljcarbonyl } piperidin-4-amine
270 N,N-diethyl-N'-[2-(8-methyl- 6-pyrazin-2-ylquinazolin-4- yO-1 ,2,3,4- tetrahydroisoquinolin-7- yl]ethane- 1 ,2-diamine
271 N,N-diethyl-N'-{2-[8-methyl-
6-(l H-pyrazol-4- yl)quinazolin-4-yl]- 1,2,3,4- tetrahydroisoquinolin-7- yl} ethane- 1 ,2-diamine
272 2-{8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-N- (piperidin-3-ylmethyl)- 1 ,2,3,4- tetrahydroisoquinolin-7-amine
273 0 N-(cyclopropy lmethyl)- 1 -[(2- {8-methyl-6-[5- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7- yl)carbonyl]piperidin-4-amine CMPD STRUCTURE NAME
274 H 2-{8-methyl-6-[6- (methyIoxy)pyridin-3- yl]quinazolin-4-yl}-N- (piperidin-3-ylmethyl)- 1 ,2,3,4- tetrahydroisoquinolin-7-amine
275 H N-({ l -[6-(3-chloropyridin-4- yl)-8-methylquinazoIin-4- c o l yl]piperidin-4- yl}methyl)methanesulfonamid e
276 N,N-diethyl-N'-[2-(8-methyl- 6-pyridazin-3-ylquinazolin-4- yl)- 1,2,3,4- tetrahydroisoquinolin-7-
N Λ yl]ethane- 1 ,2-diamine
277 2-(8-methyl-6-pyridazin-3- ylquinazolin-4-yl)-N-(2- morpholin-4-ylethyl)- 1 ,2,3,4- tetrahydroisoquinolin-7-amine
Figure imgf000093_0001
278 2-(8-methyl-6-pyrazin-2- ylquinazolin-4-yl)-N-(2- morpholin-4-ylethyl)- 1 ,2,3,4- tetrahydroisoquinolin-7-amine CMPD STRUCTURE NAME
279 N-(2-{8-methyl-6-[6- (methy loxy)pyridazin-3 - yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7- yl)acetamide
280 N-(2-fluoroethy 1)- 1 - { [2-(8- methyl-6-pyridazin-4- ylquinazolin-4-y 1)- 1 ,2,3,4- tetrahydroisoquinolin-7- yl]carbonyl}piperidin-4-amine
Figure imgf000094_0001
281 0 N-(2,2-difluoroethyl)-l -[(2- {8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-l ,2,3,4- tetrahydroisoquinolin-7- yl)carbonyl]piperidin-4-amine
282 N-ethy 1-2- { 8-methy l-6-[6- (methyloxy)pyridazin-3 - yl]quinazolin-4-yl}-N-(l- methylpiperidin-4-yl)- 1 ,2,3,4- tetrahydroisoquinoline-7- carboxamide
Figure imgf000094_0002
283 2-(8-methyl-6-pyridazin-4- ylquinazolin-4-yl)-N-(2- morpholin-4-ylethy 1)- 1 ,2,3,4- tetrahydroisoquinolin-7-amine CMPD STRUCTURE NAME
284 2-{8-methyl-6-[6- (methy loxy)pyridazin-3- yl]quinazolin-4-yl}-N- (piperidin-4-ylmethyl)- 1 ,2,3,4- tetrahydroisoquinolin-7-amine
285 2-{8-methyl-6-[6- (methy loxy)pyridazin-3 - yl]quinazolin-4-yl}-N- (piperidin-2-ylmethyl)-l,2,3,4- tetrahydroisoquinolin-7-amine
Figure imgf000095_0001
286 2-{8-methyl-6-[5- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-N-(2- morphol in-4-ylethy 1)- 1 ,2,3 ,4-
Γ ll tetrahydroisoquinolin-7-amine
287 1 , 1 -dimethylethyl (3R)-3-{ [(2- {8-methyl-6-[6- (methy loxy)pyridazin-3 - yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7- yl)carbonyl]amino}piperidine- 1 -carboxylate
288 2-{8-methyl-6-[6- (methy loxy)pyridazin-3 - yl]quinazolin-4-yl}-N-[(3R)- piperidin-3-yl]-l , 2,3,4- tetrahydroisoquinoline-7- carboxamide CMPD STRUCTURE NAME
289 1 , 1 -dimethylethyl (3R)-3-{[(2- {8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl} -1 ,2,3,4- tetrahydroisoquinolin-7- T yl)carbonyl]amino}piperidine- 1-carboxylate
290 2-{8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-N-[(3R)- piperidin-3-yl]- 1 ,2,3,4- tetrahydroisoquinoline-7- carboxamide
Figure imgf000096_0001
291 2-{8-methyl-6-[6- (methyloxy)pyrimidin-4- yl]quinazolin-4-yl}-N-(2- morpholin-4-ylethyl)- 1 ,2,3,4- tetrahydroisoquinolin-7-amine
292 l -[(2-{6-[3,4- bis(methyloxy)phenyl]-8- methyIquinazolin-4-yl}- 1 ,2,3,4-tetrahydroisoquinolin-
7-yl)carbonyl]-N- (cyclopropylmethyl)piperidin- 4-amine
293 4-[7-{[4-(3,3- difluoropyrrolidin-1- yl)piperidin-l -yl]carbonyl}- 3,4-dihydroisoquinolin-2(l H)- yl]-8-methyI-6-[6- (methyloxy)pyridazin-3- yl]quinazoline
Figure imgf000097_0001
Figure imgf000098_0001
CMPD STRUCTURE NAME
304 2-[6-(5-amino-6- chloropyridin-3-yl)-8-
HM¾ methy lquinazolin-4-y 1] -N- [(3R)-piperidin-3-yl]-l , 2,3,4- tetrahydroisoquinoline-7- carboxamide
305 2-{8-methyl-6-[6- (methyloxy)pyridin-3- yl]quinazolin-4-yl}-N-[(3S)- piperidin-3-yl]- 1 ,2,3,4- tetrahydroisoquinoline-7- carboxamide
Figure imgf000099_0001
306 2-{8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-N-[(3S)- piperidin-3-yl]-l,2,3,4- tetrahydroisoquinoline-7- carboxamide
307 2-[8-methyl-6-( 1 H-pyrazol-4- yl)quinazolin-4-yl]-N-[(3S)- piperidin-3-yl]-l ,2,3,4- tetrahydroisoquinoline-7- carboxamide
308 2-{8-methyl-6-[2- (methyloxy)pyridin-4- yl]quinazolin-4-yl}-N-[(3S)- piperidin-3-yl]-l ,2,3,4- tetrahydroisoquinoline-7- carboxamide
Figure imgf000099_0002
CMPD STRUCTURE NAME
309 0 l -[(2-{8-methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7- yl)carbonyl]-N-[2- (methyloxy)ethyl]piperidin-4- amine
3 10 (3S,4S)-3-fluoro-l-[(2-{8- methyl-6-[6- (methyloxy)pyridazin-3- yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7- yl)carbonyl]piperidin-4-amine
31 1 (3R,4S)-3-fluoro- l -[(2-{8- methyl-6-[6- (methy loxy)pyridazin-3 - yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinol in-7- yl)carbonyl]piperidin-4-amine
312 (3R,4S)-3-fluoro-l-[(2-{8- methyl-6-[6- (methy loxy)pyridazin-3 - yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7- yI)carbonyl]piperidin-4-ol
3 13 N-methyl-2-[8-methyl-6-( 1 H- pyrazol-5-yl)quinolin-4-yl]-N- (piperidin-4-ylmethyl)-l, 2,3,4- tetrahydroisoquinoline-7- sulfonamide
Figure imgf000100_0001
CMPD NAME
2-[6-(3,3-difluoropyrrolidin-l- yl)-8-methylquinolin-4-yl]-N- methyl-N-(piperidin-4- ylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline-7- sulfonamide
[00160] Another embodiment is a pharmaceutical composition comprising a compound of
Formula 1 or a compound in Table 1 or a pharmaceutically acceptable salt thereof admixed with a pharmaceutically acceptable carrier, excipient, and/or diluent.
[00161] Compounds of the invention have activity for PI3 , particularly PI3K-alpha, and may be useful for treating diseases, particularly cancer in which activity against PI3 -alpha contributes to the pathology and/or symptomatology of the disease. For example, cancers in which activity against PI3 -alpha contributes to its pathology and/or symptomatology include breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NP /AL -transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, and head and neck cancer.
[00162] Compounds of the invention may also be used as inhibitors of PI3 in vivo for studying the in vivo role of PI3K in biological processes, including the diseases described herein. Accordingly, the invention also comprises a method of inhibiting P13 in vivo comprising administering a compound or composition of the invention to a mammal.
[00163] Thus, in another embodiment, the invention provides a method of treating a disease, disorder, or syndrome wherein the disease is associated with uncontrolled, abnormal, and/or unwanted cellular activities effected directly or indirectly by PI3K comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula I, or a compound in Table 1 , or a pharmaceutically acceptable salt thereof, and admixed with a pharmaceutically acceptable carrier, excipient, and/or diluent. In one embodiment of embodiment, the disease is cancer. In another embodiment of embodiment, the disease is cancer, and the compound is a compound of formula I or of Table 1. [00164] In another embodiment, the invention provides a method of treating a disease, disorder, or syndrome comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a compound in Table 1 , or a pharmaceutically acceptable salt thereof, and admixed with a pharmaceutically acceptable carrier, excipient, and/or diluent. In another embodiment, the disease is cancer. In another embodiment, the disease is cancer, and the compound is a compound of formula I or of Table 1.
[00165] In another embodiment, the cancer is breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NPM/AL - transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma,
rhabdomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, or head and neck cancer.
[00166] Embodiment 1. A compound of Formula I:
Figure imgf000102_0001
or a pharmaceutically acceptable salt thereof, wherein:
X, and X2 are each independently N, C-H, C-Halo, C-(C|-C6)alkyl, or C-(Ci- C6)alkoxy, C-CN;
X2 is N, C-H, C-Halo, C-(Ci-C6)alkyl, or C-(Ci-C6)alkoxy, C-CN;
Rx and Ry are each independently H, (Ci-Ce)alkyl, halo(C[-C6)alkyl, (C3- C6)cycloalkyI, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3-C6)cycloalkyl, (C|-C6)alkylene- (C3-C6)heterocycloalkyl, (C , -C6)alky lene-(C3-C6)heteroaryl, (C , -C6)alky lene-(C3-C6)aryl, (C C6)haloalkoxy, (Ci-C6)alkylene-NH2, (C|-C6)alkylene-NH(CrC6)alkyl, (C,-C6)alkylene- NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(C,-C6)alkyl)2, (C ,-C6)alkylene-OH, (C,- C6)alky lene-(C , -C6)alkoxy, (C , -C6)alkylene-NHS02-(C , -C6)alky 1, (Ci -C6)alky lene- NH(C=0)-(C,-C6)alkyl, or (C|-C6)alkylene-(C=0)-(C|-C6)alkyl, any of which may be optionally substituted; or Rx and Ry taken together with the atom to which they are attached form a 4-6
membered ring represented by ^^N^^ optionally containing an additional heteroatom selected from NH, N-(C|-C6)alkyl, S, SO, or S02, and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(C] -C6)alkyl, (Ci- C6)haloalkoxy, (CrC6)alkylene-NH2, (C,-C6)alkylene-NH(C,-C6)alkyl, (CrC6)alkylene- NH(C|-C6)haloalkyl, (C|-C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,- C6)alkylene-OH, (C 1-C6)alkylene-(C|-C6)alkoxy, NH(C|-C6)alkylene-NH2, NH(Cr
C6)alky lene-NH(C , -C6)alky 1, N H(C , -C6)alkyleneN((C , -C6)alky 1)2, NH(C , -C6)alkylene-(C3- C7)cyloalkyl, NH(C rC6)alkylene-(C3-C7)heterocyloalkyl, N((C,-C6)alkylene-(C3- C7)heterocycloalkyl)2, N((Ci-C6)alkyl)(C|-C6)alkylene-(C3-C7)cyloalkyl, N((C|-C6)alkyl)(Ci- C6)alky lene-(C3-C7)heterocy loalkyl, N((C i -C6)alkyl)2, (C i -C6)alkylene-NHS02-(C i -C6)alkyl, (C, -C6)alkylene-NH(C=0)-(C,-C6)alkyl, -(C=0)-(C,-C6)alkyl, S(0)-(C ,-C6)alkyl, S02-(C,- C6)alkyl, aryl, hetreroaryl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)heterocycloalkyl, nitro, (C,-C6)alkylene-CN, (C|-C6)alkylene-OC(0)-(C|-C6)alkyl, (C=0)-NRaRb, NH(C=0)-(CrC6)alkylene-NH2, NH(C=0)-(C3-C7)cycloalkylene, NH(C=0)- (C3-C7)heterocycloalky lene, ((C , -C6)alky 1)(C=0)-(C , -C6)alky lene- H2, N((C , - C6)alkyl)(C=0)-(C3-C7)cycloalkylene, N((C|-C6)alkyl)(C=0)-(C3-C7)heterocycloalkylene, NH-S02-NRaRb, or S02-NRaRb, wherein Ra and R are each independently H, (Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C | -C6)alkylene-(C3- C7)cycloalkyl, (Ci -C6)alkylene-(C3-C7)heterocycloalkyl, (C,-C6)alkylene-NH2, (C,- C6)alkylene-NH(Ci -C6)alkyl)s (C|-C5)alkylene-N(C |-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C] -C6)alkyl, NH(C i-C6)alkoxy, NH(C,-C6)haloalkyl, N((C,-C6)alkyl)2, (C=0)-ORa, -OH, (C,-C6)alkyl, (C I -C6)haloalky 1, (C , -C6)alky lene-(C3-C7)cycloalkyl, (C, -C6)alkylene-(C3- C7)heterocycloalkyl optionally substituted with 1 -3 halo, (C3-C7)heterocycloalkyl optionally substituted with 1 -3 halo, (C|-C6)alkoxy, or (Ci-C6)haloalkoxy;
Rz is halo, cyano, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from halo, hydroxy, (Ci-C6)alkyl, (Ci-C6)haloalkyl (C,-C6)alkoxy, halo(C,-C6)alkyl, (C,-C6)haloalkoxy, (C=0)-NH2, NH(C=0)-(Ci-C6)alkyl, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)- N((C,-C6)alkyl)2; or
R2 is NR3R4, wherein R3 and R4 are each independently H or (C|-C6)alkyl optionally substituted with one , two, or three groups selected from halo, hydroxy, cyano, oxo, (C|- Q alkyl, (CrC6)alkoxy, halo(CrC6)alky], (C,-C6)haloalkoxy, S(0)-(C,-C6)alkyl, S02-(C,- C6)alkyl, (Q-Q alkylene-NHs, (C^alkylene-NHCd-Q alkyl, (C,-C6)alkylene-NH(Ci- C6)haloalkyl, (Ci-C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,-C6)alkylene-OH, (C I -C6)alky lene-(C, -C6)alkoxy, NH(C , -C6)alky leneNH2, NH(C , -C6)alkylene-NH(C , - C6)alkyl,
Figure imgf000104_0001
NH(C,-C6)alkylene-cyloalkyl, NH(C
C6)alkylene-heterocyloalkyl, N((C,-C6)alkyl)2, (Ci-C6)alkylene-NHS02-(Ci-C6)alkyl, (C,- C6)alkylene-NH(C=0)-(d-C6)alkyl, (C=0)-(d-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(d- C6)alkyl, (C4-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Cp C6)alkylene-CN, (Ci-C6)alkylene-0C(0)-(C|-C6)alkyl, (C=0)-NRcRd, or S02-NRcRd, wherein Rc and ¾ are each independently are H, (CpC6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)cycloalkyl, (C C6)alkylene-(C3- C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (C|-C6)alkylene-NH(C|-C6)alkyl), or (Cp
C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C, -C6)alkyl)2, OH, (C C6)alkyl, (C(-C6)alkoxy, or (Ci-C6)haloalkoxy.
R3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from H, halo, hydroxy, cyano, oxo, (Ci-C6)alkyl, (C|-C6)alkoxy, halo(Ci-C6)alkyl, (C [-C6)haloalkoxy, (Ci- C6)alkylene-NH2, (C,-C6)alkylene-NH(Ci -C6)alkyl, (C|-C6)alkylene-NH(C|-C6)haloalkyl, (C,-C6)alkylene-N(C ,-C6)alkyl)2, S(0)-(C,-C6)alkyl, S02-(C,-C6)alkyl, NH2, NH(Ct- C6)alkyl, (C C6)alkylene-OH, (C, -C6)alkylene-(Ci-C6)alkoxy, NH(C,-C6)alkyleneNH2, NH(C I -C6)alky lene-NH(C , -C6)alkyl, NH(C , -C6)alkyleneN((C , -C6)alky 1)2, NH(C , - C6)alkylene-cyloalkyl, NH(C |-C6)alkylene-heterocyloalkyl, N((Ct-C6)alkyl)2, (C|- C6)alky lene-NHS02-(C , -C6)alky 1, (C , -C6)alky lene-NH(C=0)-(C , -C6)alkyl, (C=0)-(C , - C6)alkyl, S(0)-(C|-C6)alkyl, S02-(C,-C6)alky], (C -C7)heterocycloalkyl, (C, -C6)alkylene-(C3- C7)heterocycloalkyl, nitro, (C |-C6)alkylene-CN, (C|-C6)alkylene-OC(0)-(Ci-C6)alkyl, (C=0)-NReRf, or S02-NReRr, wherein Re and Rr are each independently H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalk l, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)cycloalkyl, (C| -C6)alkylene-(C3-C7)heterocycloalkyl, (C C6)alkylene-NH2, (C C6)alkylene-NH(Ci-C6)alkyl), or (CpC6)alkylene-N(CpC6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|-C6)alkyl, N((C,-C6)alkyl)2, OH, (Ci-C6)alkyl, (C|-C6)alkoxy, or (CpC6)haloalkoxy; and
R5 is H, halo, (C,-C6)alkyl, halo(C,-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyI, (C2- C6)alkynyl, or (CpC6)alkoxy.
[00167] Embodiment 2. The compound of embodiment 1 , wherein X is N, C-H, C-Halo, or C-(C|-C6)alkyl.
[00168] Embodiment 3. The compound of embodiment 1 -2, wherein X is N or C-H.
[00169] Embodiment 4. The compound of embodiment 1 -3, wherein R5 is (C|-C6)alkyl, halo-(CrC6)alkyl, (C2-C6)alkenyl, halo-(C2-C6)alkenyl, or (CrC6)alkoxy.
[00170] Embodiment 5. The compound of embodiment 1-4, wherein X is N or C-H, and R5 is (CrC6)alkyI.
[00171] Embodiment 6. The compound of embodiment 1 -5, wherein the compound of formula I is a compound of formula IA:
Figure imgf000105_0001
IA
wherein ring
Figure imgf000105_0002
is a 6-membered saturated or partially saturated heterocycle optionally containing an additional heteroatom selected from NH, N-(C]-C6)alkyl, S, SO, and S02, and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (Cp C6)alkoxy, halo(C,-C6)alkyl, (CpC6)haloalkoxy, (C C6)alkylene-NH2, (CrC6)alkylene- NH(CpC6)alkyl, (CpC6)alkylene-NH(CpC6)haloalkyl, (CpC6)alkyiene-N(CpC6)alkyl)2, NH2, NH(CpC6)alkyl, (CpC6)alkylene-OH, (CpC6)alkylene-(CpC6)alkoxy, NH(Cp
C6)alky lene-NH2, NH(C , -C6)alky lene-NH(C , -C6)alky I, NH(C , -C6)alky leneN((C , -C6)alkyl)2, NH(CpC6)alkylene-(C3-C7)cyloalkyl, NH(CpC6)alkylene-(C3-C7)heterocyloalkyl, N((Cp C6)alkylene-(C3-C7)heterocycloalkyi)2, N((Ci-C6)alkyl)(C|-C6)alkylene-(C3-C7)cyloalkyl, N((Ci-C6)alkyl)(C, -C6)alkylene-(C3-C7)heterocyloalkyl, N((C,-C6)alkyl)2, (C,-C6)alkylene- NHS02-(Ci -C6)alkyl, (C,-C6)alkylene-NH(C=0)-(Ci-C6)alkyl, -(C=0)-(CrC6)alkyl, S(O)- (Ci-C6)alkyl, S02-(C C6)alkyl, aryl, hetreroaryl, (C3-C7)cycloaIkyl, (C3-C7)heterocycloalkyl, (C] -C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (CrC6)alkylene-CN, (Ci-C6)alkylene- OC(0)-(C,-C6)alkyl, (C=0)-NRaRb, NH(C=0)-(Ci-C6)alkylene-NH2, NH(C=0)-(C3- C7)cycloalkylene, NH(C=0)-(C3-C7)heterocycloalkylene, N((Ci-C6)alkyl)(C=0)-(Cr C6)alkylene-NH2, N((C,-C6)alkyl)(C=0)-(C3-C7)cycloalkylene, N((Ci-C6)alkyl)(C=0)-(C3- C )heterocycloalkylene, NH-S02-NRaRb, or S02-NRaRb, wherein Ra and Rb are each independently H, (Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C ! -C6)alkylene-(C3-C7)cycloalky 1, (C , -C6)alky lene-(C3-C7)heterocycloalkyl, (C i - C6)alkylene-NH2, (C, -C6)alkylene-NH(C,-C6)alkyl), or (Ci-C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C, -C6)alkyl, NH(C,-C6)alkoxy, NH(C,-C6)haloalkyl, N((C,-C6)alkyl)2, (C=0)- ORa, OH, (CrC6)alkyl, (C|-C6)haloalkyl, (Ci-C6)alkyIene-(C3-C7)cycloalkyl, or (Ci- C6)alkylene-(C3-C )heterocycloalkyl optionally substituted with 1-3 halo, (C3- C?)heterocycloalkyl optionally substituted with 1-3 halo, (Ci-C6)alkoxy, or (Ci- C6)haloalkoxy.
[00172] Embodiment 7. The compound of embodiment 1 -6, wherein the compound of formula I is a compound of formula IA-1 or IA-2:
Figure imgf000106_0001
IA-1 IA-2
wherein R6 is H, halo, hydroxy, cyano, (C|-C6)alkyl, -(Ci-C6)alkoxy, halo(Ci-C6)alkyl, (Ci- C6)alkylene-NH2, (C,-C6)alkylene-NH(C,-C6)alkyl, (C,-C6)alkylene-NH(C,-C6)haloalkyl, (C , -C6)alky lene-N(C i -C6)alkyl)2, (C, -C6)alkylene-NHS02Me,NH2, NH(C, -C6)alkyl, hydroxyalkyl, (C,-C6)alkylene-0(Ci-C6)alkyl, NH(C|-C6)alkylene-NH2, NH(C C6)alkylene- cyloalkyl, NH(C,-C6)alkylene-heterocyloalkyl, N((Ci-C6)alkyl)2, (C,-C6)alkylene-NHS02- (C i -C6)alky 1, (C , -C6)alkylene-NH(C=0)-(C , -C6)alky 1, NH(C=0)-(C i -C6)alkylene-1MH2, NH(C=0)-(C3-C7)cycloalky]ene, NH(C=0)-(C3-C7)heterocycloalkylene, (C=0)-(Ci-C6)alkyl, NHS02-(C,-C6)alkyl, N((C|-C6)alkyl)S02-(C,-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(Cr
C6)alkyl, (C3-C7)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci- C6)alky lene-CN, NH(C i -C6)alky lene-NH(C i -C6)alky 1, N H(C , -C6)alky lene-N((C , -C6)alky 1)2, (Ci-C6)alkylene-OC(0)-(C, -C6)alkyl,
Figure imgf000107_0001
or S02-N 6aR6b, wherein R6a and Reb are each independently H, (C|-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalk l, (C3- C6)heterocycloalkyl, (Ci -C6)alkylene-(C3-C6)cycloalkyl, (Ci-C6)alkylene-(C3- C6)heterocycloalkyl, (C, -C6)alkylene-NH2, (d^alkylene-NHid-Q alkyl), or (C,- C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(CrC6)alkyl, N((Ci-C6)alkyl)2, OH, (C,-C6)alkyl, (Ci-Ce)alkoxy, or (d-CeJhaloalkoxy.
[00173] Embodiment 8. The compound of embodiment 1 -7, wherein the compound of formula I is a compound of formula IA-3 or IA-4:
Figure imgf000107_0002
IA-3 IA-4
wherein Q is C=0, S=0, or S02 and R| is OH or NR6a 6b, R6a and Re are each
independently H, (C, -C6)alkyl, halo(Ci-C6)alkyl, (C|-C6)alkylene-NH2, (CrC6)alkylene- NH(C ,-C6)alkyl, (d-C6)alkylene-NH(C,-C6)haloalkyl, (Ci-CeJalkylene-Nid-Ceialky z, (C,- C6)alkylene-OC(0)-(C|-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (C|-C6)alkylene-aryl, (C|-C6)alkylene-heteroaryl, (CrC6)alkylene-(C3- Ce)cycloalkyl, or (C|-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|-C6)alkyl, N((C|- C6)alkyl)2, OH, (C,-C6)alkyl, (C,-C6)alkoxy, or (C,-C6)haloalkoxy.
[00174] Embodiment 9. The compound of embodiment 1 -8, wherein the compound of formula I is a compound of formula IA-5 or IA-6:
Figure imgf000108_0001
wherein Rz is halo, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from (Ci-C6)alkyl, (Ci -C6)haloalkyl (C|-C6)alkoxy, halo(C,-C6)alkyl, (C,-C6)haloalkoxy, (C=0)-NH2, NH(C=0)-(C,-C6)alkyl, NH2, NH(C |- C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(CrC6)alkyl, and (C=0)-N((C,- C6)alkyl)2.
[00175] Embodiment 10. The compound of embodiment 1 -9, wherein Rz is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
[00176] Embodiment 1 1. The compound of embodiment 1 -10, wherein Rz is phenyl optionally substituted with hydroxyl, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
[00177] Embodiment 12. The compound of embodiment I - 1 1 , wherein Rz is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
[00178] Embodiment 13. The compound of embodiment 1 -12, wherein Rz is isoxazolyl, pyrimidinyl, or indazolyl, optionally substituted with amino or methyl.
[00179] Embodiment 14. The compound of embodiment 1 - 13, wherein Rz is pyridinyl optionally substituted with fluoro, chloro, amino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, or (C=0)-NHMe,
[00180] Embodiment 15. The compound of embodiment 1 - 14, wherein Rz is
benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, or triazolyl, optionally substituted with methyl or amino.
[00181] Embodiment 16. The compound of embodiment 1 -15, wherein Rz is pyridazinyl optionally substituted with hydroxyl, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
[00182] Embodiment 17. The compound of embodiment 1 -16, wherein Rz is thienyl or furanyl optionally substituted with methyl.
[00183] Embodiment 18. The compound of embodiment 1 -17, wherein Rz is bromo, chloro, or fluoro. |uui84| tmrjodiment i y. i ne compound ot embodiment 1 - 1 8, wherein Kz is NK3K4, wherein R3 and R4 are each independently (C|-C6)alkyl optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (C|-C6)alkyl, (d-C6)alkoxy, halo(Ci- C6)alkyl, (C,-C6)haloalkoxy, (CrC6)a]kylene-NH2, (C-CeJalkylene-NHCC-CeJalkyl, (C,- C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (Ci-C6)alkylene-OH, (C,-C6)alkylene-(C|-C6)alkoxy, NH(C, -C6)alkyleneNH2, NH(C r
C6)alkylene-NH(C1-C6)alkyl, NH(C l-C6)alkyleneN((C1 -C6)alkyl)2, NH(C,-C6)alkylene- cyloalkyl, NH(CrC6)alkylene-heterocyloalkyl, N((Ci-C6)alkyl)2, (d-C6)alkylene-NHS02- (C,-C6)alkyl, (C,-C6)alkylene-NH(C=0)-(C,-C6)alkyl, -(C=0)-(C,-C6)alkyl, S(0)-(C,- C6)alkyl, S02-(Ci-C6)alkyl, -(C4-C7)heterocycloalkyl, (C,-C6)alkylene-(C3- C7)heterocycloalkyl, nitro, (CrC6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(Ci-C6)alkyl, (C=0)-NRcRd, or S02-NRcRd, wherein Rc and Rd are each independently are H, (C]-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalk l, (C3-C6)heterocycloalkyl, (C| -C6)alkylene-(C3- C7)cycloalkyl, (C, -C6)alkylene-(C3-C7)heterocycloalkyl, (Ci-C6)alkylene-NH2, (C
C6)alkylene-NH(C] -C6)alkyl), or (Ci-C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|-C6)alkyl, N((Ci-C6)alkyl)2, OH, (C|-C6)alkyl, (C|-C6)alkoxy, or (C|-C6)haloalkoxy.
[00185] Embodiment 20. The compound of embodiment 1 - 19, wherein R3 is H and R4 is methyl, ethyl, propyl, butyl, pentyl, CH2CH2-OCH3, or (C=0)-CH2-OH.
[00186] Embodiment 21. The compound of embodiment 1 -20, wherein R3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (CrC6)alkoxy, halo(CrC6)alkyl, (Ci -C6)haloalkoxy, (C C6)alkylene-NH2, (Ci-C6)alkylene- H(C , -C6)alky 1, (C , -C6)alky lene- H(C , -C5)haloalky 1, (C , -C6)alky lene-N(C , -C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,-C6)alkylene-OH, (C|-C6)alkylene-(Ci-C6)alkoxy, NH(Ci- C6)alkyleneNH2, NH(C,-C6)alkylene-NH(C,-C6)alkyl, NH(C, -C6)alkyleneN((C,-C6)alkyl)2, NH(Ci-C6)alkylene-cyloalkyl, NH(C|-C6)alkylene-heterocyloalkyl, N((Ci-C6)alkyl)2, (C C6)alkylene-NHS02-(C,-C6)alkyl, (C |-C6)alkylene-NH(C=0)-(C, -C6)alkyl, (C=0)-(d- C6)alkyl, S(0)-(C| -C6)alkyl, S02-(Ci-C6)alkyl, -(C4-C7)heterocycloalkyl, (Ci-C6)alkylene- (C3-C7)heterocycloalkyl, nitro, (C|-C6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(C, -C6)alkyl,
Figure imgf000109_0001
or S02-NReRf, wherein e and Rf are each independently H, (CrC6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C| -C6)alkylene-(C3- C7)cycloalkyl, (C, -C6)alkylene-(C3-C7)heterocycloalkyl, (C(-C6)alkylene-NH2, (C (J6)alkylene-NH((J|-L'6)a!kyl), or ( |-C6)alkylene-N(Ui-L-6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)alkyl, N((C C6)alkyl)2, OH, (CrC6)alkyl, (CrC6)alkoxy, or (d-C6)haloalkoxy.
[00187] Embodiment 22. The compound of embodiment 1 -21 , wherein Rz is
Figure imgf000110_0001
[00188] Embodiment 23. The compound of embodiment 1 -22 and embodiments 10-22, wherein the compound of formula I is a compound of formula IA-7 or IA-8:
Figure imgf000110_0002
IA-7 IA-8
wherein Q is C=0 or S02; and
Ria and R^ are each independently H, (Ci-Cejalkyl, halo(Ci-C6)alkyl, (C] -C6)alkylene-NH2, (C , -C6)alky lene-NH(C , -C6)alky I, (C , -C6)alkylene-NH(C, -C6)haloalky 1, (C , -C6)alkylene- N(C,-C6)alkyl)2, (C|-C6)alkylene-OC(0)-(C|-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci-C6)alkylene-heteroaryl, (C]-C6)alkylene- (C3-C6)cycloalkyl, or (C |-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-Ce)alkyl, N((C|-C6)alkyl)2, OH, (d-C6)alkyl, (C|-C6)alkoxy, or (C |-C6)haloalkoxy.
[00189] Embodiment 24. The compound of embodiment 1 -23, wherein:
Ria is H or (C, -C6)alkyl;
Rib is H, (C, -C6)alkyl, halo(Ci-C6)aIkyl, (Ci -C6)alkylene-NH2, (C,-C6)alkylene- NH(C, -C6)alkyl, (C, -C6)alkylene-NH(C]-C6)haloalkyl, (C1 -C6)alkylene-N(Ci-C6)alkyl)2, (Cr C6)alkylene-OC(0)-(CrC6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci -C6)alkylene-heteroaryl, (C|-C6)alkylene-(C3- C6)cycloalkyl, or (Ci-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; and
Rs is methyl. |UU190] embodiment 1 . 1 he compound or emoodiment i-zq, wnerein K|a is n, metnyi, pyrrolidiny, piperidinyl, CH2-cyclopropyl, CH2-pyrrolidinyl, or CH2-piperidinyl.
[00191] Embodiment 26. The compound of embodiment 1 -25, wherein R]b is H, methyl, ethyl, or fluoroethyl.
[00192] Embodiment 27. The compound of embodiment 1 -26, wherein Ria is H, and Rib is H.
[00193] Embodiment 28. The compound of embodiment 1-27, wherein R is methyl,
ethyl,
Figure imgf000111_0001
and Rlb is H, methyl, ethyl, or fluoroethyl.
[00194] Embodiment 29. The compound of embodiment 1 -28, wherein Ria and R|b are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|-C6)alkyl, N((Ci-C6)alkyl)2, OH, (C|-C6)alkyl, (C| -C6)alkoxy, or (C| -C6)haloalkoxy.
00195 Embodiment 30. The com ound of embodiment 1-29 wherein in a further
Figure imgf000111_0002
[00196] Embodiment 31 . The compound of embodiment 1 -30, wherein in a further
embodiment, RiaRibN is
Figure imgf000111_0003
wherein:
Z is O, or C;
R2a is absent when Z is O; or is H, OH, NH2, NH-(C2-C6)alkylene-0-(C,-C6)alkyl, NH(C,-C6)haloalkyl, (Ci-C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(Cl-C6)alkyl when Z is N or C; R2b is absent when Z is N or O; or is H, (Ci -C6)alkyl, or (Ci-C6)haloalkyl when Z is C;
each occurrence of R2c is independently halo, (C|-C6)alkyl, or (Ci-C6)haloalkyl; and n is 0, 1 , or 2. [00197] Embodiment 32. The compound ot embodiment 1-3 1 , wherein in a turtner
Figure imgf000112_0001
Z is N or C;
R2a is H, OH, NH2, NH-(C2-C6)alkylene-0-(Ci-C6)alkyl, NH(Ci-C6)haloalkyl, (Ci- C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or H(C=0)NH-(C2-C6)alkylene-0-(C|-C6)alkyl;
R2b is absent when Z is N; or is H, (Ci-C6)alkyl, or (Ci-C6)haloalkyl when Z is C; each occurrence of R2c is independently halo, (Ci-C6)alkyl, or (Ci-C6)haloalkyl; and n is 0, 1 , or 2.
[00198] Embodiment 33. The compound of embodiment 1 -32, wherein the compound of formula I is a compound of formula IA-9 or IA-10:
Figure imgf000112_0002
IA-9 IA-10 wherein Q is C=0 or S02;
Z is N or C;
R2a is H, OH, NH2, NH-(C2-C6)alkylene-0-(C, -C6)alkyl, NH(C,-C6)haloalkyl, (C,- C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or H(C=0)NH-(C2-C6)alkylene-0-(C,-C6)alkyl;
R2b is absent when Z is N; or is H, (d-C6)alkyl, or (C|-C6)haloalkyl when Z is C; each occurrence of R2c is independently halo, (C|-C6)alkyl, or (Ci-Cejhaloalkyl; and n is 0, 1 , or 2.
[00199] Embodiment 34. The compound of embodiment 1 -33, wherein the compound of formula IA-9 or IA-10 is a compound of formula IA-9a or IA- 10a:
Figure imgf000113_0001
[00200] Embodiment 35. The compound of embodiment 1 -34, wherein:
R2a is OH, NH2, NH-(C2-C6)alkylene-0-(C,-C6)alkyl, NH(C,-C6)haloalkyl, (C, -
C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(C,-C6)alkyl;
R2b is absent H, (C|-C6)alkyl, or (C C6)haloalkyl;
each occurrence of R2c is independently halo, (Ci-Cejalkyl, or (Ci-C6)haloalkyl; and n is 0, I , or 2.
compound of emb -35, wherein
Figure imgf000113_0002
IS
Figure imgf000113_0003
[00202] Embodiment 37. The compound of embodiment 1 -36, wherein the compound of formula I is a compound of formula IA-9b or !A- l Ob:
Figure imgf000114_0001
lA-9b lA-l Ob
[00203] Embodiment 38. The compound of embodiment 1 -37, wherein R2a is H, methyl, ethyl, propyl, or butyl; R2c is methyl; and n is 1.
[00204] Embodiment 39. The compound of embodiment 1 -38, wherein R5 is methyl.
[00205] Embodiment 40. The compound of embodiments 1 -39, wherein the compound of formula 1 is a compound of formula IB- 1 or IB-2:
Figure imgf000114_0002
IB- I IB-2
wherein Q is CH2, C=0, S=0, or S02;
Rb is H, (C,-C6)alkyl, (C,-C6)alkylene-NH(C|-C6)haloalkyl, (C,-C6)alkylene-N(Ci- C6)alkyl)2, (C|-C6)alkylene-OC(0)-(C|-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (C|-C6)alkylene-heteroaryl, (Ci-C6)alkylene-(C3- Cejcycloalkyl, (Ci-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, OH, (C,-C6)alkyl, (C,- C6)alkoxy, or (C | -C6)haloalkoxy; and
Ri , is H, (Ci-C6)alkyl, halo(CrC6)alkyl, (C|-C6)alkylene-NH2, (C,-C6)alkylene- NH(Ci-C6)alkyl, (C, -C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(C,-C6)alkyl)2, (C C6)alkylene-OC(0)-(Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (CrC6)alkylene-heteroaryl, (Ci-C6)alkylene-(C3- C6)cycloalkyl, (C|-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, OH, (C,-C6)alkyl, (C,- C6)alkoxy, or (Ci-C6)haloalkoxy.
[00206] Embodiment 41. The compound of embodiment 1 -40, wherein the compound of formula 1 is a compound of formula 1B-3 or IB-4:
Figure imgf000115_0001
IB-3 IB-4
wherein Rz is halo, cycloalkyi, aryl, heterocycloalkyi, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from (C| -C6)alkyl, (Ci -C6)haloalkyl (C| -C6)alkoxy, halo(C,-C6)alkyl, (Ci-C6)haloalkoxy, -(CO)-NH2, NH(C=0)-(C,-C6)alkyl, NH2, NH(Ci- C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)-N((C,- C6)alkyl)2.
is
Figure imgf000115_0002
[00208] Embodiment 43. The compound of embodiment 1 -42, wherein R5 is methyl.
[00209] Embodiment 44. The compound of embodiments 1 -43, wherein the compound of formula 1 is a compound of formul
Figure imgf000116_0001
IC
wherein R¾c is halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-Ce)alkyl, (Ci- C6)haloalkoxy, (C,-C6)alkylene-NH2, (C|-C6)alkylene-NH(C|-C6)alkyl, (C|-C6)alkylene- NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(Cl-C6)alkyl)2, NH2, NH(C C6)alkyl, (Cr
C6)alkylene-OH, (C,-C6)alkylene-(Ci-C6)alkoxy, NH(Ci-C6)alkylene-NH2, NH(Cr
C6)alkylene-NH(C1 -C6)alkyl, NH(CrC6)alkyleneN((C,-C6)alkyl)2, NH(C,-C6)alkylene-(C3- C7)cyloalkyl, NH(C|-C6)alky]ene-(C3-C7)heterocyloalkyl, iiCr^alkylXQ^alkylene- (C3-C7)cyloalkyl, N((C , -C6)alkyl)(C , -C6)alky lene-(C3-C7)heterocyloalkyl, N((C , -C6)alkyl)2, (C, -C6)alky lene-NHS02-(C , -C6)alky I, (C , -C6)alky lene-NH(C=0)-(C , -C6)alky I, (C=0)-(C , - C6)alkyl, S(0)-(Ci-C6)alkyl, S02-(C|-C6)alkyl, aryl, hetreroaryl, -(C3-C7)cycloalkyl, -(C3- C7)heterocycloalkyl, (d-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci-C6)alkylene-CN, (C,-C6)alkylene-OC(0)-(C |-C6)alkyl, (C=0)-NRaRb, or S02-NRaRb, wherein Ra and Rb are each independently H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (Ci -C6)alkylene-(C3-C7)cycloalkyl, (C|-C6)alkylene-(C3- C7)heterocycloalkyl, (C rC6)alkylene-NH2, (C|-C6)alkylene-NH(C|-C6)alkyl), or (C
C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, OH, (C C6)alkyl, (C| -C6)alkoxy, or (C|-C6)haloalkoxy.
[00210] Embodiment 45. A compound selected from Table 1.
[00211] Embodiment 46. A pharmaceutical composition comprising a compound of embodiments 1 -45 admixed with a pharmaceutical carrier, excipient, or diluent.
(00212] Embodiment 47. A method for treating a disease, disorder, or syndrome which method comprises administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of embodiments 1 -46.
[00213] Embodiment 48. The method of embodiment 1 -47, wherein the disease is cancer. [00214] Embodiment 49. The method of embodiment 1 -48, wherein the cancer is breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NPM/AL -transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, or head and neck cancer.
[00215] Embodiment 50. A process for making a compound of formula I, comprising process for making a compound of formula 1 or of embodiments 1 -49, comprising reacting a compound of formula F with NHR3R to provide a compound of formula I:
Figure imgf000117_0001
wherein:
NRxRy is as defined in embodiment I ; and
X, R3, R4, and R5 are as defined in embodiment 1.
General Administration
[00216] In one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of PI3 according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain other specific embodiments, administration is by the oral route. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesical ly, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, and the like, specifically in unit dosage forms suitable for simple administration of precise dosages. [00217] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include carriers, adjuvants, and the like.
[00218] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[00219] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, and the like.
[00220] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4, 107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5, 145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[00221] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[00222] One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[00223] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient or carrier, such as sodium citrate or dicalcium phosphate; or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate; (e) solution retarders, such as, for example paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, magnesium stearate, and the like; (h) adsorbents, such as, for example, kaolin and bentonite; and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate; or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
[00224] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[00225] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a
pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like;
solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol,
1 ,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
polyethyleneglycols, and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
[00226] Suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
[00227] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
[00228] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
[00229] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, and the like
[00230] Generally, depending on the intended mode of administration, the
pharmaceutically acceptable compositions will contain about 1 % to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
[00231 ] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
[00232] The compounds of the invention, or their pharmaceutically acceptable salts or solvates, are administered in a therapeutically effective amount which will vary depending upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1 ,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
[00233] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
General Synthesis
[00234] Compounds of this invention can be made by the synthetic procedures described below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wis.) or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 -17 (John Wiley and Sons, 1991 ); Rodd's Chemistry of Carbon Compounds, Volumes 1 -5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1 -40 (John Wiley and Sons, 1991 ); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), each of which is incorporated herein by reference. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
[00235] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure and over a temperature range from about -78 °C to about 150 °C, more specifically from about 0 °C to about 125 °C, and more specifically at about room (or ambient) temperature, i.e., about 20 °C. Unless otherwise stated (as in the case of
hydrogenation), all reactions are performed under an atmosphere of nitrogen.
[00236] Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche (American Pharmaceutical Association and Pergamon Press, 1987), both of which are incorporated herein by reference for all purposes.
[00237] The compounds of formula I, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of the Invention that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
[00238] Some of the compounds of the invention contain an active ketone C(0)CF3 and may exist in part or in whole as the C(OH2)CF3 form. Regardless of whether the compound is drawn as the C(0)CF3 or C(OH2)CF3 form, both are included within the scope of the invention. Although an individual compound may be drawn as the C(0)CF form, one of ordinary skill in the art would understand that the compound may exist in part or in whole as the C(OH2)CF3 form and that the ratio of the two forms may vary depending on the compound and the conditions in which it exists.
[00239] Some of the compounds of the invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention. [00240] The present invention also includes N-oxide derivatives and protected derivatives of compounds of the invention. For example, when compounds of the invention contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of the Invention contain groups such as hydroxy, carboxy, thiol, or any group containing a nitrogen atom(s), these groups can be protected with a suitable "protecting group" or "protective group." A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis (John Wiley & Sons, Inc. 1991 ), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the invention can be prepared by methods well known in the art.
[00241 ] Methods for the preparation and/or separation and isolation of single
stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Enantiomers ((R)- and (S)-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid
chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired
enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
[00242] In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. [00243] The chemistry for the preparation of the compounds of this invention is known to those skilled in the art. In fact, there may be more than one process to prepare the compounds of the invention. The following examples illustrate but do not limit the invention. All references cited herein are incorporated by reference in their entirety.
[00244] As indicated previously, compounds of the invention can be prepared by reacting a compound of formula F with NHR3R4 to provide a compound of formula I:
Figure imgf000124_0001
wherein NRxRy is defined above and X, R3, R4, and R5 are also as defined above. This transformation can be performed using palladium-catalyzed coupling chemistry according to Suzuki-type or Buchwald-type methods, which is readily available to the skilled artisan, using a primary or secondary alkyl amine or a cyclic amine such as NHR3R4. For instance the amine can be optionally substituted pyrrolidine, piperidine, piperizine, or the like.
[00245] Using similar coupling conditions, the compound of formula F can be prepared by reacting a compound of formula E with NHRxRy:
wherein NRxRy is
Figure imgf000124_0002
as defined above and X and R5 are also as defined above.
[00246] Compounds of formula E wherein X is N generally can be prepared from amino benzoic acid A as outlined in Scheme 1 below. Thus, bromination of amino benzoic acid A under Freidel Crafts-type conditions using HBr provides the brominated benzoic acid B. Esterification of the acid moiety in compound B provides C. Treatment of C with ammonium formamide gives rise to quinazoline D. Quinazoline D can be converted to the chloride E-l using thionyl chloride or the like and a catalytic amount of DMF. Conversion of E-l to a compound of formula 1-1 can be accomplished as described above according to Buchwald- type coupling chemistry for compounds when Rz is NR3R4 or to Suzuki-type coupling chemistry when Rz is aryl or heteroaryl. Scheme 1
Figure imgf000125_0001
[00247] A representative example of the preparation of a compound of formula l- l is provided below.
Example 1
l-({2-[6-(3,3-difluoropyrroIidin-l-yl)-8-methylquinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine.
Figure imgf000125_0002
Benzyl piperidin-4-ylcarbamate hydrochloride salt
Figure imgf000125_0003
[00248] To a mixture of ter/-butyl 4-aminopiperidine-l -carbox late (2.20 g, 10.98 mmol) and triethyl amine (TEA) ( 1.9 mL, 14.3 mmol) in dichloromethane ( 15 mL) was added a benzyl chloroformate (2.24 g, 13.2 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 hours (h) and diluted with water. The mixture was partioned with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated, and the aqueous layer was further extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure, and the residue was purified by silca gel
chromatography to give tert-buty\ 4-(benzyloxycarbonylamino)piperidine-l -carboxylate (2.13 g, 58 %). MS (EI) for C,8H26N204: 235.0 (MH+- BOC).
[00249] To a solution of ½r/-butyl 4-(benzyloxycarbonylamino)piperidine-l -carboxylate (2.13 g, 6.38 mmol) in methanol (20 mL) was added 4 N hydrogen chloride in dioxane (8.0 mL, 31.8 mmol) in a dropwise manner at room temperature, then heated to 40 °C for 1 hour. The mixture was concentrated and dried to give benzyl piperidin-4-ylcarbamate
hydrochloride as a white solid, which was used without further purification. MS (EI) for C |3H,8N202: 235.0 (MH+).
Step 2:Benzyl l-(l,2,3,4-tetrahydroisoquinoline-7-carbonyl)piperidin-4-ylcarbamate hydrochloride salt
Figure imgf000126_0001
[00250] To a mixture of benzyl piperidin-4-ylcarbamate hydrochloride (640 mg, 2.46 mmol), 2-(/er/-butoxycarbonyl)- l ,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (681 mg, 2.46 mmol) and HATU (1 .40 g, 3.69 mmol) in DMF (10 mL) was added a
diisopropylethylamine (0.95 g, 7.38 mmol) at room temperature. The resulting mixture was stirred for 3 hours and monitored by LCMS. The mixture was concentrated upon completion, and the residue was purified by silica gel chromatography to give /ert-butyl 7-(4- (benzyloxycarbonylamino)piperidine- 1 -carbonyl)-3,4-dihydroisoquinoline-2( 1 H)-carboxylate (815 mg, 67 % ). MS (EI) for C28H35N3O5: 494.1 (MH+).
[00251] To solution of tert-butyl 7-(4-(benzyloxycarbonylamino)piperidine-l -carbonyl)- 3,4-dihydroisoquinoline-2( l H)-carboxylate (815 mg, 1 .65 mmol) in methanol (20 mL) was added 4 N hydrogen chloride in dioxane (2mL), and the mixture was stirred at 40 °C for 1 hour, then concentrated and triturated with diethyl ether then further dried under high vacuum. The resulting crude benzyl l -( l ,2,3,4-tetrahydroisoquinoline-7-carbonyl)piperidin- 4-ylcarbamate hydrochloride salt (598 mg, 92% yield) was used without further purification. MS (EI) for C23H27N303: 394.0 [MH+].
Step 3: Methyl -amino-5-bromo-3-methylbenzoate
Figure imgf000127_0001
[00252] 2-Amino-3-methylbenzoic acid (1 .0 g, 6.62 mmol) was taken into DMSO (7.5 mL), and to the resulting solution was added concentrated aqueous hydrobromic acid (48 W%, 2 mL), and the mixture was allowed to stir at room temperature over 36 hours. The solution was then diluted with an excess of water, and the resulting solid was collected by filtration. The filter cake was washed with additional water then air dried.
[00253] The above filter cake was taken into methanol (100 mL) followed by addition of concentrated sulfuric acid (2 mL), then heated to reflux over 72 hours. On cooling to room temperature, the solution was concentrated, and the residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed twice with additional saturated aqueous sodium bicarbonate then dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 2-amino-5-bromo-3-methylbenzoate ( 1.1 g) as a colorless solid. GCMS for C9H,oBrN02: 245 (M+).
Step 4:6-Bromo-8-methylquinazolin-4(3H)-one
Figure imgf000127_0002
[00254] Methyl 2-amino-5-bromo-3-methylbenzoate ( 1 .1 g, 4.51 mmol) and ammonium formate (640 mg) was taken into formamide ( 10 mL) and the mixture was heated at 165 °C for 12 hours. On cooling to room temperature, the mixture was diluted with excess water, and the resulting crystalline solid was collected by filtration, and the filter cake was air dried to give 6-bromo-8-methylquinazolin-4(3H)-one (887 mg) as a tan solid. LCMS (ES) tor C9H7BrN20: 239, 241 (MH+, Br isotope pattern).
Step 5: 6-Bromo-4-chloro-8-methylquinazoline
Figure imgf000128_0001
[00255] 6-Bromo-8-methylquinazolin-4(3H)-one (887 mg, 3.71 mmol) was taken into thionyl chloride (20 mL), followed by addition of catalytic DMF, and the solution was brought to reflux for 2 hours. The solution was concentrated, and the solid residue was digested into a mixture of ethyl acetate and hexanes. The slurry was filtered, and the filter cake was air dried to give 6-bromo-4-chloro-8-methylquinazoline (418 mg) as a tan solid. LCMS (ES) for C9H6BrClN2: 259, 257 (MH+, Br,Cl isotope pattern).
Step 6:Phenylmethyl (l-{[2-(6-bromo-8-methylquinazoIin-4-yl)-l,2,3,4- tetrahydroisoquinolin-7-yl|carbonyl}piperidin-4-yl)carbamate
Figure imgf000128_0002
[00256] 6-Bromo-4-chloro-8-methylquinazoline (68 mg, 0.26 mmol) and benzyl 1 - (l ,2,3,4-tetrahydroisoquinoline-7-carbonyl)piperidin-4-ylcarbamate hydrochloride salt (1 13 mg, 0.26 mmol) were taken into dimethylacetamide (0.7 mL), followed by addition of diisopropylethylamine (0.25 mL), and the mixture was heated at 120 °C for 30 minutes. On cooling to room temperature, the solution was partitioned with ethyl acetate and water. The organic solution was washed with water (3 times), then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using ethyl acetate and hexanes (1 : 1 ) to 100% ethyl acetate as eluent. The second eluting fraction was collected and concentrated to give phenylmethyl (l-{ [2-(6- bromo-8-methylquinazolin-4-yl)- l ,2,3,4-tetrahydroisoquinolin-7-yl]carbonyl}piperidin-4- yl)carbamate (38.9 mg) as a colorless oil. LCMS (ES) tor 32H32Br 5U3: 614, 010 (MH , Br isotope pattern).
Step 7: l-({2-[6-(3,3-Difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine
Figure imgf000129_0001
[00257] Phenylmethyl ( l -{[2 -(6-bromo-8-methylquinazolin-4-yl)- 1 ,2,3,4- tetrahydroisoquinolin-7-yl]carbonyl}piperidin-4-yl)carbamate (38.9 mg, 0.063 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.1 mg), XANTPHOS (10.7 mg), 3,3- difluoropyrrolidine hydrochloride salt (27.4 mg), and tribasic potassium phosphate ( 80 mg) were placed in a sealable glass vessel, followed by addition of anhydrous toluene (1 mL), and the mixture was heated at 1 15 °C for 12 hours. The resulting mixture was cooled to room temperature, then concentrated, and the residue was purified by silica gel chromatography using ethyl acetate as eluent to give phenylmethyl [ l -({2-[6-(3,3-difluoropyrrolidin-l-yl)-8- methylquinazolin-4-yl]- l ,2,3,4-tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-yl]carbamate ( 13.6 mg) as an amorphous residue. LCMS (ES) for C36H38F2N6O3: 641 (MH+).
[00258] Phenylmethyl [ l -({2-[6-(3,3-difluoropyrrolidin- l -yl)-8-methylquinazolin-4-yl]- l ,2,3,4-tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-yl]carbamate (13.6 mg, 0.021 mmol) was taken into hydrogen bromide in acetic acid (30 weight percent, 1 mL), and the resulting solution was stirred for 30 minutes at room temperature. The mixture was then concentrated, and the residue was purified by preparative reverse phase HPLC using ammonium acetate buffered aqueous acetonitrile mobile phase. Pure fractions were combined and concentrated, and the residue was partitioned with 10% methanol in chloroform and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to provide l -({2-[6-(3,3-difluoropyrrolidin-l -yl)-8-methylquinazolin-4-yl]- l ,2,3,4-tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine (7.5 mg) as a colorless amorphous residue. LCMS (ES) for C28H32F2N60: 507 (MH+).
[00259] Following the Example 1 procedure and using dimethylamine in step 6, 6-(3,3- difluoropyrrolidin-l -yl)-N,N,8-trimethylquinazolin-4-amine was prepared.
Figure imgf000130_0001
[00260] LCMS(ES)forCi5H,8F2N4: 293 (MH+). Ή NMR (400 MHz, CDC13): 8.63 (s, IH), 7.02 (d, IH), 6.68 (d, IH), 3.77 (tr, 2H), 3.63 (tr, 2H), 3.25 (s, 6H), 2.69 (s, 3H), 2.61- 2.50 (m, 2H).
[00261] Table 2 lists the compounds, as well as supporting characterization data that were prepared similarly to Example 1. "Compound Number" refers to the compound numbering provided in Table 1.
Table 2
Figure imgf000130_0002
CMPD CHARACTERIZATION DATA
16 Ή NMR (400 MHz, d6-DMSO): 10.72 (s, IH), 8.54 (s, IH), 7.68 (dd,
IH), 7.60 (t, IH), 7.42 (d, IH), 7.30 (m, 2H), 6.62 (d, IH), 3.90 (m, 8H), 3.75 (m, 2H), 3.65 (m, 2H), 2.64 (s, 3H), 2.58 (m, 2H). MS (EI) for C24H25F2N702S:515(MH+).
17 . lH NMR (400 MHz, DMSO-d6) S 8.63 (s, IH), 7.64 (dd, IH), 7.37 (dd,
IH), 7.29 (s, IH), 7.06 (d, IH), 6.61 (s, IH), 3.87 (t, 2H), 3.80 (s, 3H), 3.67 (d, 4H), 3.63 (d, 4H), 2.58 (m, 2H), 2.58 (s, 3H).. MS (ES) for C25H27C1F2N602: 517 (MH+).
18 Ή NMR (400 MHz, CDC13): 8.63 (s, IH), 7.02 (d, IH), 6.68 (d, IH),
3.77 (tr, 2H), 3.63 (tr, 2H), 3.25 (s, 6H), 2.69 (s, 3H), 2.61-2.50 (m, 2H). MS (EI) for C,5H|8F2N4: 293 (MH+).
19 Ή NMR (400 MHz, DMSO-d6) 58.69 (s, IH), 8.62 (s, IH), 8.21 (s, IH),
7.85 (s, IH), 7.64 (d, IH), 7.38 (dd, IH), 7.06 (d, IH), 6.89 (s, IH), 3.80 (s, 3H), 3.70 (d, 4H), 2.67 (s, 3H), 2.37 (d, 4H). MS (ES) for C24H24C1N702: 478 (MH+).
20 'HNMR(400MHz,d5-DMSO): 13.00 (brs, IH), 10.76 (brs, 1H),8.68
(s, 1 H), 8.22 (br s, 2H), 7.82 (br s, 1 H), 7.68 (d, 1 H), 7.58 (t, 1 H), 7.44 (d, 1 H), 7.31 (t, 1 H), 6.90 (s, 1 H), 3.93 (br s, 8H), 2.66 (s, 3H). MS (EI) for C23H22N802S: 475 (MH+).
22 Ή NMR (400 MHz, CD3OD) δ 8.70 (d, IH), 8.59 (s, IH), 8.55-8.44 (m,
IH), 7.97 (s, IH), 7.71 (s, IH), 7.66-7.59 (m, IH), 7.48 (d, IH), 5.00 (s, 2H), 4.07 (t, 2H), 3.45-3.37 (m, 2H), 3.08-2.85 (m, 4H), 2.74 (s, 3H), 2.63 (s, 3H), 2.03-1.81 (m, 5H), 1.51-1.32 (m, 2H). MS (EI) for
C28H32N603S: 533 (MH+).
23 Ή NMR (400 MHz, DMSO) 58.68 (s, IH), 8.23 (d, 2H), 7.81 (s, IH),
7.68 (s, IH), 7.61 - 7.46 (m, 2H), 6.89 (d, IH), 5.06 (s, 2H), 4.03 (m, 4H), 3.51 (m, 2H), 3.24 (m, 2H), 2.51 (s, 3H), 2.36 (s, 2H), 1.88 (m, IH), 1.29 (m, 2H); MS (EI) for C26H29N702S: 504.0 (MH+).
24 Ή NMR (400 MHz, DMSO-d6): δ 8.63 (s, IH), 8.24 (br s, 2H), 8.01 (d,
2H), 7.30 (m, 2H), 7.20 (d, IH), 4.95 (s, 2H), 4.27 (brs, 1H),4.01 (brt, 2H), 3.27 (m, 2H), 3.17-2.82 (m, 4H), 2.64 (s, 3H), 1.87 (s, 3H-OAc peak), 1.75 (m, 2H), 1.18 (m, 2H); MS (EI) for C27H29N70: 468.0 (MH+).
25 Ή NMR (400 MHz, DMSO-d6): 68.67 (s, IH), 8.27 (s, IH), 8.18 (s,
IH), 7.81 (s, 1 H), 7.41 - 7.26 (m, 2H), 7.21 (d, 1 H), 6.90 (d, 1 H), 4.95 (s, 2H), 4.28 (br s, 1 H), 4.03 (br t, 2H), 3.25 (br t, 2H), 3.18-2.80 (m, 4H), 2.66 (s, 3H), 1.87 (s, 3H-OAc), 1.76 (m, 2H), 1.19 (br s, 2H); MS (EI) for C27H29N70: 468.1 (MH+).
26 Ή NMR (400 MHz, DMSO-d6): δ 8.74 (s, 2H), 8.66 (s, IH), 8.00 (d,
2H), 7.37 - 7.26 (m, 2H), 7.19 (d, IH), 6.88 (br s, 2H), 4.99 (s, 2H), 4.27 (br m, IH), 4.04 (br t, 2H), 3.15 (m, 4H), 2.84 (m, 4H), 2.66 (s,3H), 1.86 (s, 2H-OAc peak), 1.75 (m, 2H), 1.18 (brs, 2H); MS (EI) for C28H30N8O: 495.1 (MH+).
27 Ή NMR (400 MHz, DMSO-d6): δ 8.70 (s, IH), 8.27 (s, 3H), 7.90 (d,
2H), 7.59 (d, 1 H), 7.31 (d, 2H), 7.20 (d, 1 H), 5.02 (s, 2H), 4.27 (br s, CMPD CHARACTERIZATION DATA
1 H), 4.07 (br t, 2H), 3.16 (br t, 2H), 2.83 (m, 4H), 2.69 (s, 3H), 1.87 (s, 3H-OAc), 1.75 (m, 2H), 1.18 (brs, 2H); MS (EI) for C3|H3iN70: 518.0 (MH+).
28 Ή NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.19 (d, 2H), 8.10 (d,
2H), 7.84 (d, 1H), 7.68 (d, 1H), 7.35 (m, 2H), 7.20 (d, 1H), 5.00 (s, 2H), 4.39 (br m, 1H), 4.07 (br t, 2H), 3.16 (br t, 2H), 3.10-2.80 (m, 6H), 2.69 (s, 3H), 1.86 (s, 3H-OAc), 1.75 (m, 2H), 1.30 - 1.00 (br s, 2H).; MS (EI) forC3iH31N70: 518.0 (MH+).
29 Ή NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.65 (d, IH), 8.27 (s, 1H),
7.51-7.24 (m, 4H), 5.70-5.41 (m, 2H), 4.59-4.46 (m, 2H), 3.46-3.37 (m, IH), 3.28-3.22 (m, 3H), 3.17 (s, 3H), 2.74 (s, 3H), 2.24-1.91 (m, 3H), 1.72-1.47 (m,3H), 1.43-1.17 (m, 3H). MS (EI) for C30H32ClN7O3S: 606, 608 (MH+, CI isotopes).
30 Ή NMR (400 MHz, CD3OD) 58.53 (s, IH), 7.75 (s, IH), 7.74-7.65 (m,
IH), 7.53 (d, IH), 7.43 (s, IH), 7.24 (s, IH), 5.41 (s, 2H), 4.51-4.25 (m, 2H), 3.60-3.49 (m, IH), 3.48-3.37 (m, 2H), 3.29-3.23 (m, 2H), 3.10-2.86 (m, 5H), 2.74 (s, 3H), 2.60 (s, 3H), 2.08-1.89 (m, 2H), 1.54-1.34 (m, 2H), 1.22 (d, 3H), 1.06 (d, 3H), 1.00 (t, 3H). MS (EI) for C3oH42N602S: 551 (MH+).
31 Ή NMR (400 MHz, CD3OD) δ 8.57 (s, IH), 7.42-7.38 (m, IH), 7.35 (d,
IH), 7.31-7.19 (m,3H), 4.91 (s, 2H), 4.78-4.51 (m, IH), 4.31-4.21 (m, 2H), 4.01 (t, 2H), 3.97-3.73 (m, 2H), 3.46 (s, 3H), 3.22 (2, 3H), 3.07-2.84 (m, IH), 2.65 (s, 3H), 2.18-1.98 (m, 2H), 1.70-1.38 (m, 2H). MS (El) for C27H33N503: 476 (MH+).
32 Ή NMR (400 MHz, DMSO-d6): δ 8.47 (s, IH), 7.32 (d, 2H), 7.25 (s,
IH), 7.20 (d, IH), 7.16 (s, IH), 6.56 (s, IH), 6.03 (d, IH), 4.71 (s, 2H), 4.55 (br s, 1 H), 3.80 (br t, 2H), 3.15 (br m, 2H), 2.97 - 2.78 (m, 2H), 1.91 (br m, 2H), 1.61 (m, 2H), 1.49 (m, 2H), 1.31 (br s, 2H), 1.17 (d, 3H), 0.92 (t, 3H).; MS (EI) for C28H36N60: 473.1 (MH+).
33 lH NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1 H), 7.37 - 7.26 (m, 2H),
7.20 (d, 2H), 6.63 (s, IH), 6.24 (t, IH), 5.99 (d, IH), 5.82 (t, IH), 4.73 (s, 2H), 4.23 (br s, IH), 3.82 (br t, 2H), 3.56 (t, 4H), 3.27 (s, 3H), 3.24 (s, 3H), 3.14 (t, 4H), 3.02 - 2.93 (m, 1 H), 1.75 (br m, 2H), 1.23 (br s, 2H).; MS (EI) forC3,H4|N704: 576.1 (MH+).
34 Ή NMR (400 MHz, DMSO-d6) δ 8.65 (d, IH), 8.50 (dd, IH), 8.16 (d,
IH), 8.10 (s, IH), 7.72 (d, IH), 7.65 (d, IH), 7.57 (d, IH), 7.46 (m, IH), 5.06 (s, 2H), 4.04 (t, 2H), 3.18 (d, 2H), 3.16 (m, 2H), 2.61 (m, 2H), 2.50 (m, 2H), 2.49 (s, 3H), 2.35 (m, IH), 1.82 (s, 3H), 1.72 (m, 2H), 1.20 (m, 2H). MS (ES) for C29H34N802S: 559 (MH+).
35 Ή NMR (400 MHz, methanol-d4) δ 8.62 (s, IH), 8.31 (s, IH), 8.04 (s,
IH), 7.94 (s, IH), 7.91 (d, IH), 7.35 (d, IH), 7.29 (s, IH), 7.27 (d, IH), 5.03 (s, 2H), 4.12 (t, 2H), 3.29 (m, 4H), 3.22 (t, 2H), 2.93 (m, IH), 2.71 (s, 3H), 1.76 (m, 4H). MS (ES) for C30H3lFN6O2: 527 (MH+).
36 Ή NMR (400 MHz, DMSO-d6): δ 8.60 (s, IH), 7.87 (s, 2H), 7.49-7.17
(m, 2H), 6.89 - 6.80 (br m, 1 H), 5.25 - 5.00 (br s, 2H), 4.53 - 4.37 (br s, CMPD CHARACTERIZATION DATA
1 H), 4.27 - 4.06 (br m, 2H), 3.64 - 3.51 (m, 2H), 3.20 (s, 3H), 3.16 (br m, 2H), 1.91 (br s, 2H), 1.75 (s, 3H), 1.40 (br s, 2H); MS (EI) for
C27H34 602: 475.2 (MH+).
37 Ή NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.13 (d, 1H), 7.95 (m,
3H), 7.72 (m, 1H), 7.34 (s, 2H), 5.03 (br s, 2H), 4.57 - 4.34 (m, 1H), 4.09 (br s, 2H), 3.35 (s, 3H), 3.27 (m, 4H), 2.93 - 2.79 (m, 1H), 2.74 (s, 3H), 2.65 (m, 3H), 1.99 (s, IH-Oac peak), 1.62 (m, 2H) 1.32 (brm, 2H); MS (EI) for C32H33N70: 532.1 (MH+).
38 Ή NMR (400 MHz, methanol-d4): 8.67 (s, 1H), 8.52 (m, 1H), 8.15 (s,
1H), 8.04 (s, 1H), 7.99 (m, 1H), 7.71 (s, 1H), 7.63 (d, 1H), 7.48 (d, 1H), 5.12 (s, 2H), 4.17 (m, 2H), 3.37 (m, 2H), 2.99-2.87 (m, 4H), 2.75 (s, 3H), 2.72 (s, 3H), 1.96 (m, 2H), 1.90 (s, 6H), 1.38 (m, 2H). MS (EI) for C3iH34N802S2:615 (MH+).
39 Ή NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.34 (s, 1H), 8.05 (s, 1H),
7.96 (d, J = 1.9 Hz, 2H), 7.76 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 5.03 (s, 2H), 4.00 (t, J = 5.5 Hz, 2H), 3.91 (s, 4H), 3.24 (t, J = 5.3 Hz, 2H),3.10(d, J= 11.4 Hz, 2H), 2.76 (t, J= 19.0 Hz, 2H), 2.63 (m, 9H), 1.65 (m, 2H), 1.26- 1.10 (m, 2H). MS (EI) for C29H35N702S, found 546.0.
40 Ή NMR (400 MHz, DMSO-d6): 58.69 (s, 1H), 8.10 (d, 2H), 7.84 - 7.66 (m, 2H), 7.56 (dd, 1 H), 7.39 - 7.10 (m, 4H), 5.00 (s, 2H), 4.26 (br s, 1 H), 4.07 (br t, 2H), 3.15 (br m, 2H), 2.82 (br m, 4H), 2.63 (s, 3H), 1.89 (s, 3H- OAc), 1.75 (br m, 2H), 1.16 (br s, 2H).; MS (EI) for C30H30FN5O: 496.0 (MH+).
41 Ή NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.02 (d, 2H), 7.89 (dd,
2H), 7.43 - 7.26 (m, 4H), 7.19 (d, 1 H), 4.99 (s, 2H), 4.28 (br s, 1 H), 4.05 (br t, 2H), 3.1 (br t, 2H), 2.83 (br m, 4H), 2.66 (s, 3H), 1.87 (s, 3H- OAc), 1.75 (br m, 2H), 1.17 (br s, 2H); MS (EI) for C3oH3oFN50: 496.1 (MH+).
42 Ή NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.05 (s, 1H), 7.91 (s,
1 H), 7.74 (t, 1 H), 7.58 - 7.44 (m, 1 H), 7.43 - 7.23 (m, 4H), 7.19 (d, 1 H), 6.93 (d, 1H), 4.96 (s, 2H), 4.29 (s, 1H), 4.04 (br t, 2H), 3.16 (br t, 2H), 3.00-2.97 (br m, 2H), 2.65 (s, 3H), 1.87 (s, 3H-OAc), 1.82 - 1.62 (m, 2H), 1.25 (br s, 2H); MS (EI) for C30H3oFN50: 496.0 (MH+).
43 Ή NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 7.93 (d, 2H), 7.34 - 7.22 (m, 3H), 7.22-7.04 (m, 3H), 6.75 (d, 1H),4.90 (s, 2H),4.21 (s, 1 H), 3.97 (br t, 2H), 3.09 (br t, 2H), 2.78 (m, 4H), 2.61 (s, 3H), 1.78 (s, 3H-OAc), 1.65 (m, 2H), 1.13 (br s, 2H); MS (EI) for C3oH3,N502: 494.1 (MH+).
44 Ή NMR (400 MHz, DMSO) δ 8.72 (d, 1H), 8.15 (t, 1H), 8.03 (d, 1H),
7.82 (d, 1H), 7.73 (dd, 1H), 7.31 - 7.24 (m, 3H), 4.94 (d, 2H), 4.38 - 4.21 (m, 1H), 4.03 (m, 2H), 3.17 (s, 3H), 3.13 (m, 2H), 3.10-2.78 (m, 4H), 2.65 (d, 2H) 1.98 (m, 1H), 1.59 (m, 1H), 1.18 (m, 2H); MS (EI) for C29H28Cl2 60: 546.9(MH+).
45 Ή NMR (400 MHz, DMSO) 58.69 (s, 1H), 8.05 (t, 2H), 7.84 (d, 2H), CMPD CHARACTERIZATION DATA
7.75 (dd, IH), 7.57-7.49 (m, 2H), 7.35- 7.27 (m, 2H), 7.19 (t, IH), 4.99 (s, 2H), 4.26 (d, IH), 4.11 - 3.99 (m, 2H), 3.16 (d, 2H), 3.03 (m, 2H), 2.87 (m, 2H), 2.69 (s, 3H), 1.75-1.61 (m, 4H), 1.16 (d, 2H); MS (EI) for C30H31N5O: 478.1 (MH+).
46 Ή NMR (400 MHz, DMSO) δ 8.70 (s, IH), 8.20 - 8.10 (m, 4H), 7.81 -
7.75 (m, 2H), 7.33 - 7.28 (m, 2H), 7.19 (dt, IH), 4.98 (d, 2H), 4.19 (s, IH), 4.08 (t, 2H), 3.14 (t, 2H), 3.02 (m, 2H), 2.84 (m, 2H), 2.70 (m, 2H),
1.76 - 1.61 (m, 2H), 1.16 (m, 2H); MS (EI) for C3) H30F3N5O: 481.9(MH+).
47 Ή NMR (400 MHz, DMSO-d6): δ 8.78 - 8.64 (m, 2H), 8.57 (s, IH),
8.43 (s, 1 H), 8.14 (d, 1 H), 7.93 (t, 1 H), 7.39 (dd, 1 H), 7.34 - 7.25 (m, 2H), 7.19 (d, 1H),4.98 (s, 2H),4.27 (brs, 1H),4.05 (brt, 2H), 3.15 (br s, 2H), 2.93 (br m, 4H), 2.68 (s, 3H), 1.84 (s, 3H-OAc), 1.71 (br m, 2H), 1.18 (br s, 2H).; MS (EI) for C29H30 6O: 479.1 (MH+).
48 Ή NMR (400 MHz, CD3OD) δ 8.97 (M, 2H), 8.81-8.65 (m, 2H), 8.60
(d, 2H), 8.49 (s, IH), 7.49-7.25 (m, 3H), 5.75-5.28 (m, 2H), 4.81-4.62 (m, IH), 4.62-4.38 (m, 2H), 3.83 (brs, IH), 3.53-3.35 (m, 2H), 3.28-3.15 (m, 3H), 3.07-2.85 (m, 1 H), 2.76 (s, 3H), 2.25-1.88 (m, 2H), 1.60 (br s, 2H). MS (EI) for C28H29N70: 479 (MH+).
49 Ή NMR (400 MHz, CD3OD) δ 9.09 (s, IH), 8.74 (s, IH), 8.48 (s, IH),
8.23 (d, 2H), 7.86 (s, IH), 7.71 (d, IH), 7.55 (d, IH), 5.56 (s, 2H), 4.93- 4.80 (m, 2H), 4.53 (t, 2H), 4.02 (s, 3H), 3.54-3.35 (m, 2H), 3.07-2.85 (m, 4H), 2.74 (s, 3H), 2.73 (s, 3H), 2.10-1.88 (m, 3H), 1.55-1.29 (m, 2H). MS (EI) for C29H35N702S: 546 (MH+).
50 Ή NMR (400 MHz, methanol-d4): 8.63 (s, IH), 8.12 (s, IH), 7.74 (m,
2H), 7.63 (d, IH), 7.48 (d, IH), 6.84 (s, IH), 5.13 (s, 2H), 4.15 (m, 2H), 2.89 (d, 2H), 2.71 (s, 6H), 2.63 (m, 4H), 1.92 (s, 6H), 1.80 (br s, IH), 1.39 (m, 2H). MS (EI) for C29H35N702S: 546 (MH+).
51 Ή NMR (400 MHz, DMSO) δ 8.66 (s, IH), 7.82 (s, IH), 7.78 (m, 2H),
7.32 (m, 2H), 7.19 (m, IH), 4.89 (d, IH), 4.32 (s, IH), 4.01 (t, 2H), 3.81 (d, 3H), 3.16 (d, 2H), 2.97 (m, 2H), 2.65 (m, 2H), 1.85 (s, 3H), 1.67 (m, 2H), 1.32 - 1.14 (m, 2H); MS (EI) for C29H33N70: 496.1 (MH+).
52 Ή NMR (400 MHz, DMSO) δ 8.68 (d, IH), 8.02 (d, IH), 7.86 (d, IH),
7.30 (d, 3H), 7.24 -7.16 (m, 1H),4.94 (s, 2H),4.31 (m, 1H),3.98 (dd, 2H), 3.11 (m, 4H), 2.93 (m, 4H), 2.60 (s, 3H), 1.83 (s, 3H), 1.78 - 1.63 (m, 2H), 1.19 (d, 2H); MS (EI) for C28H3iN70: 481.9(MH+).
53 Ή NMR (400 MHz, DMSO) δ 8.63 (s, IH), 8.41 (s, IH), 8.04 (s, IH),
7.99 (d, 2H), 7.32 (d, 2H), 7.19 (t, IH), 4.95 (s, 2H), 4.60-4.49 (m, IH), 4.29 (m, IH), 4.01 (t, 2H), 3.16 (d, 2H), 3.09-2.87 (m, 4H), 2.63 (s, 3H), 1.75 (m, 2H), 1.23 (m, 2H); MS (EI) for C3oH35 70: 510.6 (MH+).
54 Ή NMR (400 MHz, CD3OD) δ 8.67 (s, IH), 8.56 (d, IH), 8.27-8.15 (m,
IH), 7.96 (d, IH), 7.74 (s, IH), 7.71 (d, IH), 7.67-7.62 (m, IH), 7.50 (d, IH), 5.15 (s, 2H), 4.18 (t, 2H), 3.44-3.35 (m, 2H), 3.03-2.84 (m, 6H), 2.73 (s, 6H), 2.04-1.93 (m, 3H), 1.93-1.89 (m, 6H), 1.41 (d, 2H). MS (EI) for C28H32N602S2: 549 (MH+). CMPD CHARACTERIZATION DATA
55 Ή NMR (400 MHz, CD3OD) 88.51 (s, IH), 7.54 (d, IH), 7.35 (d, IH),
7.27 (d, 2H), 7.08 (d, IH), 4.74-4.42 (m, 2H), 3.98 (t, 2H), 3.94 - 3.70 (m, IH), 3.26 - 3.06 (m, 6H), 3.08 - 2.82 (m, 2H), 2.62 (s, 3H), 2.17 - 1.94 (m, 4H), 1.84 - 1.72 (m, 4H), 1.73 - 1.61 (m, 2H), 1.61 - 1.34 (m, 2H). MS (EI) for C29H36N60: 485 (MH+).
56 Ή NMR (400 MHz, CD3OD) 88.53 (s, IH), 7.55 (d, IH), 7.34 (d, IH),
7.30 - 7.19 (m, 2H), 7.09 (d, 1 H), 4.92 - 4.87 (m, 3H), 4.76 - 4.40 (m, 2H), 4.17 - 3.59 (m, 7H), 3.29 - 2.89 (m, 7H), 2.64 (s, 3H), 2.19-1.73 (m, 3H), 1.60 - 1.21 (m, 3H). MS (EI) for C28H34 602: 469 (MH+).
57 Ή NMR (400 MHz, CD3OD) 58.93 (s, IH), 8.64 (s, IH), 8.58 (d, IH),
8.28 - 8.18 (m, 1 H), 8.13 (d, 1 H), 8.00 (s, 1 H), 7.58 (dd, 1 H), 7.34 (d, IH), 7.27 (dd, 2H), 5.05 (s, 2H), 4.75-4.55 (m, IH), 4.14 (t, 2H), 3.98 - 3.65 (m, IH), 3.41 - 3.33 (m, IH), 3.27 - 3.11 (m, 3H), 3.09 - 2.83 (m,
1.94 (m, 2H), 1.71 - 1.39 (m, 2H). MS (EI) for
Figure imgf000135_0001
58 Ή NMR (400 MHz, d6-DMSO): 8.79 (s, IH), 8.18 (d, 2H), 7.81 (s, IH),
7.64 (d, IH), 7.54 (d, IH), 7.42 (dd, IH), 7.41 (s, IH), 7.30 (d, IH), 5.30 (br s, 2H), 4.22 (br s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.31 (d, 2H), 3.23 (t, 2H), 2.82 (m, 4H), 2.68 (s, 3H), 2.63 (s, 3H), 1.83 (m, IH), 1.81 (d, 2H), 1.24 (d, 2H). MS (EI) for C33H39N504S: 602 (MH+).
59 Ή NMR (400 MHz, d6-DMSO): 10.02 (br s, IH), 8.80 (s, IH), 8.42 (s,
1 H), 8.32 (s, 1 H), 7.88 (s, 1 H), 7.42 (br s ( 1 H), 7.40 (s, 1 H), 7.33 (br s, IH), 6.98 (s, IH), 5.28 (br s, 2H), 4.29 (br s, 2H), 3.40 (br s, 4H), 3.18 (t, 3H), 3.04 (br s, 3H), 2.80 (s, 3H), 2.64 (s, 3H). MS (EI) for C27H29N7O: 468 (MH+).
60 Ή NMR (400 MHz, d6-DMSO): 8.88 (dd, IH), 8.81 (s, IH), 8.77 (d,
IH), 8.42 (d, IH), 8.40 (s, IH), 8.33 (s, IH), 8.12 (dd, IH), 7.80 (s, IH), 7.63 (d, IH), 7.52 (d, IH), 5.28 (br s, 2H), 4.22 (br s, 2H), 3.28 (d, 2H), 3.20 (t, 2H), 2.84 (d, 3H), 2.82 (m, 4H), 2.72 (s, 3H), 2.63 (s, 3H), 1.82 (m, 1 H), 1.80 (d, 2H), 1.24 (d, 2H). MS (EI) for C32H37N703S: 600 (MH+).
61 Ή NMR (400 MHz, DMSO-d6) δ 8.65 (d, IH), 8.50 (dd, IH), 8.16 (d,
IH), 8.07 (d, IH), 7.72 (s, IH), 7.71 (s, IH), 7.65 (d, IH), 7.56 (t, IH), 7.46 (m, IH), 5.06 (s, 2H), 4.04 (t, 2H), 3.61 (s, 3H), 3.18 (t, 2H), 2.63 (m, 2H), 2.51 (m, 2H), 2.49 (s, 3H), 2.35 (m, 1 H), 1.82 (s, 3H), 1.72 (m, 2H), 1.20 (m, 2H). MS (ES) for C31H36N602S: 557 (MH+).
62 Ή NMR (400 MHz, DMSO-d6) δ 8.73 (s, IH), 8.46 (s, IH), 8.01 (s, IH),
7.75 (s, IH), 7.60 (d, IH), 7.48 (d, IH), 5.16 (s, 2H), 4.09 (t, 2H), 3.17 (s, 2H), 3.05 (d, 2H), 2.76 (d, 2H), 2.66-2.55 (m, 8H), 1.77-1.45 (m, 3H), 1.18-0.98 (m, 2H). MS (EI) for C26H3oN602S: 491 (MH+).
63 Ή NMR (400 MHz, CD3OD) δ 8.66 (s, IH), 8.60 (d, IH), 8.46 (d, IH),
8.01 (s, 2H), 7.38 (d, IH), 7.33-7.24 (m, 2H), 4.74-4.60 (m, 2H), 4.14 (t, 2H), 4.01 - 3.69 (m, 1 H), 3.28 - 3.09 (m, 5H), 3.08 - 2.83 (m, 1 H), 2.76 (s, 3H), 2.19 - 2.02 (m, 2H), 1.72 - 1.37 (m, 2H). MS (EI) for
C26H28N80: 469 (MH+). CMPD CHARACTERIZATION DATA
64 Ή NMR (400 MHz, CD3OD) 88.59 (s, IH), 7.87 (s, IH), 7.75 (d, IH),
7.44 (s, 1 H), 7.35 (d, 1 H), 7.32 - 7.18 (m, 2H), 4.70 - 4.42 (m, 1 H), 4.06 (t, 2H), 3.92 - 3.57 (m, 1 H), 3.27 - 3.05 (m, 5H), 3.03 - 2.85 (m, 2H), 2.66 (s,3H), 2.09- 1.91 (m, IH), 1.85- 1.69 (m, IH), 1.45- 1.32 (m, 2H). MS (EI) for C27H29N7OS: 500 (MH+).
65 Ή NMR (400 MHz, CD3OD) δ 8.64 (s, IH), 8.06 (d, IH), 7.98 (dd, IH),
7.77 (s, 1 H), 7.54 (dd, 1 H), 7.32 (d, 1 H), 7.28 - 7.20 (m, 3H), 6.82 (dd, 2H), 4.76-4.46 (m, 2H), 4.12 (t, 2H), 3.81 - 3.66 (m, IH), 3.22 - 3.08 (m, 4H), 3.02-2.85 (m, 2H), 2.71 (s, 3H), 2.04 - 1.88 (m, IH), 1.85- 1.68 (m, 1 H), 1.49 - 1.33 (m, 2H). MS (El) for C29H3iN70: 494 (MH+).
66 Ή NMR (400 MHz, CD3OD) δ 8.64 (s, IH), 8.12 (d, IH), 7.97 (s, 2H),
7.36 (d, 1 H), 7.28 (dd, 2H), 6.98 (d, 2H), 5.04 (s, 2H), 4.78 - 4.62 (m, IH), 4.19-4.09 (m, 2H), 3.78 (s, 2H), 3.23 (m, 4H), 3.03-2.88 (m, 2H), 2.72 (s, 3H),1.57 (m, 2H); MS (EI) for C29H3,N70: 494.1 (MH+).
67 1 H NMR (400 MHz, DMSO) δ 8.65 (d, 1 H), 8.59 (t, 1 H), 8.04 - 7.95 (m,
5H), 7.33 (d, 2H), 7.21 (d, IH), 6.78 (d, IH), 4.96 (d, 2H), 4.44 (m, lh), 4.04 (m, 2H), 3.18 (d, 2H), 3.10 (s, 6H), 2.88 (m, 4H), 2.67 (s, 3H), 2.33 (s, IH), 1.95 (m,2H), 1.35 (m, 2H); MS (EI) for C3iH35F2N70: 522.1 (MH+).
68 Ή NMR (400 MHz, CD3OD) δ 9.20 (dd, IH), 8.72 (d, IH), 8.67 (s, IH),
8.38 (d, IH), 8.34 (dd, IH), 7.85 (dd, IH), 7.38 - 7.29 (m, 2H), 7.26 (dd, IH), 5.11 (s, 2H), 4.71-4.48 (m, 2H), 4.19 (t, 2H), 3.84 - 3.64 (m, IH), 3.25 - 3.06 (m, 4H), 3.05 - 2.84 (m, 2H), 2.76 (s, 3H), 2.05 - 1.90 (m, 1 H), 1.86 - 1.71 (m, 1 H), 1.49 - 1.31 (m, 2H). MS (EI) for C28H29N70: 480 (MH+).
69 Ή NMR (400 MHz, CD3OD) δ 8.94 (d, IH), 8.65 (s, IH), 8.58 (dd, IH),
8.28-8.21 (m, IH), 8.13 (d, IH), 8.01 (s, 1H),7.69 (s, IH), 7.65-7.54 (m, 2H), 7.45 (d, IH), 5.09 (s, 2H), 4.14 (t, 2H), 3.79 - 3.69 (m, IH), 3.69 - 3.66 (m, 1 H), 3.62 - 3.52 (m, IH), 3.25 (t, 2H), 3.14- 2.99 (m, 2H), 2.82 (d, 2H), 2.73 (s, 3H), 2.70 (s, 3H), 2.60 (td, IH), 1.73 (d, 2H), 1.21-1.11 (m, 2H). MS (EI) for C30H34 6OS: 543 (MH+).
70 Ή NMR (400 MHz, DMSO-d6) δ 8.72 (s, IH), 7.82 (s, IH), 7.76 (s, IH),
7.68 (s, IH), 7.59 (m, IH), 7.48 (m, IH), 5.04 (s, 2H), 4.03 (m, 2H), 3.20 (m, 2H), 3.02 (m, 2H), 2.75 (m, 3H), 2.65 (m, 6H), 2.33 (s, 3H), 1.86 (s, 3H), 1.63 (m, 2H), 1.07 (m, 2H). MS (El) for C3oH36N603S, found 561.0.
71 Ή NMR (400 MHz, CD3OD) δ 8.59 (s, IH), 8.26 (d, IH), 7.94 (s, IH),
7.91 - 7.84 (m, 2H), 7.35 (d, 1 H), 7.27 (dd, 2H), 6.81 - 6.68 (m, 1 H), 4.99 (d, 2H), 4.69 (s, IH), 4.17-4.02 (m, 2H), 3.82 (d, IH), 3.53 - 3.38 (m, 1 H), 3.21 (dd, 4H), 2.96 (m, 1 H), 2.69 (s, 3H), 2.13 (m, 1 H), 1.57 (m, 2H); MS (EI) for C29H3iN70: 494.1 (MH+).
72 Ή NMR (400 MHz, CD3OD) δ 8.59 (s, IH), 8.43 (t, IH), 8.01 (dd, IH),
7.95 (s, IH), 7.88 (d, IH), 7.33 (d, IH), 7.26 (d, 2H), 6.90 (t, IH), 4.97 (d, 3H), 4.68 (s, IH), 4.08 (t, 2H), 3.97 (s, 3H), 3.92 - 3.80 (m, IH), 3.35 (d, IH), 3.19 (t,3H), 2.89 (d, IH), 2.68 (s, 3H), 2.18 -2.02 (m, IH), 1.49 CMPD CHARACTERIZATION DATA
(d, 2H); MS (EI) for C3oH32N602: 509.1 (MH+).
73 Ή NMR (400 MHz, DMSO-d6) δ 8.71 (s, IH), 8.46 (d, IH), 8.29-8.22
(m, IH), 8.01 (d, IH), 7.88 (d, IH), 7.34 (d, IH), 7.29 (s, IH), 7.21 (dd, IH), 4.99 (s, 2H), 4.28 (br s, IH), 4.07 (t, 2H), 3.57 (br s, IH), 3.24-3.12 (m, 2H), 3.12-2.78 (m, 3H), 2.67 (s, 3H), 1.89-1.80 (m, 12H), 1.82-1.57 (m, 2H), 1.23 (br s, 2H). MS (EI) for C27H28 6OS: 485 (MH+).
74 Ή NMR (400 MHz, CD3OD) 58.83 (s, IH), 8.66 (s, IH), 8.52 (s, IH),
8.19 (s, 1 H), 8.08 (d, 1 H), 8.02 (d, 1 H), 7.36 (d, 1 H), 7.33 - 7.24 (m, 2H), 5.08 (s,2H),4.66 (s, IH), 4.21 -4.11 (m, 2H), 3.92 - 3.76 (m, 2H), 3.23 (m, 4H), 2.85 (m, IH), 2.74 (s, 3H), 2.07 (m, IH), 1.53 (m, 2H); MS (EI) for C29H29FN60: 497.0 (MH+).
75 Ή NMR (400 MHz, CD3OD) δ 9.02 (s, IH), 8.61 (s, IH), 8.31 (s, IH),
8.09 (d, IH), 7.99 (s, IH), 7.34 (d, IH), 7.25 (dd, 2H), 5.01 (s, 2H), 4.70 - 4.42 (m, 3H), 4.10 (t, 2H), 3.90 - 3.63 (m, 1 H), 3.27 - 2.80 (m, 5H), 2.68 (s, 3H), 2.13 - 1.65 (m, 2H), 1.51 - 1.27 (m, 2H). MS (EI) for C27H28N6OS: 485 (MH+).
76 Ή NMR (400 MHz, CD3OD) 58.68 - 8.60 (m, 2H), 8.24 (s, IH), 8.08
(s, 1 H), 7.85 (dd, 1 H), 7.70 (d, 1 H), 7.67 - 7.57 (m, 2H), 7.57 - 7.42 (m, 2H), 5.11 (s, 2H), 4.16 (t, 2H), 3.79 - 3.69 (m, IH), 3.69 - 3.60 (m, 3H), 3.60-3.52 (m, IH), 3.27 - 3.11 (m, 3H), 2.89-2.81 (m, 2H), 2.73 (s, 3H), 2.69 (s, 3H), 1.89 - 1.69 (m, 2H), 1.36 - 1.12 (m, 2H). MS (EI) for C30H34N6O2S: 543 (MH+).
77 Ή NMR (400 MHz, d6-DMSO): 8.79 (s, IH), 8.53 (m, IH), 8.28 (m,
IH), 8.19 (s, IH), 7.82 (s, 0.5H), 7.64 (d, IH), 7.54 (s, 0.5H), 7.48 (m, 2H), 7.38 (s, IH), 7.02 (m, IH), 5.30 (br s, 2H), 4.26 (br s, 2H), 3.88 (s, 3H), 3.28 (m, 4H), 2.88 (m, 4H), 2.68 (s, 3H), 2.63 (s, 3H), 1.86 (m, IH), 1.80 (d, 2H), 1.26 (m, 2H). MS (EI) for C32H37N503S: 572 (MH+).
78 Ή NMR (400 MHz, d6-DMSO): 8.79 (s, IH), 8.54 (m, IH), 8.24 (m,
1 H), 8.16 (s, 1 H), 8.13 (s, 1 H), 7.84 (m, 3.5H), 7.64 (d, 1 H), 7.53 (d, 1.5H), 7.10 (d, 2H), 5.28 (brs, 2H), 4.22 (br s, 2H), 3.84 (s, 3H), 3.29 (m, 2H), 3.22 (t, 2H), 2.84 (m, 4H), 2.68 (s, 3H), 1.90 (m, IH), 1.80 (d, 2H), 1.24 (m, 2H). MS (EI) for C32H37N503S: 572 (MH+).
79 Ή NMR (400 MHz, d6-DMSO): 8.82 (s, 1 H), 8.58 (m, 1 H), 8.29 (m,
IH), 8.22 (s, IH), 7.83 (s, IH), 7.66 (m, 2H), 7.54 (d, IH), 7.43 (t, IH), 7.27 (d, IH), 5.32 (brs, 2H), 4.28 (t, 2H), 3.29 (d, 2H), 3.21 (t, 2H), 2.82 (m, 4H), 2.68 (s, 3H), 2.64 (s, 3H), 2.42 (s, 3H), 1.90 (m, IH), 1.80 (d, 2H), 1.26 (m, 2H). MS (EI) for C32H37N502S: 556 (MH+).
80 Ή NMR (400 MHz, DMSO-d6) δ 9.16 (s, IH), 8.70 (s, IH), 8.53 (s, IH),
8.13-8.02 (m, 2H), 7.75 (d, IH), 7.60 (dd, IH), 7.49 (d, IH), 5.08 (s, 2H), 4.05 (t, 2H), 3.24 (t, 2H), 2.95 (d, 2H), 2.81-2.66 (m, 2H), 2.66 (s, 3H), 2.63 (s, 3H), 2.48-2.38 (m, 2H), 1.87 (s, 6H), 1.58 (d, 3H), 1.01 (d, 2H).. MS (EI) for C28H32N602S2: 549 (MH+).
81 Ή NMR (400 MHz, DMSO-d6) 511.51 (s, IH), 8.74 (s, IH), 8.01 (s,
1 H), 7.89 (s, IH), 7.22 (s, 2H), 6.95 (s, 2H), 3.86 (m, 4H), 3.72 (m, 4H), 2.62 (s, 3H). MS (EI) for C2oH,9BrN6, found 423.0. CMPD CHARACTERIZATION DATA
82 Ή NMR (400 MHz, DMSO-d6) δ 13.15 (s, IH), 8.66 (s, IH), 7.48-7.42
(m, 2H), 7.39 (s, IH), 7.32 - 7.26 (m, 2H), 4.09 (s, 4H), 3.86 (m, 6H), 3.64 (m, 2H), 2.80 - 2.55 (m, 5H). MS (EI) for C24H25F2N7, found 450.0.
83 Ή NMR (400 MHz, DMSO-d6) 58.75-8.65 (m, 3H), 8.24 (d, IH), 8.17
(s, IH), 7.90 (dd, 2H), 7.77 (d, IH), 7.59 (dd, IH), 7.49 (d, IH), 5.11 (s, 2H), 4.08 (t, 2H), 3.22 (t, 2H), 2.78-2.66 (m, 6H), 2.63 (s, 3H), 2.12 (s, 3H), 1.82-1.72 (m, 2H), 1.58 (d, 2H), 1.52-1.39 (m, IH), 1.19-1.00 (m, 2H). MS (EI) for C3,H36N602S: 557 (MH+).
84 Ή NMR (400 MHz, DMSO-d6) δ 8.70 (s, IH), 8.46 (d, IH), 8.30-8.21
(m, IH), 8.01 (d, IH), 7.88 (d, IH), 7.78-7.68 (m, IH), 7.60 (dd, IH), 7.51 (d, IH), 5.09 (s, 2H), 4.08 (t, 2H), 3.23 (t, 2H), 2.79-2.65 (m, 7H), 2.63 (s, 3H), 2.12 (s, 3H), 1.83-1.73 (m, 2H), 1.59 (d, 2H), 1.53-1.39 (m, IH), 1.17-1.03 (m, 2H). MS (EI) for C29H34N602S2: 563 (MH+).
85 Ή NMR (400 MHz, CD3OD) δ 8.64 (s, IH), 8.08 (m, 2H), 7.95 (m, 2H),
7.42 (s, IH), 7.36 (d, IH), 7.27 (dd, 2H), 5.05 (s, 2H), 4.63 (s, IH), 4.21 -4.06 (m, 2H), 3.75 (s, IH), 3.32 (s, IH), 3.22 (dd, 4H), 3.01-2.88 (m, IH), 2.73 (s, 3H), 2.09 (s, IH), 1.54 (m, 2H); MS (EI) for C29H3iN70: 494.1 (MH+).
86 Ή NMR (400 MHz, CD3OD) δ 9.21 (dt, IH), 8.72 (d, IH), 8.69 (s, IH),
8.38 (dd, IH), 8.35 (dd, IH), 7.86 (dd, IH), 7.73 (d, IH), 7.63 (dd, IH), 7.48 (d, IH), 5.19 (s,3H), 4.21 (t, IH), 2.92 - 2.80 (m, 4H), 2.77 (s, 3H), 2.70 (s, 3H), 2.25 (s, 3H), 2.00 (t, 2H), 1.74 (d, 2H), 1.69 - 1.46 (m, IH), 1.40 - 1.13 (m, 3H). MS (EI) for C30H3SN7O2S: 558 (MH+).
87 Ή NMR (400 MHz, CD3OD) δ 8.96 (d, IH), 8.67 (s, IH), 8.59 (dd, IH),
8.26 (ddd, IH), 8.16 (d, IH), 8.04 (s, IH), 7.71 (d, IH), 7.67-7.53 (m, 2H), 7.48 (d, 1 H), 5.12 (s, 2H), 4.72 - 4.45 (m, 1 H), 4.17 (t, 2H), 2.89 (d, 2H), 2.75 (s, 3H), 2.72 (s, 3H), 2.70-2.61 (m, 3H), 1.97- 1.92 (m, 6H), 1.92 - 1.88 (m, 1 H), 1.88 - 1.74 (m, 1 H), 1.58 - 1.21 (m, 2H). MS (EI) for C3,H36N602S:557(MH+).
88 Ή NMR (400 MHz, DMSO-d6): δ 8.63 (s, IH), 8.49 (m, IH), 8.20 (m,
IH), 8.02 (d, 2H), 7.73 (s, IH), 7.66 (m, 2H), 7.49 (d, IH), 5.04 (s, 2H), 4.02 (br t, 2H), 3.48 (s, 3H), 3.25 (br t, 2H), 2.74 (m, 2H), 2.64 (d, 6H), 2.15 (s, 3H), 1.91 (s, 3H-OAc peak), 1.85 (br t, 2H), 1.60 (d, 2H), 1.49 (br s, 1 H), 1.12 (m, 2H).; MS (EI) for C29H3sN702S: 546.0 (MH+).
89 Ή NMR (400 MHz, DMSO-d6) δ 9.33 (s, 2H), 9.24 (s, IH), 8.71 (s, IH),
8.25 (d, IH), 8.18 (d, IH), 7.77 (d, IH), 7.58 (dd, IH), 7.48 (d, IH), 5.14 (s, 2H), 4.10 (dd, 2H), 3.19 (t, 2H), 2.80-2.66 (m, 7H), 2.62 (s, 3H), 2.13 (s, 3H), 1.80 (t, 2H), 1.58 (d, 2H), 1.55-1.35 (m, IH), 1.19-1.00 (m, 2H). MS (EI) for C30H35N7O2S: 558 (MH+).
90 Ή NMR (400 MHz, DMSO-d6) δ 9.33 (s, 2H), 9.24 (s, IH), 8.71 (s, IH),
8.25 (d, IH), 8.18 (d, IH), 7.77 (d, IH), 7.58 (dd, IH), 7.48 (d, IH), 5.14 (s, 2H), 4.10 (dd, 2H), 3.19 (t, 2H), 2.80-2.66 (m, 7H), 2.62 (s, 3H), 2.13 (s, 3H), 1.80 (t, 2H), 1.58 (d, 2H), 1.55-1.35 (m, IH), 1.19-1.00 (m, 2H). MS (EI) for C30H35N7O2S: 558 (MH+). CMPD CHARACTERIZATION DATA
91 Ή NMR (400 MHz, CD3OD) 58.63 (s, IH), 7.80 (d, 2H), 7.66 (dd, 3H),
7.48 (d, 1 H), 5.02 (s, 2H), 4.10 (t, 2H), 3.88 (s, 3H), 3.29 - 3.20 (m, 4H), 2.89 (d, 3H), 2.82 (d, 2H), 2.72 (s, 3H), 2.69 (s, 3H), 2.51 (s, 3H), 1.94 - 1.85 (m, 3H), 1.32 (dd, 2H); MS (EI) for C30H37N7O2S: 560.1 (MFT).
92 Ή NMR (400 MHz, CD3OD) δ 8.58 (s, IH), 7.73 (s, 2H), 7.63 (dd, 3H),
7.44 (d, IH), 4.96 (s, 2H), 4.04 (t, 2H), 3.86 (d, 3H), 3.31 (s, 3H), 3.20 (t, 2H), 3.12 (d, 2H), 2.87 (d, 2H), 2.68 (s, 3H), 2.59 (s, 3H), 2.49 (d, 3H), 2.4 (m, 2H), 2.46 - 2.31 (m, 2H), 1.84 (m, 2H), 1.44 - 1.27 (m, 2H); MS (EI) forC31H39N702S: 574.0 (MH+).
93 Ή NMR (400 MHz, CD3OD) δ 9.03 (d, IH), 8.65 (s, IH), 8.34 (s, IH),
8.13 (d, IH), 8.02 (d, IH), 7.70 (d, IH), 7.63 (dd, IH), 7.48 (d, IH), 5.08 (s, 2H), 4.13 (t, 2H), 3.27 (d, 2H), 2.92-2.78 (m, 4H), 2.71 (s, 6H), 2.25 (s,3H), 2.05- 1.94 (m, 2H), 1.73 (d, 2H), 1.69- 1.54 (m, IH), 1.31 - 1.25 (m, 2H). MS (EI) for C29H34N602S2: 563 (MH+).
94 Ή NMR (400 MHz, d6-DMSO): 8.79 (S, IH), 8.54 (m, IH), 8.22 (m,
IH), 8.18 (s, 2H), 7.83 (s, 0.5H), 7.80 (m, IH), 7.74 (m, IH), 7.64 (m, 0.5H), 7.53 (d, IH), 7.32 (t, IH), 5.26 (br s, 2H), 4.24 (br s, 2H), 3.28 (m, 2H), 3.20 (t, 2H), 2.82 (m, 4H), 2.68 (s, 3H), 2.34 (s, 3H), 1.88 (m, IH), 1.80 (m, 2H), 1.26 (m, 2H). MS (EI) for
Figure imgf000139_0001
574 (MH+).
95 Ή NMR (400 MHz, d6-DMSO): 8.80 (s, IH), 8.52 (m, IH), 8.28 (d,
2H), 8.19 (m, 3H), 7.82 (d, 2H), 7.79 (t, IH), 7.63 (dd, IH), 7.52 (d, IH), 5.29 (br s, 2H), 4.26 (br s, 2H), 3.29 (m, 2H), 3.20 (t, 2H), 2.82 (m, 3H), 2.68 (s, 3H), 2.64 (s, 3H), 1.88 (m, IH), 1.80 (m, 2H), 1.24 (m, 2H). MS (EI) for C32H34F3N502S: 610 (MH+).
96 Ή NMR (400 MHz, d6-DMSO): 8.79 (s, IH), 8.52 (m, IH), 8.24 (d,
2H), 8.22 (m, IH), 7.94 (d, IH), 7.88 (s, IH), 7.83 (s, IH), 7.69 (t, IH), 7.64 (dd, IH), 7.53 (d, IH), 7.45 (d, IH), 5.29 (br s, 2H), 4.22 (br s, 2H), 3.29 (m, 2H), 3.21 (t, 2H), 2.82 (m, 3H), 2.69 (s, 3H), 2.63 (s, 3H), 1.89 (m, IH), 1.78 (m, 2H), 1.22 (m, 2H). MS (EI) for C32H34F3N503S: 626 (MH+).
97 Ή NMR (400 MHz, d6-DMSO): 8.81 (s, IH), 8.60 (m, IH), 8.53 (m,
IH), 8.26 (m, 2H), 8.04 (d, IH), 7.90 (d, IH), 7.83 (s, IH), 7.82 (dd, IH), 7.65 (d, 1 H), 7.63 (t, 1 H), 7.52 (d, 1 H), 5.32 (br s, 2H), 4.28 (br s, 2H), 3.28 (m, IH), 3.21 (t, 2H), 2.84 (m, 3H), 2.78 (d, 3H), 2.69 (s, 3H), 2.64 (s, 3H), 1.89 (m, IH), 1.80 (m, 2H), 1.28 (m, 2H). MS (EI) for C33H38N603S: 599 (MH+).
98 Ή NMR (400 MHz, d6-DMSO): 9.32 (d, IH), 8.78 (s, IH), 8.58 (dd,
1 H), 8.50 (m, 1 H), 8.34 (s, 1 H), 8.29 (s, 1 H), 8.20 (m, I H), 8.08 (d, 1 H), 7.81 (s, IH), 7.62 (dd, IH), 7.52 (d, IH), 5.28 (m, 2H), 4.22 (m, 2H), 3.29 (m, 2H), 3.21 (t, 2H), 2.82 (m, 2H), 2.70 (s, 3H), 2.64 (s, 3H), 1.88 (m, IH), 1.78 (m, 2H), 1.26 (m, 2H). MS (EI) for C3,H33F3N602S: 611 (MH+).
99 Ή NMR (400 MHz, d6-DMSO): 9.42 (d, IH), 9.04 (s, IH), 8.81 (s, IH),
8.68 (s, IH), 8.54 (m, IH), 8.42 (s, IH), 8.35 (s, IH), 8.22 (m, IH), 7.82 (s, IH), 7.63 (d, 0.5H), 7.52 (d, 0.5H), 5.31 (br s, 2H), 4.24 (br s, 2H), 3.29 (m, 2H), 3.20 (t, 2H), 2.82 (m, 4H), 2.69 (s, 3H), 2.64 (s, 3H), 1.87 CMPD CHARACTERIZATION DATA
(m, IH), 1.80 (m, 2H), 1.26 (m, 2H). MS (EI) for C3iH33F3N602S: 611 (MH+).
100 Ή NMR (400 MHz, methanol-^,) δ 8.59 (d, IH), 8.49 (d, IH), 7.82 (s,
IH), 7.69 (s, IH), 7.68 (s, IH), 7.62 (d, IH), 7.61 (s, IH), 7.53 (s, IH), 7.44 (d, IH), 5.49 (s, 3H), 5.01 (s, 2H), 4.10 (t, 2H), 3.23 (t, 2H), 2.89 (m, 4H), 2.89 (d, 2H), 2.79 (m, IH), 2.70 (s, 3H), 2.63 (s, 3H), 1.92 (m, 2H), 1.43 (m, 2H). MS (ES) for C3|H36N603S: 573 (MH+).
101 Ή NMR (400 MHz, DMSO-d6) δ 11.59 (s, IH), 8.56 (s, IH), 8.00-7.82
(m, IH), 7.61 (m, IH), 7.30 (m, IH), 7.01 (m, IH), 6.64 (m, IH), 4.53 (m, IH), 4.33 (m, 2H), 3.86 (m, 2H), 3.63 (m, 2H), 3.34 (s, 3H), 3.18 (m, 3H), 2.66 - 2.56 (m, 6H). MS (EI) for C24H25F2 7O, found 466.1.
102 Ή NMR (400 MHz, DMSO-d6) δ 8.73 (s, IH), 8.41 (s, IH), 8.23 (s, IH),
7.99 (m, IH), 7.95 - 7.78 (m, 3H), 7.62 (m, IH), 7.00 (m, IH), 4.73 - 4.26 (m, 4H), 3.48 - 3.37 (m, 4H), 2.71 (m, 4H), 2.57 (m, 2H), 1.91 (m, 2H). MS (EI) for C23H2iN7OS, found 444.7.
103 Ή NMR (400 MHz, CD3OD) δ 9.04 (s, IH), 8.64 (s, IH), 8.34 (s, IH),
8.14 (s, IH), 8.03 (s, IH), 7.40 -7.17 (m, 3H), 4.13 (t, 2H), 3.82-3.67 (m, IH), 3.65 -3.54 (m, IH), 3.51 - 3.44 (m, IH), 3.27- 3.19 (m, 3H), 3.10-2.96 (m,3H), 2.92 (s, IH), 2.85-2.73 (m, IH), 2.71 (s, 3H), 2.35 -2.23 (m,2H), 2.23- 1.97 (m, 3H), 1.97-1.91 (m, IH), 1.90- 1.84 (m, 2H), 1.82 - 1.71 (m, 1 H), 1.60 - 1.50 (m, 1 H). MS (EI) for C3oH34N6OS: 527 (MH+).
104 . Ή NMR (400 MHz, DMSO-d6): δ 8.85 (s, IH), 8.67 (s, IH), 8.44 (s,
IH), 8.17 -7.98 (m, 3H), 7.34 (s, IH), 7.27 (m, IH), 7.21 - 7.09 (m, IH), 4.99 (s, 2H), 4.05 (brt, 2H), 3.13 (br t, 2H), 2.88 (d, 3H), 2.73 (m, 1H),2.72 (s,3H), 2.71 (m, IH), 2.47 (s, 3H), 2.39 - 2.35 (m, 3H), 1.88 (s, 3H-OAc peak), 1.79 (m, 4H), 1.40 (d, IH), 1.19 (m, 2H), 0.80 (m, IH); MS (EI) for C33H38N60: 535.1 (MH+).
105 Ή NMR (400 MHz, CD3OD) δ 8.79 (s, IH), 8.60 (s, IH), 8.49 (s, IH),
8.12 (s, 1 H), 8.03 (d, 1 H), 7.98 (s, 1 H), 7.35 - 7.15 (m, 3H), 5.03 (s, 2H), 4.18-4.05 (m, 2H), 3.47 (d, 1H),3.45 (m, 1 H), 3.21 (m, 2H), 2.96 (m, 1H),2.69 (s,3H),2.58 (m, 3H), 2.44 - 2.21 (m, 2H), 2.05 (m, IH), 1.98 (m, IH), 1.72 (m, IH), 1.60 (m, IH), 1.45 (d, IH), 1.21 (d, IH), 0.99 (d, IH); MS (EI) for C32H35FN60: 539.1 (MH+).
106 Ή NMR (400 MHz, DMSO-d6) δ 8.61 (s, IH), 7.79 (m, 4H), 7.72 (m,
IH), 7.61 (m, 3H), 4.15 (m, 2H), 3.43-3.24 (m, IH), 3.12-2.88 (m, 2H), 2.68 (m, 2H), 2.55 (s, 3H), 1.73 (m, 3H), 1.28 (m, 2H). MS (EI) for C2iH23BrN402S, found 477.0.
107 Ή NMR (400 MHz, methanol-d4): 8.67 (s, IH), 7.97 (s, IH), 7.83 (s,
IH), 7.78 (s, IH), 7.69 (s, IH), 7.63 (d, IH), 7.47 (d, IH), 7.23 (s, IH), 5.07 (s, 2H), 4.13 (m, 2H), 3.84 (s, 3H), 3.24 (m, 2H), 2.89 (d, 2H), 2.72 (s, 6H), 2.66 (s, 3H), 1.93 (s, 3H), 1.83 (br. s, IH), 1.41 (m, 2H). MS (EI) for C30H37N7O2S: 560 (MH+).
108 . Ή NMR (400 MHz, DMSO-d6): δ 8.64 (s, IH), 7.67 (d, 2H), 7.58 (d,
IH), 7.48 (d, 2H), 4.88 (s, 2H), 3.90 (brt, 2H), 3.21 (brt, 2H), 3.02 (s, CMPD CHARACTERIZATION DATA
3H), 2.83 - 2.65 (m, 4H), 2.60 (d, 6H), 2.11 (s, 3H), 1.89 (s, 3H-OAc peak), 1.78 (m, 2H), 1.58 (d, 2H), 1.47 (m, 1 H), 1.28 - 0.99 (m, 2H); MS (El) for C27H36N604S2: 573.0 (MH+).
109 . Ή NMR (400 MHz, CD3OD) δ 8.92 (dd, IH), 8.61 (s, IH), 8.57 (dd,
IH), 8.21 (ddd, IH), 8.12 (d, IH), 8.03-7.92 (m, IH), 7.58 (ddd, IH), 6.97 (d, IH), 6.62 (dd, IH), 6.59 (d, IH), 4.08 (t, 2H), 3.03 (t, 2H), 2.73 (s, 3H). MS (EI) for C23H2,N5: 368 (MH+).
110 Ή NMR (400 MHz, CD3OD) δ 8.94 (d, IH), 8.64 (s, IH), 8.58 (dd, IH),
8.24 (ddd, IH), 8.16 (s, IH), 8.01 (dd, IH), 7.59 (ddd, IH), 7.17-7.08 (m, 1 H), 7.08 - 6.98 (m, 2H), 4.99 (s, 2H), 4.13 (t, 2H), 3.18- 3.07 (m, 2H), 2.85 (s, 3H), 2.74 (s, 3H). MS (El) for C24H23N502S: 446 (MH+).
111 Ή NMR (400 MHz, CD3OD) δ 8.95 (dd, IH), 8.67 (s, IH), 8.58 (dd,
IH), 8.27 -8.18 (m, IH), 8.16 (d, IH), 8.03 (dd, IH), 7.78 (d, IH), 7.73 (dd, IH), 7.59 (ddd, IH), 7.41 (d, IH), 5.09 (s, 2H), 4.25-4.08 (m, 2H), 3.24 (t, 2H), 2.75 (s, 3H). MS (EI) for C23H2,N502S: 432 (MH+).
112 Ή NMR (400 MHz, DMSO-d6) 58.48 (s, IH), 7.87 - 7.75 (m, 2H), 7.73
(s, IH), 7.69-7.52 (m, 3H), 7.25 (s, IH), 6.45 (m, IH), 4.10 (m, 2H), 3.82 (m, 2H), 3.59 (m, 2H), 2.89 (m, 2H), 2.71 (s, 2H), 2.67-2.51 (m, 5H), 1.77 (m, 2H), 1.67 (m, IH), 1.42 - 1.18 (m, 2H). MS (EI) for
C25H29F2N502S, found 500.1.
113 Ή NMR (400 MHz, methanol-d4) δ 9.27 (s, IH), 8.82 (s, IH), 8.82 (s,
2H), 8.75 (s, IH), 8.53 (s, IH), 8.33 (s, IH), 8.02 (s, IH), 7.80 (s, IH), 7.69 (d, IH), 7.55 (d, IH), 5.57 (s, 2H), 4.54 (t, 2H), 3.84 (d, 2H), 3.34 (t, 2H), 3.08 (m, IH), 2.76 (s, 3H), 2.43 (t, 2H), 2.04 (m, 2H), 1.65 (m, 2H). MS (ES) for C2gH30N6O2S: 515 (MH+).
114 Ή NMR (400 MHz, DMSO-d6): δ 9.07 (s, IH), 8.70 (s, IH), 8.63 (d,
IH), 8.27 (d, IH), 8.13 (d, 2H), 7.89 (s, IH), 7.77 (d, IH), 7.63-7.47 (m, IH), 7.35 (d, IH), 5.06 (s, 2H), 4.08 (br t, 2H), 3.18 (br t, 2H), 2.66 (s, 3H); MS (EI) for C24H20N4O2: 397.0 (MH+).
115 Ή NMR (400 MHz, DMSO-d6) δ 9.15 (d, IH), 8.65 (s, IH), 8.48 (d,
IH), 8.12-7.98 (m, 2H), 6.93 (d, IH), 6.54-6.40 (m, 2H), 5.26 (d, IH), 4.81 (s, 2H), 3.97 (t, 2H), 3.52-3.05 (m, 3H), 2.97 (t, 2H), 2.77-2.57 (m, 5H), 2.15 (s,3H), 2.05-1.91 (m, 2H), 1.43-1.26 (m, 2H). MS (EI) for C27H30N6S: 471 (MH+).
116 Ή NMR (400 MHz, CD3OD D) δ 8.95 (dd, IH), 8.66 (s, IH), 8.58 (dd,
IH), 8.24 (ddd, IH), 8.17 (d, IH), 8.02 (dd, IH), 7.75 (d, IH), 7.72 (dd, IH), 7.59 (ddd, IH), 7.34 (d, IH), 5.09 (s, 2H), 4.16 (t, 2H), 3.23 (t, 2H), 2.74 (s, 3H). MS (EI) for C24H2| 50: 396 (MH+).
117 Ή NMR (400 MHz, CD3OD) δ 8.95 (dd, IH), 8.66 (s, IH), 8.59 (dd,
1 H), 8.24 (ddd, 1 H), 8.17 (d, 1 H), 8.02 (s, 1 H), 7.72 - 7.62 (m, 2H), 7.59 (dd, IH), 7.33 (d, IH), 5.08 (s, 2H), 4.15 (t, 2H), 3.22 (t, 2H), 2.90 (s, 3H), 2.74 (s, 3H). MS (EI) for C25H23N50: 410 (MH+).
118 Ή NMR (400 MHz, CD3OD) δ 8.94 (d, IH), 8.65 (s, IH), 8.58 (dd, IH),
8.24 (ddd, IH), 8.15 (d, IH), 8.01 (dd, IH), 7.59 (ddd, IH), 7.32 (dd, 2H), 7.27 (dd, IH), 5.06 (s, 2H), 4.15 (t, 2H), 3.21 (t, 2H), 3.08 (s, 3H), CMPD CHARACTERIZATION DATA
3.00 (s, 3H), 2.74 (s, 3H). MS (EI) for C26H25N5O: 424 (MH+).
119 . Ή NMR (400 MHz, CD3OD) 59.03 (s, IH), 8.62 (s, IH), 8.32 (s, IH),
8.12 (d, IH), 8.01 (s, IH), 7.23 - 7.12 (m, IH), 7.12 - 7.05 (m, 2H),4.96 (s, 2H), 4.10 (t, 2H), 3.14 (t, 2H), 2.89 (s, 3H), 2.70 (s, 3H). MS (EI) for C22H21N5O2S2: 452 (MH+).
120 . Ή NMR (400 MHz, DMSO-d6): δ 9.00 (s, IH), 8.68 (s, IH), 8.61 (d,
IH), 8.24 (d, IH), 8.11 (d, 2H), 7.63-7.47 (m, IH), 7.44 - 7.19 (m, 3H), 5.01 (s, 2H), 4.06 (t, 2H), 3.15 (brt, 2H), 2.95 (br s, 2H), 2.65 (s, 3H), 2.60 (m, 2H), 1.89 (s, 1.5H-OAc peak); MS (EI) for C29H30N6O: 479.1 (MH+).
121 Ή NMR (400 MHz, DMSO-d6): δ 9.05 (s, IH), 8.68 (s, IH), 8.61 (d,
IH), 8.24 (d, IH), 8.10 (d, 2H), 7.53 (dd, IH), 7.41-7.14 (m, 3H), 5.00 (s, 2H), 4.05 (t, 2H), 3.56 (br s, 8H), 3.17 - 3.08 (m, 2H), 2.67 (s, 3H), 1.88 (s, 1.5H-OAc peak); MS (EI) for C28H27 5O2: 466.0 (MH+).
122 Ή NMR (400 MHz, DMSO-d6): δ 9.05 (s, IH), 8.67 (s, IH), 8.60 (d,
IH), 8.24 (d, IH), 8.10 (d, 2H), 7.52 (dd, IH), 7.45 (s, IH), 7.30 (dd, 2H), 5.00 (s, 2H), 4.05 (t, 2H), 3.17 (t, 2H), 2.67 (s, 3H), 1.86 (s, 1.5H- OAc peak), 1.87 - 1.64 (m, 4H); MS (EI) for C28H27N5O: 450.1 (MH+).
123 Ή NMR (400 MHz, DMSO-d6): δ 10.27 (s, IH), 8.62 (s, IH), 8.45 (s,
IH), 7.80 (d, 2H), 7.60 (d, IH), 7.41 (d, IH), 4.88 (s, 2H), 3.90 (t, 2H), 3.21 (br t, 2H), 2.73 (m, 4H), 2.60 (d, 6H), 2.09 (d, 6H), 1.85 (s, 2H-OAc peak), 1.77 (t, 2H), 1.57 (d, 2H), 1.46 (m, IH), 1.09 (m, 2H); MS (EI) for C28H36N603S: 537.0 (MH+).
124 Ή NMR (400 MHz, DMSO-d6) δ 9.05 (d, IH), 8.67 (s, IH), 8.62 (dd,
1 H), 8.29-8.18 (m, 1 H), 8.11 (d, 2H), 7.59-7.45 (m, 1 H), 6.95 (d, 1 H), 6.56-6.39 (m, 2H), 5.27-5.02 (m, IH), 4.87 (s, 2H), 4.02 (t, 2H), 3.19- 2.84 (m, 4H), 2.68 (s, 3H), 2.61-2.35 (m, 6H), 1.17-0.81 (m, 6H). MS (EI) for C29H34N6: 467 (MH+).
125 Ή NMR (400 MHz, CD3OD) δ 8.94 (d, IH), 8.64 (s, IH), 8.58 (dd, IH),
8.29 - 8.20 (m, IH), 8.15 (d, IH), 8.02 (dd, IH), 7.59 (ddd, IH), 7.47 (d, IH), 7.34 (dd, IH), 7.18 (d, IH), 4.99 (s, 2H), 4.13 (t, 2H), 3.13 (t, 2H), 2.74 (s, 3H), 2.10 (s, 3H). MS (EI) for C25H23N5O: 410 (MH+).
126 Ή NMR (400 MHz, DMSO-d6) δ 8.99 (s, IH), 8.67 - 8.52 (m, 2H), 8.16
(m, IH), 8.05 (s, IH), 7.94 (s, IH), 7.84-7.79 (m, 2H), 7.75 (m, IH), 7.71 - 7.58 (m, 3H), 7.53 (m, IH), 4.28 (m, 2H), 3.20 - 2.98 (m, 2H), 2.81 -2.62(m, 5H), 1.74 (m,3H), 1.48- 1.18 (m, 2H). MS (EI) for C26H27N5O2S, found 474.0.
127 Ή NMR (400 MHz, DMSO-d6) δ 8.66 (s, IH), 7.84 (m, 2H), 7.10 (m,
IH), 4.19 (m, 2H), 3.11 (m, 2H), 2.90 (s, 3H), 1.78 (m, 3H), 1.44 - 1.23 (m, 2H). MS (EI) for
Figure imgf000142_0001
found 413.0.
128 Ή NMR (400 MHz, DMSO-d6) δ 8.99 (m, IH), 8.72 - 8.50 (m, 2H),
8.19 (m, 1 H), 8.06 (s, 1 H), 7.97 (s, 1 H), 7.62 - 7.43 (m, 2H), 7.21 - 7.05 (m, IH), 4.33 (m, 2H), 3.20 (m, 2H), 2.92 (m, 5H), 2.68 (s, 3H), 1.98 - 1.68 (m, 3H), 1.51-1.27 (m, 2H). MS (EI) for C2iH25 s02S, found CMPD CHARACTERIZATION DATA
411.9.
129 . Ή NMR (400 MHz, DMSO-d6) δ 8.49 (s, IH), 7.25 (s, IH), 7.09 (m,
IH), 6.51 (m, IH), 4.13 (m, 2H), 3.84 (m, 2H), 3.60 (m, 2H), 3.08-2.80 (m, 8H), 2.72 - 2.54 (m, 6H), 1.85 (m, 2H), 1.73 (m, 1 H), 1.51 - 1.28 (m, 2H). MS (EI) for C2oH27F2N502S, found 439.9.
130 Ή NMR (400 MHz, CD3OD) δ 8.95 (bs, IH), 8.64 (s, IH), 8.63 (bs,
IH), 8.23 (d, IH), 8.12 (s, IH), 8.00 (s, IH), 7.66 (s, IH), 7.58 (d, 2H), 7.45 (d, IH), 5.09 (s, 2H), 4.59 (s, IH), 4.47 (s, IH), 4.13 (t, 2H), 3.76 (d, 2H), 3.27 - 3.18 (m, 2H), 3.03 (d, 2H), 2.71 (s, 3H), 2.70 (m, IH), 2.34 (t, 2H), 2.00 (d, 2H), 1.48 (d, 2H); MS (EI) for C30H33FN6O2S: 561.0 (MH+).
131 'H MR(400MHz,DMSO-d6): 58.82-8.51 (m, 2H), 8.17 (dd, IH),
8.01 (s, 2H), 7.45 (s, IH), 7.30 (dd, 2H), 6.92 (dd, IH), 4.98 (s, 2H), 4.03 (t, 2H), 3.89 (s, 3H), 3.49 - 3.36 (m, 2H), 3.14 (t, 2H), 2.59 (s, 3H), 1.88 (s,1.5H-OAc peak), 1.85 - 1.73 (m, 4H); MS (EI) for ¾Η29Ν502: 480.0 (MH+).
132 Ή NMR (400 MHz, DMSO-d6): δ 8.61 (s, IH), 8.40-8.12 (brd, 2H),
7.99 (d, 2H), 7.44 (s, 3H), 7.31 (dd, 2H), 4.93 (s, 2H), 3.98 (br t, 2H), 3.42 (m, 2H), 3.16 (brt, 2H), 2.62 (s, 3H), 1.88 (s, 0.8H-OAc peak), 1.88 - 1.70 (m, 4H); MS (EI) for C26H26N60: 439.1 (MH+).
133 Ή NMR (400 MHz, DMSO-d6) δ 8.70-8.59 (m, 2H), 8.17 (dd, IH), 8.04
(s, 2H), 7.02-6.87 (m, 2H), 6.55-6.40 (m, 2H), 5.27-5.06 (m, IH), 4.85 (s, 2H), 3.99 (t, 2H), 3.93 (s, 3H), 3.13-2.88 (m, 4H), 2.67 (s, 3H), 2.60- 2.36 (m, 6H), 1.07-0.86 (m, 6H). MS (EI) for C3oH36N60: 497 (MH+).
134 Ή NMR (400 MHz, DMSO-d6) δ 8.68-8.60 (m, 2H), 8.17 (dd, IH), 8.03
(s, 2H), 6.97 (d, IH), 6.92 (d, IH), 6.50-6.43 (m, 2H), 5.26 (d, IH), 4.83 (s, 2H), 4.57 (t, IH), 4.45 (t, IH), 3.99 (t, 2H), 3.92 (s, 3H), 3.24-3.10 (m, IH), 2.95 (t, 2H), 2.88-2.78 (m, 2H), 2.67 (s, 3H), 2.62 (t, IH), 2.56 (t, IH), 2.12 (t, 2H), 1.90-1.82 (m, 2H), 1.41-1.27 (m, 2H). MS (EI) for C31H35FN60: 527 (MH+).
135 Ή NMR (400 MHz, d6-DMSO): 9.00 (d, IH), 5.56 (dd, IH), 8.18 (dd,
IH), 8.07 (d, IH), 7.93 (dd, IH), 7.64 (s, 0.5H), 7.50 (m, 2.5H), 7.44 (d, IH), 6.46 (s, 2H), 5.01 (s, 2H), 3.98 (t, 2H), 3.48 (d, 2H), 3.22 (t, 2H), 2.64 (m, IH), 2.36 (t, 2H), 1.77 (m, 2H), 1.33 (m, 2H). MS (EI) for C27H29N702S: 516 (MH*).
136 Ή NMR (400 MHz, d6-DMSO): 9.09 (d, IH), 8.72 (s, IH), 8.63 (dd,
1 H), 8.28 (m, 1 H), 8.18 (s, 1 H), 8.13 (s, 1 H), 7.78 (s, 1 H), 7.59 (m, 1 H), 7.55 (m, 2H), 5.94 (s, IH), 5.16 (s, 2H), 4.10 (t, 2H), 3.62 (d, IH), 3.34 (br s, 2H), 3.22 (t, 1 H), 2.70 (s, 3H), 2.39 (m, 2H), 1.72 (m, 4H). MS (EI) for C29H28F3N503S: 584 (MH+).
137 Ή NMR (400 MHz, methanol-d4): 8.65 (s, IH), 8.53 (s, IH), 8.10 (m,
IH), 8.07 (s, IH), 7.97 (s, IH), 7.69 (s, IH), 7.61 (d, IH), 7.48 (d, IH), 6.95 (d, IH), 5.11 (s, 2H), 4.51 (d, 2H), 4.15 (m, 2H), 3.99 (s, 3H), 3.75 (d, 2H), 3.26 (m, 2H), 2.93 (d, 2H), 2.73 (s, 3H), 2.51 (br. S, IH), 2.37 (m, 2H), 1.98 (m, 2H), 1.94 (s, 3H), 1.45 (br. s, 2H). MS (EI) for CMPD CHARACTERIZATION DATA
C31H35FN6O3S: 591 (MH+).
138 Ή NMR (400 MHz, methanol-d4): 8.64 (s, IH), 8.52 (s, IH), 8.08 (m,
2H), 7.96 (s, IH), 7.35 (d, IH), 7.28 (m, 2H), 6.94 (d, IH), 5.02 (s, 2H), 4.61 (s, 2H), 4.49 (s, IH), 4.13 (m, 2H), 3.98 (s, 3H), 3.79 (m, IH), 3.25- 2.83 (m, 8H), 2.72 (s, 3H), 2.07 (m, IH), 1.92 (s, 6H), 1.36 (m, 2H). MS (El) for C32H35FN602: 555 (MH+).
139 lH NMR (400 MHz, DMSO-d6) 58.62-8.57 (m, IH), 8.55 (s, IH), 8.16- 8.10 (m, 2H), 7.99-7.96 (m, IH), 6.95 (d, IH), 3.91 (s, 3H), 3.35 (s, 6H), 2.65 (s, 3H). MS (El) for Ci7Hi8N40: 295 (MH+).
140 Ή NMR (400 MHz, CD3OD) δ 8.95 (d, IH), 8.66 (s, IH), 8.58 (dd, IH),
8.25 (ddd, IH), 8.17 (d, IH), 8.02 (dd, IH), 7.59 (ddd, IH), 7.34 (d, IH), 7.22 (d, IH), 7.14 (dd, IH), 5.07 (s, 2H),4.16(t, 2H), 3.24-3.20 (m, 5H), 2.74 (s, 3H), 1.84 (s, 3H). MS (EI) for C26H25N50: 424 (MH+).
141 Ή NMR (400 MHz, CD3OD) δ 8.94 (d, IH), 8.65 (s, IH), 8.58 (dd, IH),
8.24 (ddd, IH), 8.18 -8.13 (m, IH), 8.05 - 7.99 (m, IH), 7.59 (ddd, IH), 7.35 - 7.30 (m, IH), 7.28 (d, 2H), 5.05 (s, 2H), 4.14 (t, 2H), 3.28 (s, 3H), 3.22 - 3.14 (m, 2H), 2.87 (s, 3H), 2.74 (s, 3H). MS (EI) for C25H25 502S: 460 (MH+).
142 Ή NMR (400 MHz, CD3OD) δ 8.94 (dd, IH), 8.64 (s, IH), 8.58 (dd,
IH), 8.24 (ddd, IH), 8.16 (d, IH), 8.01 (dd, IH), 7.59 (ddd, IH), 7.39- 7.29 (m, 2H), 7.19 (d, IH), 5.03 (s, 2H), 4.14 (t, 2H), 3.15 (t, 2H), 2.74 (s, 3H), 1.51 (s, 6H). MS (EI) for C26H26N40: 411 (MH+).
143 Ή NMR (400 MHz, CD3OD) δ 9.13 - 8.98 (m, IH), 8.71 - 8.56 (m,
IH), 8.33 (d, lH),8.12(s, IH), 8.01 (dd, IH), 7.46-7.27 (m, 3H), 5.03 (s, 2H), 4.12 (t, 2H), 3.58 (t, 2H), 3.48 (t, 2H), 3.23 (t, 2H), 2.70 (s, 3H), 2.05 - 1.73 (m, 4H). MS (EI) for C26H25N5OS: 456 (MH+).
144 Ή NMR (400 MHz, CD3OD) δ 8.68 (s, 2H), 8.62 (s, IH), 8.03 (d, IH),
7.92 (dd, IH), 7.44-7.27 (m, 3H), 5.05 (s, 2H),4.13 (t, 2H), 3.65 - 3.53 (m, 2H), 3.46 (t, 2H), 3.22 (t, 2H), 2.71 (s, 3H), 2.05 - 1.81 (m, 4H). MS (EI) for C27H27N70: 466 (MH+).
145 Ή NMR (400 MHz, CD3OD) δ 8.64 (s, IH), 8.34 (d, IH), 8.09 (s, IH),
7.99-7.90 (m, 2H), 7.41 (d, IH), 7.40-7.31 (m, 2H), 5.06 (s, 2H),4.14 (t, 2H), 4.07 (s, 3H), 3.65 - 3.42 (m, 4H), 3.23 (t, 2H), 2.72 (s, 3H), 2.04 - 1.82 (m, 4H). MS (EI) for C29H28FN502: 498 (MH+).
146 Ή NMR (400 MHz, DMSO-d6): 610.04 (s, IH), 8.60 (s, IH), 8.48 (s,
IH), 7.91 (s, IH), 7.41 - 7.20 (m, 3H), 5.73 (br s, IH), 4.83 (br s, 2H), 4.00 (s, 2H), 3.92 (br s, 2H), 3.52 - 3.34 (m, 4H), 3.13 (br t, 2H), 2.53 (s, 3H), 1.77 (m, 4H); MS (EI) for C25H27N503: 446.0 (MH+).
147 Ή NMR (400 MHz, DMSO-d6): δ8.66 (s,l), 8.27 (s, IH), 8.01 (s, IH),
7.42 (s, IH), 7.33 (dd, 2H), 4.89 (s, 2H), 4.11 - 3.79 (m, 4H), 3.43 (m, 4H), 3.18 (br t, 2H), 2.64 (s, 3H), 2.56 (t, 2H), 2.21 - 2.04 (m, 2H), 1.84 (ddd, 4H); MS (EI) for C27H29N502: 456.1 (MKT).
148 Ή NMR (400 MHz, DMSO-d6): 68.63 (s, IH), 8.05 - 7.82 (m, 4H),
7.44 (s, IH), 7.30 (dd, 2H), 6.46 (d, IH), 4.96 (s, 2H), 4.01 (br t, 2H), CMPD CHARACTERIZATION DATA
3.53 - 3.36 (m, 2H), 3.19- 3.05 (m, 2H), 2.63 (s, 3H), 1.98 - 1.69 (m, 4H); MS (EI) for C28H27N502: 466.0 (MH+).
149 Ή NMR (400 MHz, DMSO-d6): 88.71 (s, IH), 8.67 (s, IH), 8.44 (dt,
1 H), 8.09 (d, 2H), 7.46 (s, IH), 7.36 - 7.18 (m, 3H), 5.00 (s, 2H), 4.05 (br t, 2H), 3.57 - 3.34 (m, 2H), 3.13 (br t, 2H), 2.66 (s, 3H), 1.90 (s, O.lH-OAc peak).1.90-1.71 (m, 4H); MS (EI) for C28H26FN50: 468.0 (MH+).
150 Ή NMR (400 MHz, DMSO-d6) δ 8.99 (m, IH), 8.79-8.47 (m, 3H),
8.24 - 8.13 (m, 1 H), 8.05 (s, 1 H), 7.97 (s, 1 H), 7.93 - 7.80 (m, 2H), 7.51 (m, 4H), 4.31 (m, 2H), 3.21 (m, 5H), 2.68 (s, 3H), 2.05 - 1.75 (m, 3H), 1.56 - 1.33 (m, 2H). MS (EI) for C27H27N50, found 438.0.
151 Ή NMR (400 MHz, DMSO-d6) 58.64 (s, IH), 8.59 (m, IH), 8.13 (m,
1 H), 8.00 (s, 1 H), 7.89 (s, 1 H), 7.10 (m, 1 H), 6.97 (m, 1 H), 4.34 (m, 2H), 3.91 (m, 3H), 3.15 (m, 2H), 2.91 (m, 5H), 2.66 (s, 3H), 1.84 (m, 3H), 1.53 - 1.27 (m, 2H). MS (EI) for C22H27N503S, found 441.9.
152 Ή NMR (400 MHz, DMSO-d6) δ 8.63 (s, IH), 8.58 (m, IH), 8.12 (m,
IH), 8.00 (s, IH), 7.71 (m, 7H), 6.97 (m, IH), 4.28 (m, 2H), 3.92 (s, 3H), 3.08 (m, 2H), 2.71 (s, 2H), 2.66 (s, 3H), 1.79 (m, 3H), 1.33 (m, 2H). MS (EI) for C27H29 503S, found 504.0.
153 Ή NMR (400 MHz, methanol-d4) δ 9.39 (s, IH), 8.99 (d, IH), 8.94 (s,
IH), 8.81 (s, IH), 8.57 (s, 1H),8.42 (d, lH),8.18(s, IH), 7.83 (s, IH), 7.71 (d, IH), 7.56 (d, IH), 5.60 (s, 2H), 4.55 (t, 2H), 3.87 (d, 2H), 3.36 (m, 2H), 3.07 (m, IH), 2.44 (t, 2H), 2.03 (m, 2H), 1.67 (m, 2H). MS (ES) for C27H27FN502S: 519 (MH+).
154 Ή NMR (400 MHz, methanol-d4) δ 9.41 (s, IH), 9.08 (s, IH), 8.93 (d,
IH), 8.76 (s, IH), 8.59 (s, IH), 8.37 (s, IH), 8.23 (d, IH), 7.81 (s, IH), 7.68 (s, IH), 7.55 (d, IH), 5.60 (s, 2H), 4.55 (t, 2H), 3.87 (d, 2H), 3.61 (t, 2H), 3.38 (s, 3H), 3.31 (m, 2H), 3.20 (t, 2H), 3.10 (m, IH), 2.77 (s, 3H), 2.40 (t, 2H), 2.14 (d, 2H), 1.68 (m, 2H). MS (ES) for C3iH36N603S: 573 (MH+).
155 Ή NMR (400 MHz, methanol-d4) δ 8.72 (s, IH), 8.41 (s, IH), 8.32 (s,
IH), 8.21 (s, IH), 8.03 (d, IH), 7.78 (s, IH), 7.69 (d, IH), 7.55 (d, IH), 5.50 (s, 2H), 4.48 (t, 2H), 4.08 (s, 3H), 3.88 (m, 2H), 3.60 (t, 2H), 3.38 (s, 3H), 3.32 (m, 2H), 3.19 (t, 2H), 3.09 (m, IH), 2.73 (s, 3H), 2.38 (t, 2H), 2.15 (d, 2H), 1.69 (m, 2H). MS (ES) for C32H37FN604S: 621 (MH+).
156 Ή NMR (400 MHz, methanol-d4) δ 8.73 (s, IH), 8.50 (s, IH), 8.40 (s,
IH), 8.31 (m, IH), 8.25 (s, IH), 7.79 (s, IH), 7.68 (s, IH), 7.56 (s, IH), 7.33 (s, IH), 5.56 (s, IH), 4.52 (t, 2H), 4.13 (s, 3H), 3.88 (m, 2H), 3.61 (t, 2H), 3.38 (s, 3H), 3.32 (m, 2H), 3.20 (t, 2H), 3.10 (m, IH), 2.73 (s, 3H), 2.40 (t, 2H), 2.14 (m, 2H), 1.68 (m, 2H). MS (ES) for C32H38N604S: 603 (MH+).
157 Ή NMR (400 MHz, methanol-d4) δ 9.35 (s, IH), 8.96 (s, IH), 8.89 (d,
IH), 8.76 (s, IH), 8.57 (s, IH), 8.36 (s, IH), 8.14 (m, IH), 7.81 (s, IH), 7.70 (d, IH), 7.55 (d, IH), 5.59 (s, 2H), 4.55 (t, 2H), 3.88 (d, 2H), 3.36 CMPD CHARACTERIZATION DATA
(m, 2H), 3.02 (m, I H), 2.77 (s, 3H), 2.66 (s, 3H), 2.44 (t, 2H), 2.13 (d, 2H), 1.63 (m, 2H). MS (ES) for C29H32N6O2S: 529 (MH+).
158 Ή NMR (400 MHz, methanol-d4): 8.63 (s, I H), 8.51 (s, I H), 8.07 (m,
2H), 7.96 (s, I H), 7.35 (d, I H), 7.30 (s, IH), 7.27 (d, I H), 6.94 (d, IH), 5.05 (s, 2H), 4.13 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.48 (m, 2H), 3.22 (m, 2H), 2.72 (s, 3H), 2.47 (m, 4H), 2.32 (s, 3H), 1.94 (s, 6H). MS (EI) for C30H32N6O2: 509 (MH+).
159 lH NMR (400 MHz, DMSO-d6): 59.05 (s, I H), 8.69 (s, I H), 8.61 (d,
I H), 8.24 (d, I H), 8.1 1 (d, 2H), 7.53 (dd, IH), 7.47 (s, I H), 7.31 (m, 2H), 5.01 (s, 2H), 4.06 (br t, 2H), 3.85 - 3.46 (m, 10H), 3.15 (br t, 2H), 2.68 (s, 3H), 2.15 (m, 3H), 1.89 (s, 3H, OAc peak), 1.88 (br s, 2H); MS (EI) for C30H32N6O: 493.1 (MH+).
160 Ή NMR (400 MHz, DMSO-d6) 6 9.00 (d, I H), 8.64-8.58 (m, IH), 8.57
(s, I H), 8.25-8.12 (m, 2H), 8.04 (s, I H), 7.53 (dd, lH), 3.37 (s, 6H), 2.66 (s, 3H). MS (EI) for C|6H,6N4: 264 (MH+).
161 Ή NMR (400 MHz, CD3OD) 5 8.61 (s, I H), 8.46 (s, I H), 8.02 (dd, IH),
7.96 (s, I H), 7.90 (s, IH), 7.76 (s, I H), 7.72 (d, IH), 7.41 (t, IH), 6.88 (t, I H), 5.02 (s, 2H), 4.09 (t, 2H), 3.97 (s, 3H), 3.23 (s, 4H), 3.09 (m, I H), 2.84 (m, 2H), 2.69 (s, 3H), 1.88 (m, I H), 1.73 (t, IH), 1.61 (m, IH), 1.43 (t, I H); MS (El) for Ca^N^S: 545.0 (MH+).
162 Ή NMR (400 MHz, DMSO-d6) δ 8.69 (s, I H), 8.63 (d, I H), 8.21-8.12
8.01 (d, IH), 6.97 (d, I H), 4.31 (s, 2H), 4.06-3.96 8-3.36 (m, 2H), 2.68 (s, 3H). MS (EI) for
Figure imgf000146_0001
163 Ή NMR (400 MHz, DMSO-d6): 59.04 (s, I H), 8.67 (s, IH), 8.61 (d,
1 H), 8.24 (d, 1 H), 8.1 1 (d, 2H), 7.59 - 7.42 (m, 3 H), 7.15 (d, 1 H), 4.94 (s, 2H), 4.04 (br t, 2H), 3.05 (br t, 2H), 2.67 (s, 3H), 1.85 (s, 3H-OAc peak), 1.25 (s, 6H); MS (EI) for C27H28N60: 453.1 (MH+).
164 Ή NMR (400 MHz, CD3OD) 5 8.94 (d, IH), 8.65 (s, I H), 8.58 (dd, IH),
8.35 - 8.20 (m, I H), 8.16 (d, IH), 8.02 (dd, I H), 7.59 (ddd, IH), 7.50 - 7.25 (m, 3H), 5.08 (s, 2H), 4.16 (t, 2H), 3.87 - 3.56 (m, 4H), 3.22 (t, 2H), 2.74 (s, 3H), 2.46 - 1.96 (m, 3H). MS (EI) for C29H26F 5O: 468 (MH+).
165 Ή NMR (400 MHz, CD3OD) 5 8.95 (d, IH), 8.66 (s, I H), 8.58 (dd, IH),
8.30 - 8.20 (m, 1 H), 8.17 (d, 1 H), 8.03 (d, 1 H), 7.59 (dd, 1 H), 7.47 - 7.28 (m, 3H), 5.08 (s, 2H), 4.16 (t, 2H), 3.80 - 3.62 (m, 4H), 3.28 - 3.18 (m, 4H), 2.75 (s, 3H), 2.21 - 1.93 (m, I H). MS (EI) for C28H27N5O2: 466 (MH+).
166 Ή NMR (400 MHz, CD3OD) 5 8.95 (d, IH), 8.66 (s, I H), 8.58 (dd, IH),
8.31 - 8.21 (m, I H), 8.17 (d, IH), 8.02 (dd, I H), 7.59 (ddd, IH), 7.50 - 7.26 (m, 3H), 5.09 (s, 2H), 4.16 (t, 2H), 3.93 - 3.52 (m, 5H), 3.22 (t, 2H), 2.74 (s, 3H), 2.39 - 1.99 (m, 2H). MS (EI) for C28H26FNsO: 468 (MH+).
167 Ή NMR (400 MHz, CD3OD) 8 8.82 (t, I H), 8.65 (s, I H), 8.51 (d, I H),
8.19 (d, I H), 8.12 - 8.04 (m, IH), 8.03 (d, I H), 7.43 - 7.25 (m, 3H), 5.08 (s, 2H), 4.16 (t, 2H), 3.58 (dd, 2H), 3.46 (t, 2H), 3.22 (t, 2H), 2.74 (s, 3H), 1.97 (dd, 2H), 1.93 - 1.80 (m, 2H). MS (EI) for C28H26FN50: 468
Figure imgf000147_0001
CMPD CHARACTERIZATION DATA
(s, 2H), 6.96 (dd, 2H), 6.56-6.39 (m, 2H), 5.25 (t, IH), 4.85 (s, 2H), 4.00 (t, 2H), 3.93 (s, 3H), 3.64-3.50 (m, 4H), 3.10 (q, 2H), 2.96 (t, 2H), 2.67 (s, 3H), 2.49-2.44 (m, 2H), 2.40 (s, 4H). MS (EI) for C3oH34N602: 511 (MH+).
179 Ή NMR (400 MHz, DMSO-d6): 58.60 (s, IH), 8.35 (br s, IH), 8.1 (br s, IH), 7.99 (d, 2H), 6.89 (d, IH), 6.56 - 6.24 (m, 2H), 4.91 (s, 2H), 4.76 (s, 2H), 3.93 (br t, 2H), 2.96 (br t, 2H), 2.65 (s, 3H); MS (EI) for
C2iH20N6: 357.0 (MH+).
180 Ή NMR (400 MHz, DMSO-d6): 58.59 (s, IH), 8.22 (s, IH), 8.11 (s,
1 H), 7.89 - 7.63 (m, 1 H), 7.50 (s, 1 H), 7.43 (d, 1 H), 7.12 (d, 1 H), 6.83 (s, IH), 4.83 (s, 2H), 3.94 (brt, 2H), 3.02 (brt, 2H), 2.55 (s, 3H), 1.83 (s, 3H-OAc peak), 1.20 (s, 6H); MS (EI) for C25H27N70: 442.1 (MH+).
181 'HNMR(400MHz,DMSO-d6): 58.59 (s, IH), 8.22 (br s, 1H),8.11 (br s, IH), 7.89-7.63 (brs, lH),7.50(s, IH), 7.43 (d, IH), 7.14 (d, IH), 6.83 (s, I H), 4.83 (s, 2H), 3.94 (br t, 2H), 3.00 (br t, 2H), 2.57 (s, 3H), 1.83 (s, 3H-OAc peak), 1.20 (s, 6H); MS (EI) for C25H27N70: 442.0 (MH+).
182 Ή NMR (400 MHz, DMSO-d6) 512.46 (s, IH), 9.05 (s, IH), 8.68 (s,
IH), 8.51 (s, 2H), 8.19 (m, IH), 8.07 (s, IH), 7.57 (m, IH), 7.45 (s, IH), 7.16 (s, IH), 7.00 (m, IH), 5.01 (s, 2H), 3.92 (s, 3H), 2.65 (s, 3H). MS (EI) for C23H,9C1N60, found 431.1.
183 Ή NMR (400 MHz, DMSO-d6) 512.44 (s, IH), 9.20 - 8.93 (m, 2H),
8.61 (m, 2H), 8.53 (s, 1 H), 8.24 (m, 1 H), 8.12 (s, 1 H), 7.75 - 7.34 (m, 3H), 7.16 (m, IH), 5.02 (m, 2H), 2.66 (s, 3H). MS (EI) for C22Hi7ClN6, found 399.1.
184 Ή NMR (400 MHz, DMSO-d6) 58.64 (s, IH), 8.58 (m, IH), 8.12 (m,
IH), 7.99 (s, IH), 7.94 - 7.56 (m, 7H), 6.96 (m, IH), 4.29 (m, 2H), 3.92 (s, 3H), 3.10 (m, 2H), 2.75 (m, 2H), 2.66 (s, 4H), 1.78 (m, 3H), 1.36 (m, 2H). MS (EI) for C27H28CIN503S, found 538.1.
185 Ή NMR (400 MHz, DMSO) 58.59 (dd, 2H), 8.12 (dt, IH), 7.96 (s, 2H),
7.00 - 6.86 (m, 2H), 6.52 - 6.37 (m, 2H), 5.07 (bs, 1 H), 4.79 (s, 2H), 3.96 (t, 2H), 3.90 (s, 3H), 3.04 (m, 2H), 2.91 (t, 2H), 2.63 (s, 3H), 2.41 (t, 2H), 2.30 (d, 2H), 1.51 - 1.41 (m, 4H), 1.33 (m, 2H); MS (EI) for C3iH36 60: 509.10 (MH+).
186 Ή NMR (400 MHz, DMSO) 58.60 (dd, 2H), 8.17 - 8.10 (m, IH), 7.98
(s, 2H), 6.98 - 6.88 (m, 2H), 6.49 - 6.38 (m, 2H), 5.19 (bs, IH), 4.80 (t, 2H), 4.01 - 3.93 (m, 2H), 3.90 (s, 3H), 3.06 (t, 2H), 2.91 (d, 2H), 2.63 (s, 3H), 2.55 (d, 2H), 2.43 (d, 2H), .40 (s, 2H), 1.62 (d, 2H); MS (EI) for C30H34N6O: 495.1 (MH+).
187 Ή NMR (400 MHz, DMSO-d6) 58.67 (s, IH), 8.66 (d, IH), 8.17 (d,
IH), 8.12-8.02 (m, IH), 7.97 (d, IH), 6.96 (d, IH), 6.56-6.36 (m, 2H), 5.20 (br s, 1 H), 4.86 (s, 2H), 4.01 (t, 2H), 3.05 (br s, 2H), 2.98 (t, 2H), 2.66 (s, 3H), 2.61-2.46 (m, 4H), 1.06-0.84 (m, 6H). MS (EI) for
C27H32N6S: 473 (MH+). CMPD CHARACTERIZATION DATA
188 Ή NMR (400 MHz, methanol-d4): 8.64 (s, I H), 8.52 (s, I H), 8.08 (m,
2H), 7.96 (s, I H), 7.32 (m, 3H), 6.94 (d, I H), 5.05 (s, 2H), 4.14 (m, 2H), 3.98 (s, 3H), 3.87-3.72 (m, 2H), 3.63-3.5 1 (m, 2H), 3.23 (m, 2H), 3.1 1 - 2.75 (m, 4H), 2.72 (s, 3H), 2.64-2.43 (m, 3H), 2.00 (m, 2H), 1.96 (s, 3H). MS (El) for C3i H34N602: 523 (MH+).
189 Ή NMR (400 MHz, methanol-d4): 8.64 (s, I H), 8.52 (s, I H), 8.09 (m,
2H), 7.96 (s, I H), 7.3 1 (m, 3H), 6.95 (d, I H), 5.06 (s, 2H), 4.15 (m, 2H), 3.98 (s, 3H), 3.78 (m, 2H), 3.50 (m, 2H), 3.23 (m, 2H), 2.73 (s, 3H), 2.63-2.40 (m, 8H), 1.95 (s, 6H), 1.12 (t, 3H). MS (EI) for C31 H34N602: 523 (MH+).
190 Ή NMR (400 MHz, methanol-d4): 8.64 (s, I H), 8.52 (s, I H), 8.08 (m,
2H), 7.96 (s, I H), 7.30 (m, 3H), 6.95 (d, I H), 5.05 (s, 2H), 4.14 (m, 2H), 3.98 (s, 3H), 3.76 (m, 2H), 3.48 (m, 2H), 3.23 (m, 2H), 2.73 (s, 3H), 2.69-2.43 (m, 5H), 1 .93 (s, 6H), 1 .61 (m, I H), 1 .31 (m, IH), 1 .02 (d, 3H), 0.92 (t, 3H). MS (EI) for C33H38N602: 551 (MH+).
191 Ή NMR (400 MHz, methanol-d4): 8.63 (s, I H), 8.51 (s, I H), 8.07 (m,
2H), 7.95 (s, I H), 7.30 (m, 3H), 6.94 (d, I H), 5.04 (s, 2H), 4.14 (m, 2H), 3.98 (s, 3H), 3.76 (m, 2H), 3.47 (m, 2H), 3.22 (m, 2H), 2.73 (s, 3H), 2.50 (m, 2H), 2.36 (m, 2H), 2.13 (d, 2H), 1.82 (m, I H), 0.91 (d, 6H). MS (EI) for C33H38N602: 551 (MH+).
192 Ή NMR (400 MHz, methanol-d4): 8.64 (s, I H), 8.52 (s, I H), 8.08 (m,
2H), 7.97 (s, I H), 7.37 (d, I H), 7.28 (m, 2H), 6.95 (d, I H), 5.05 (s, 2H), 4.14 (m, 2H), 3.99 (s, 3H), 3.24 (m, 2H), 2.88 (d, 2H), 2.73 (s, 3H), 2.17 (m, I H), 2.02 (m, I H), 1.93 (s, 3H), 1.50 (m, I H), 1.05 (m, I H), 0.70 (m, 2H), 0.37 (m, 2H). MS (EI) for C34H38N602: 563 (MH+).
193 Ή NMR (400 MHz, DMSO-d6): 610.02 (s, I H), 8.61 (s, I H), 8.40-8.18
(br s, 2H), 7.99 (d, 2H), 7.88 (s, I H), 7.51 (s, I H), 7.42 (d, 2H), 7.17 (d, I H), 4.86 (s, 2H), 4.16 (dd, I H), 3.97 (br t, 2H), 3.07 (br t, 2H), 2.62 (s, 3H), 2.41 - 2.26 (m, 1 H), 2.26 - 2.06 (m, 2H), 2.06 - 1.92 (m, 1 H); MS (EI) for C26H25N702: 468.1 (MH+).
194 Ή NMR (400 MHz, DMSO-d6): 6 9.78 (br s, I H), 8.61 (s, I H), 8.45- 8.20 (br s, 2H), 7.99 (s, 2H), 7.61 - 7.42 (m, 2H), 7.17 (d, I H), 4.87 (s, 2H), 3.97 (br t, 2H), 3.07 (br s, 2H), 2.64 (br t, 2H), 1 .89 (s, 1 .5H-OAc peak), 1 .28 (br s, 2H), 0.98 (br s, 2H); MS (EI) for C25H25N70: 440.0 (MH+).
195 Ή NMR (400 MHz, DMSO) 6 8.57 (t, 2H), 8.10 (t, I H), 7.98 (s, 2H),
6.91 (m, 2H), 6.43 (m, 2H), 5.27 (t, I H), 4.80 (s, 2H), 3.93 (t, 2H), 3.90 (s, 3H), 3.08 (m, 2H), 2.94 (m, 2H), 2.87 (m, 2H), 2.65 (s, 3H), 2.58 (t, 2H), 2.30 - 2.09 (m, 2H); MS (EI) for C30H32F2N6O: 531.1 (MH+).
196 Ή NMR (400 MHz, methanol-d4): 8.63 (s, I H), 8.51 (s, I H), 8.07 (m,
2H), 7.95 (s, I H), 7.34 (d, I H), 7.27 (m, 2H), 6.95 (d, I H), 5.88 (m, I H), 5.04 (s, 2H), 4.54 (m, I H), 4.13 m, 2H), 3.98 (s, 3H), 3.75 (m, I H), 3.27 (m, 2H), 3.13 (m, 1 H), 2.97 (m, 3H), 2.80 (m, 1 H), 2.72 (s, 3H), 2.02 (m, 1 H), 1.95 (s, 3H), 1.85 (m, 1 H), 1 .32 (m, 2H). MS (EI) for C32H34F2N602: 573 (MH+). CMPD CHARACTERIZATION DATA
197 Ή NMR (400 MHz, CD3OD) δ 8.61 (s, IH), 8.33 (s, I H), 8.12 (s, IH),
7.75 (s, I H), 7.41 - 7.22 (m, 3H), 6.82 (d, l H), 5.06 (s, 2H), 4.14 (t, 2H), 3.89 - 3.67 (m, 2H), 3.56 - 3.41 (m, 2H), 3.24 (t, 2H), 2.71 (s, 3H), 2.60 - 2.33 (m, 4H), 2.31 (s, 3H). MS (EI) for C29H3iN702: 510 (MH+).
198 Ή NMR (400 MHz, CD3OD) 8 8.58 (s, I H), 8.47 (d, I H), 8.03 (dd, IH),
7.92 (s, 2H), 7.31 - 7.06 (m, 5H), 6.90 (d, I H), 4.96 (s, 2H), 4.33 (dd, 2H), 3.94 (s, 3H), 3.23 (t, IH), 3.17 - 2.95 (m, 3H), 2.72 (s, 3H), 2.10 - 1.75 (m, 4H), 1.45 - 1.20 (m, I H). MS (EI) for C29H3iN503: 498 (MH+).
199 Ή NMR (400 MHz, CD3OD) 8 8.58 (s, IH), 8.48 (dd, IH), 8.10 - 8.02
(m, IH), 7.98 - 7.88 (m, 2H), 6.93 (d, IH), 4.44 - 4.25 (m, IH), 3.97 (s, 3H), 3.06 (dd, IH), 2.71 (s, 3H), 2.66 - 2.55 (m, 2H), 2.13 - 1.72 (m, 6H), 1.43 - 1.31 (m, 3H). MS (EI) for C2,H25NsO: 364 (MH+).
200 Ή NMR (400 MHz, DMSO-d6) 8 9.01 (m, I H), 8.71 - 8.52 (m, 2H),
8.18 (m, I H), 8.05 (s, I H), 7.92 (m, 2H), 7.85 - 7.70 (m, 3H), 7.66 (m, I H), 7.53 (m, I H), 4.28 (m, 2H), 3.12 (m, 2H), 2.75 (m, 2H), 2.67 (s, 3H), 1.90 - 1.67 (m, 3H), 1.35 (m, 2H). MS (EI) for C26H26C1N502S, found 508.1.
201 Ή NMR (400 MHz, CD3OD) 8 8.58 (s, I H), 8.47 (d, I H), 8.03 (dd, IH),
7.91 (s, 2H), 7.05 (s, 2H), 6.94 (d, IH), 4.33 (dd, 2H), 3.97 (s, 3H), 3.29 - 3.19 (m, I H), 3.19 - 2.95 (m, 3H), 2.70 (s, 3H), 2.61 (s, 3H), 2.05 - 1.72 (m, 3H), 1.46 - 1.26 (m, 2H). MS (EI) for C23H28N602: 421 (MH+).
202 Ή NMR (400 MHz, CD3OD) 8 8.58 (s, I H), 8.49 (d, I H), 8.06 (dd, IH),
7.93 (s, 2H), 6.94 (d, 1 H), 4.38 - 4.22 (m, 2H), 3.97 (s, 3H), 3.39 - 3.32 (m, IH), 3.22 - 3.01 (m, 3H), 2.70 (s, 3H), 2.09 - 1.73 (m, 3H), 1.48 - 1.32 (m, 2H), 1.18 (d, 6H). MS (EI) for C23H32N602: 449 (MH+).
203 Ή NMR (400 MHz, CD3OD) 8 8.63 (s, IH), 8.49 (dd, I H), 8.12 - 8.02
(m, 2H), 7.98 - 7.93 (m, IH), 7.41 - 7.22 (m, 3H), 6.91 (d, IH), 5.04 (s, 2H), 4.47 - 4.34 (m, 2H), 4.13 (t, 2H), 3.75 (dt, 2H), 3.56 - 3.38 (m, 2H), 3.22 (t, 2H), 2.72 (s, 3H), 2.61 - 2.34 (m, 4H), 2.31 (s, 3H), 1.42 (t, 3H). MS (EI) for C3iH34N602: 523 (MH+).
204 Ή NMR (400 MHz, DMSO-d6) 8 8.81 (s, I H), 8.69 (m, IH), 8.68 (s,
I H), 8.27 (s, I H), 8.21 (dd, IH), 7.64 (d, I H), 7.38 (dd, I H), 7.07 (d, I H), 7.00 (d, I H), 4.30 (m, 2H), 3.97 (m, 4H), 3.93 (s, 3H), 3.79 (s, 3H), 3.75 (m, 2H), 2.67 (s, 3H). MS (ES) for C27H27C1N603: 519 (MH+).
205 Ή NMR (400 MHz, DMSO-d6) 8 8.67 (s, I H), 8.59-8.50 (m, I H), 8.46- 8.40 (m, I H), 8.36 (d, I H), 7.38 (d, I H), 6.95 (d, I H), 6.54-6.37 (m, 2H), 5.18 (t, I H), 4.88 (s, 2H), 4.1 1 (s, 3H), 4.03 (t, 2H), 3.09-2.90 (m, 4H), 2.68 (s, 3H), 2.57-2.44 (m, 4H), 0.94 (t, 6H). MS (EI) for C29H35N70: 498 (MH+).
206 Ή NMR (400 MHz, methanol-d4): 8.64 (s, I H), 8.52 (s, I H), 8.08 (m,
2H), 7.97 (s, I H), 7.36 (d, I H), 7.27 (m, 2H), 6.95 (d, I H), 5.05 (s, 2H), 4.63 (m, I H), 4.14 (m, 2H), 3.99 (s, 3H), 3.69 (m, 2H), 3.24 (m, 2H), 2.73 (s, 3H), 1.91 (s, 6H). MS (El) for C32H35FN602: 555 (MH+).
207 Ή NMR (400 MHz, CD3OD) 8 8.63 (s, I H), 8.51 (d, IH), 8.15-8.02 (m,
2H), 7.96 (s, IH), 7.40-7.22 (m, 3H), 6.94 (d, IH), 5.05 (s, 2H), 4.13 (t, CMPD CHARACTERIZATION DATA
2H), 3.98 (s, 3H), 3.85-3.66 (m, 2H), 3.54-3.38 (m, 2H), 3.26-3.20 (m,
.67-2.37 (m, 4H), 1.07 (d, 6H). MS (EI) for
Figure imgf000151_0001
208 Ή NMR (400 MHz, CD3OD) δ 8.63 (s, IH), 8.52 (d, IH), 8.08 (dd, 2H),
7.96 (d, IH), 7.38-7.23 (m, 3H), 6.95 (d, IH), 5.05 (s, 3H),4.14 (t, 2H), 3.98 (s, 3H), 3.77 - 3.65 (m, 2H), 3.49 - 3.36 (m, 2H), 3.22 (t, 2H), 2.97 - 2.58 (m, 8H), 1.28 (s, 3H). MS (EI) for C31H34N6O2: 523 (MH+).
209 Ή NMR (400 MHz, CD3OD) δ 8.63 (s, IH), 8.52 (d, IH), 8.08 (dd, 2H),
7.96 (d, IH), 7.38-7.23 (m, 3H), 6.95 (d, IH), 5.05 (s, 3H), 4.14 (t, 2H), 3.98 (s, 3H), 3.77 - 3.65 (m, 2H), 3.49 - 3.36 (m, 2H), 3.22 (t, 2H), 2.97 - 2.58 (m, 8H), 1.28 (s, 3H). MS (EI) for C31H34 6O2: 523 (MH+).
210 Ή NMR (400 MHz, CD3OD) δ 8.63 (s, IH), 8.52 (d, IH), 8.08 (dd, 2H),
7.96 (d, IH), 7.38-7.23 (m, 3H), 6.95 (d, 1H),5.05 (s, 3H), 4.14 (t, 2H), 3.98 (s, 3H), 3.77 - 3.65 (m, 2H), 3.49 - 3.36 (m, 2H), 3.22 (t, 2H), 2.97 - 2.58 (m, 7H). MS (EI) for C29H30 6O2: 495 (MH+).
211 Ή NMR (400 MHz, DMSO-d6) δ 8.64 (s, IH), 8.29 (s, IH), 8.19 (s, IH),
7.86 (s, IH), 6.96 (d, IH), 6.91-6.80 (m, IH), 6.49 (dd, IH), 6.46-6.38 (m, IH), 5.18 (t, IH), 4.91-4.72 (m, 2H), 4.05-3.87 (m, 2H), 3.11-2.91 (m, 4H), 2.67 (s, 3H), 2.58-2.54 (m, 2H), 2.54-2.44 (m, 4H), 0.95 (t, 6H). MS (EI) for C27H33N7: 456 (MH+).
212 Ή NMR (400 MHz, DMSO-d6) δ 9.53 (s, IH), 9.21 (s, IH), 8.64 (s, IH),
8.21 (s, IH), 8.16 (s, IH), 6.94 (d, IH), 6.52-6.44 (m, 2H), 5.16 (t, IH), 4.86 (s, 2H), 4.00 (t, 2H), 3.03 (q, 2H), 2.96 (t, 2H), 2.66 (s, 3H), 2.58- 2.52 (m, 2H), 2.52-2.42 (m, 4H), 0.94 (t, 6H). MS (EI) for C27H32N6S: 473 (MH+).
214 Ή NMR (400 MHz, CD3OD) δ 8.56 (s, IH), 8.10 (s, IH), 7.98 (d, IH),
7.93 (s, IH), 7.89 (d, IH), 7.50 (d, IH), 7.39 (dd, IH), 7.21 (d, IH), 4.94 (s, 2H), 4.06 (t, 2H), 3.96 (s, 3H), 3.14 (t, 2H), 2.66 (s, 3H), 1.40 (s, 6H). MS (EI) for C26H29N7O: 456 (MH+).
215 Ή NMR (400 MHz, DMSO-d6) δ 8.71 - 8.53 (m, 3H), 8.12 (m, 2H),
8.04 (m, 2H), 7.80 (m, 3H), 6.88 (m, 1 H), 6.50 - 6.36 (m, 2H), 4.82 (s, 1 H), 4.06 - 3.80 (m, 2H), 3.16 - 2.94 (m, 2H), 2.94 - 2.81 (m, 2H), 2.53 (m, 2H), 2.51 - 2.35 (m, 5H), 1.77 (s, 12H), 0.92 (m, 6H). MS (EI) for C29H34N6, found 467.2.
216 Ή NMR (400 MHz, DMSO-d6) δ 8.70 - 8.55 (m, IH), 8.19 - 7.96 (m,
3H), 7.80-7.61 (m, 2H), 6.91 (m, IH), 6.55 - 6.28 (m, 2H), 5.12 (m, 1 H), 4.81 (m, 2H), 4.06 - 3.79 (m, 2H), 3.20 - 2.90 (m, 4H), 2.59 - 2.37 (m, 9H), 0.96 (m, 6H). MS (EI) for C28H33N5S, found 472.2.
217 'HNMR(400 MHz,d6-DMSO): 8.69 (s, IH), 8.66 (d, IH), 8.18 (dd,
IH), 8.04 (d, 2H), 7.34 (s, IH), 7.29 (d, IH), 7.19 (d, IH), 6.96 (d, IH), 5.02 (s, 2H), 4.32 (m, IH), 4.06 (t, 2H), 3.93 (s, 3H), 3.42 (m, IH), 3.14 (t, 2H), 2.70 (s, 3H), 2.62 (m, 2H), 2.22 (m, 2H), 0.90 (d, 6H). MS (EI) for C3iH34N602: 523 (MH+).
218 Ή NMR (400 MHz, CD3OD) δ 8.57 (s, IH), 8.11 (s, 2H), 8.05 (d, IH),
7.95 (s, IH), 7.51 (d, IH), 7.42 (dd, IH), 7.22 (d, IH), 4.97 (s, 2H), 4.09 CMPD CHARACTERIZATION DATA
(t, 2H), 3.21 - 3.11 (m, 3H), 2.96 (dd, IH), 2.68 (s, 3H), 2.42 (s, 4H), 2.33 -2.19 (m, IH), 1.91 - 1.80 (m, 3H). MS (EI) for C27H29N7O: 468 (MH+).
219 Ή NMR (400 MHz, CD3OD) 58.57 (s, IH), 8.11 (s, 2H), 8.05 (d, IH),
7.95 (dd, IH), 7.52 (d, IH), 7.39 (dd, IH), 7.21 (d, IH), 4.96 (s, 3H), 4.09 (t, 2H), 3.16 (t, 2H), 2.78-2.60 (m, 6H), 1.35 (d, 4H). MS (EI) for C24H25N70: 428 (MH+).
220 Ή NMR (400 MHz, CD3OD) 58.61 (s, IH), 7.91 (d, IH), 7.87 (s, IH),
7.85 - 7.80 (m, IH), 7.49 (d, IH), 7.40 (dd, IH), 7.20 (d, IH), 4.96 (s, 2H), 4.09 (t, 2H), 3.18 - 3.05 (m, 2H), 2.69 (s, 3H), 2.54 (s, 3H), 1.40 (s, 6H). MS (EI) for C26H29N70: 456 (MH+).
221 Ή NMR (400 MHz, DMSO-d6): δ 9. 1 (s, IH), 8.62 (s, IH), 8.24 (br s,
2H), 7.99 (s, 2H), 7.53 (s. IH), 7.52 (d, IH), 7.17 (d, IH), 4.89 (s, 2H), 3.98 (br t, 2H), 3.65 (dd, IH), 3.08 (br t, 2H), 2.88 (m, 2H), 2.61 (s, 3H), 2.03 (m, IH), 1.90(s,3H-OAc peak), 1.77 (m, IH), 1.67- 1.57 (m, 2H); MS (EI) for C26H27N70: 454.0 (MH+).
222 Ή NMR (400 MHz, DMSO-d6): 59.91 (s, IH), 8.62 (s, IH), 8.24 (br s,
2H), 7.99 (s, 2H), 7.53 (s. IH), 7.52 (d, IH), 7.17 (d, IH), 4.89 (s, 2H), 3.98 (br t, 2H), 3.65 (dd, IH), 3.08 (br t, 2H), 2.88 (m, 2H), 2.61 (s, 3H), 2.03 (m, 1 H), 1.90 (s, 3H-OAc peak), 1.77 (m, 1 H), 1.67 - 1.57 (m, 2H); MS (EI) for C26H27 7O: 454.0 (MH+).
223 Ή NMR (400 MHz, DMSO-d6): δ 8.63 (s, IH), 8.23 (br s, 2H), 8.01 (s,
2H), 7.57 (s, IH), 7.51 (d, IH), 7.18 (d, IH), 4.89 (s, 2H), 3.99 (brt, 2H), 3.09 (br t, 2H), 2.65 (s, 3H), 1.92 (m, 7H-burried OAc peak), 1.81 (m, 2H); MS (EI) for C26H27N70: 454.0 (MH+).
224 Ή NMR (400 MHz, DMSO-d6): δ 8.67 (s, IH), 8.29 (s, IH), 8.18 (s,
IH), 7.81 (br s, IH), 7.58 (s, IH), 7.47 (d, IH), 7.20 (d, IH), 6.90 (s, IH), 4.91 (s, 2H), 4.01 (brt, 2H), 3.09 (brt, 2H), 2.66 (s, 3H), 1.93 (m, 7H burried OAc peak), 1.82 (m, 2H); MS (EI) for C26H27N70: 454.0 (MH+).
225 Ή NMR (400 MHz, DMSO-d6): S 8.62 (s, IH), 8.49 - 8.06 (m, 2H),
8.00 (s, 2H), 7.58 (s, IH), 7.51 (d, IH), 7.17 (d, IH), 4.89 (s, 2H), 3.99 (brt, 2H), 3.09 (brt, 2H), 2.65 (s, 3H), 2.01 (m, 2H), 1.90 (s, 3H-OAc peak), 1.73 (m, 4H), 1.52 (m, 2H); MS (EI) for C27H29N70: 468.2 (MH+).
226 Ή NMR (400 MHz, DMSO-d6): δ 8.66 (s, IH), 8.23 (br d, 2H), 7.93 - 7.75 (br s, 1 H), 7.59 (s, 1 H), 7.51 (d, 1 H), 7.19 (d, 1 H), 6.90 (s, 1 H), 4.90 (s, 2H), 4.01 (brt, 2H), 3.08 (brt, 2H), 2.66 (s, 3H), 2.01 (m, 2H), 1.73 (m, 4H), 1.54 (m, 2H); MS (EI) for C27H29N7O: 468.1 (MH+).
227 Ή NMR (400 MHz, methanol-d4): 8.65 (s, IH), 8.57 (s, IH), 8.27 (s,
IH), 7.37-7.24 (m, 4H), 5.09 (s, 2H), 4.61 (m, 2H), 4.50 (m, IH), 4.17 (m, 5H),3.79 (m, 1H),3.24 (m, 2H),3.14(m, 1H),3.04 (m, 1H),3.00- 2.85 (m, 3H), 2.74 (s, 3H), 2.07 (m, IH), 1.92 (s, 6H), 1.36 (m, 2H). MS (EI) for C31H34FN7O2: 556 (MH+). CMPD CHARACTERIZATION DATA
228 Ή NMR (400 MHz, CD3OD) 58.57 (s, IH), 8.30 (d, IH), 8.10 (s, IH),
7.74 (d, IH), 6.98 (d, IH), 6.79 (d, IH), 6.62 (dt, 2H), 4.94 (s, 2H), 4.07 (t, 2H), 3.06 (t, 2H), 2.69 (s, 3H). MS (El) for C2,H20N6: 357 (MH+).
229 Ή NMR (400 MHz, DMSO-d6) δ 8.77 - 8.57 (m, 3H), 8.08 (m, 2H),
7.92 - 7.72 (m, 2H), 7.20 - 6.95 (m, IH), 4.36 (m, 2H), 3.20 (m, 2H), 2.92 (m, 6H), 2.68 (s, 3H), 1.93 - 1.73 (m, 3H), 1.55 - 1.25 (m, 2H). MS (EI) for C21H25N5O2S, found 412.1.
230 Ή NMR (400 MHz, d6-DMSO): 8.68 (s, IH), 8.17 (d, IH), 8.07 (d, 2H),
7.68 (d, IH), 7.33 (s, IH), 7.29 (d, IH), 7.20 (d, IH), 5.00 (s, 2H), 4.24 (br s, 1 H), 4.06 (t, 2H), 3.94 (s, 6H), 3.56 (br s, 1 H), 3.12 (t, 2H), 3.00 (m, 2H), 2.70 (s, 3H), 2.68 (m, 2H), 2.38 (d, 2H), 1.78 (m, 2H), 1.18 (m, 2H), 0.82 (m, 1 H), 0.40 (m, 1 H), 0.10 (m, 2H). MS (EI) for C35H4oN603: 593 (MH+).
231 Ή NMR (400 MHz, DMSO-d6): 58.62 (s, IH), 8.43 - 8.05 (m, 2H),
8.01 (s, 3H), 7.57 (s, IH), 7.50 (d, 2H), 7.16 (d, IH), 4.88 (s, 2H), 3.98 (br t, 2H), 3.08 (br t, 2H), 2.63 (s, 3H), 1.90 (s, 2H-OAc peak), 1.79 (dt, 2H), 1.54 (m,4H), 1.27-1.08 (m, 2H); MS (EI) for C28H3iN70: 482.1 (MH+).
232 Ή NMR (400 MHz, DMSO-d6): 58.66 (s, IH), 8.24 (br d, 2H), 7.86 (s,
IH), 7.58 (s, IH), 7.50 (d, IH), 7.18 (d, IH), 6.90 (s, IH), 4.90 (s, 2H), 4.00 (br t, 2H), 3.08 (br t, 2H), 2.66 (s, 3H), 1.82 (dt, 2H), 1.68 - 1.33 (m, 4H), 1.24-1.05 (m, 2H); MS (EI) for C28H3iN70: 482.1 (MH+).
233 Ή NMR (400 MHz, methanol-d4): 8.64 (s, IH), 8.06 (m, 2H), 7.98 (s,
IH), 7.57 (s, IH), 7.35 (d, IH), 7.27 (m, 2H), 5.05 (s, 2H), 4.61 (m, 2H), 4.50 (m, IH), 4.14 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.79 (m, IH), 3.24 (m, 2H), 3.20-2.85 (m, 5H), 2.73 (s, 3H), 2.06 (m, IH), 1.92 (s, 9H), 1.36 (m, 2H). MS (EI) for C33H37FN603: 585 (MH+).
234 Ή NMR (400 MHz, DMSO-d6): δ 10.34 (br s, IH), 8.79 (s, IH), 8.49 (s,
2H), 8.07 (d, 2H), 7.66 - 7.48 (m, 2H), 7.28 (d, 1 H), 5.31 (br s, 2H), 4.33 (br s, 2H), 3.09 (br s, 2H), 2.69 (d, 3H), 2.51 (s, 3H), 2.31 (m, IH), 2.06 - 1.72 (m, 6H); MS (EI) for C28H3lN70: 482.1 (MH+).
235 Ή NMR (400 MHz, CD3OD) δ 9.25 (s, IH), 9.00 (s, IH), 8.61 (s, IH),
8.12 (d, IH), 7.97 (dd, IH), 7.52 (d, IH), 7.39 (dd, IH), 7.21 (d, IH), 5.00 (s, 2H), 4.17-4.05 (m, 2H), 3.15 (t, 2H), 2.69 (s, 3H), 1.39 (s, 6H). MS (EI) for C25H26N602: 443 (MH+).
236 Ή NMR (400 MHz, CD3OD) 58.65 (s, IH), 8.01 (s, IH), 7.81 (s, IH),
7.55 (d, IH), 7.49 (s, IH), 7.39 (d, IH), 7.19 (d, IH), 6.53 (d, IH), 4.99 (s, 2H), 4.11 (t, 2H), 3.99 (s, 3H), 3.11 (t, 2H), 2.71 (s, 3H), 1.39 (s, 6H). MS (EI) for C26H29N70: 456 (MH+).
237 Ή NMR (400 MHz, CD3OD) δ 8.65 (s, IH), 8.57 (d, IH), 8.29 (dd, IH),
8.20 (d, IH), 7.51 (d, IH), 7.40 (dd, IH), 7.31 (d, IH), 7.21 (d, IH), 5.04 (s, 2H), 4.22-4.08 (m, 5H), 3.17 (t, 2H), 2.74 (s, 3H), 1.40 (s, 6H). MS (EI) for C27H29N702: 484 (MH+).
238 lH NMR (400 MHz, methanol-d4): 8.64 (s, IH), 8.08 (s, IH), 7.81 (s,
IH), 7.34 (d, IH), 7.27 (m, 2H), 5.00 (s, 2H), 4.63 (m, 2H), 4.51 (m, IH), CMPD CHARACTERIZATION DATA
4.08 (m, 2H), 3.80 (m, IH), 3.18 (m, 2H), 3.15-2.85 (m, 4H), 2.64 (s, 3H), 2.08 (m, IH), 1.93 (s, 6H), 1.36 (m, 2H). MS (EI) for C26H29BrFN50: 526/528 (MH+).
239 Ή NMR (400 MHz, methanol-d4): 8.61 (s, IH), 8.33 (s, IH), 8.11 (s,
IH), 7.75 (s, IH), 7.35 (d, IH), 7.30 (s, IH), 7.26 (d, IH), 6.82 (s, IH), 5.06 (s, 2H), 4.62 (m, 2H), 4.50 (m, IH), 4.14 (m, 2H), 3.79 (m, IH), 3.24 (m, 2H), 3.20-2.85 (m, 4H), 2.70 (s, 3H), 2.07 (m, IH), 1.92 (s, 9H), 1.37 (m, 2H). MS (EI) for C29H32FN7O: 514 (MH+).
240 Ή NMR (400 MHz, methanol-d4): 8.70 (s, IH), 8.61 (s, IH), 8.08 (s,
IH), 7.42-7.34 (m, 3H), 5.40 (s, 2H), 4.74 (br s, IH), 4.42 (s, 2H), 3.86 (br s, 1 H), 3.46 (m, 1 H), 3.22 (m, 3H), 2.97 (d, 2H), 2.92 (br s, 1 H), 2.64 (s,3H),2.2I (brs, 1H),2.07 (brs, IH), 1.60 (brs, 2H), 1.11 (m, IH), 0.72 (m, 2H), 0.43 (m, 2H). MS (EI) for C28H32BrN50: 534, 536 (MH+, Br isotope pattern).
241 Ή NMR (400 MHz, methanol-d4): 8.60 (s, IH), 8.31 (s, IH), 8.10 (s,
IH), 7.75 (s, IH), 7.36-7.26 (m, 3H), 6.82 (s, IH), 5.05 (s, 2H), 4.72 (br s, IH), 4.13 (s,2H), 3.88 (brs, 1H),3.30 (brs, IH), 3.23 (m, 3H), 2.90 (br m, 3H), 2.34 (s, 3H), 2.18 (brs, IH), 2.05 (brs, IH), 1.55 (brs, 2H), 1.05 (br s, 1 H), 0.67 (m, 2H), 0.35 (m, 2H). MS (EI) for C3|H35N70: 522 (MH+).
242 1 H NMR (400 MHz, DMSO-d6) 88.59 (s, 1 H), 8.18 (s, 2H), 7.97 (s, 1 H),
7.85 (s, IH),4.18(m, 2H), 3.26 - 3.01 (m, 2H), 2.92 (m, 6H), 2.63 (s, 3H), 1.92 - 1.68 (m, 3H), 1.54 - 1.34 (m, 2H). MS (EI) for C,9H24N602S, found 401.1.
243 Ή NMR (400 MHz, DMSO-d6) δ 8.67 (s, IH), 8.43 (m, IH), 8.35 (s,
1 H), 8.29 (m, 1 H), 7.37 (m, 1 H), 7.20 - 7.01 (m, 1 H), 4.32 (m, 2H), 4.11 (s, 3H), 3.27 - 3.07 (m, 2H), 3.00 - 2.83 (m, 5H), 2.68 (s, 3H), 1.96 - 1.71 (m, 3H), 1.50 - 1.26 (m, 2H). MS (EI) for C21H26N603S, found 443.1.
244 Ή NMR (400 MHz, DMSO-d6): δ 10.50 (s, IH), 10.14 (s, IH), 8.78 (s,
IH), 8.34 (s, IH), 8.25 (s, IH), 7.82 (m, IH), 7.55 (m, 2H), 7.26 (m, 2H), 5.38 - 5.16 (br s, 2H), 4.34 (br t, 2H), 3.09 (br t, 2H), 2.74 - 2.59 (s, 3H), 1.90 (m, 4H), 1.68 (s, 3H), 1.24 (d, 4H), 1.16 (s, 2H); MS (EI) for C29H33N70: 496.1 (MH+).
245 Ή NMR (400 MHz, methanol-d4) 68.71 (s, IH), 8.66 (s, IH), 8.36 (s,
IH), 8.33 (d, IH), 8.22 (d, IH), 7.43 (s, IH), 7.41 (d, IH), 7.38 (s, IH), 7.17 (d, IH), 5.49 (s, IH), 4.51 (t, 2H), 4.07 (s, 3H), 4.00 (m, 2H), 3.29 (m, 2H), 3.03 (m, IH), 2.82 (s, 3H), 2.72 (s, 3H), 2.33 (m, 2H), 1.80 (m, 2H). MS (ES) for C3,H32F2N602: 559 (MH+).
246 Ή NMR (400 MHz, methanol-d4) 58.72 (s, IH), 8.66 (s, IH), 8.37 (s,
IH), 8.36 (m, IH), 8.23 (s, IH), 7.44 (s, IH), 7.43 (s, IH), 7.36 (d, IH), 7.20 (d, IH), 5.49 (s, 2H), 4.52 (t, 2H), 4.08 (s, 3H), 3.98 (m, 2H), 3.66 (tt, IH), 3.27 (m, 2H), 2.74 (s, 3H), 2.25 (m, 2H), 1.85 (m, 2H). MS (ES) for C3oH3oF2N602: 545 (MH+).
247 Ή NMR (400 MHz, DMSO-d6): δ 10.80 (br t, IH), 10.26 (s, IH), 8.80 CMPD CHARACTERIZATION DATA
(s, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.73 - 7.44 (m, 2H), 7.29 (d, 1H), 7.05 (s, 1H), 5.33 (br s, 2H), 4.35 (brt, 2H), 3.33 (m, 4H),3.10 (brs,2H), 2.67 (s, 3H), 2.08 - 1.81 (m, 4H), 1.57 (s, 4H); MS (EI) for C29H33N7O: 496.1 (MH+).
248 Ή NMR (400 MHz, methanol-d4) δ 8.62 (s, 1H), 8.49 (d, 1H), 8.05 (dd,
1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.35 (d, 1H), 7.28 (d, 1H), 7.27 (d, 1H), 6.92 (d, 1H), 5.02 (s, 2H), 4.13 (t, 2H), 3.97 (s, 3H), 3.94 (m, 1H), 3.79 (m, 2H), 3.55 (m, 2H), 3.22 (t, 2H), 2.71 (s, 3H), 1.88 (m, 2H). MS (ES) for C3oH29F2 503: 546 (MH+).
249 Ή NMR (400 MHz, DMSO-d6) δ 13.03 (brs, 1H), 8.67 (s, 1H), 8.41- 8.02 (m, 2H), 7.86 (brs, 1H), 7.31 (d, IH), 7.25 (s, 1H), 7.16 (dd, 1H), 6.90 (s, IH), 4.94 (s, 2H), 4.03 (t, 2H), 3.19 (s, 2H), 2.90 (s, 4H), 2.63 (s, 3H), 2.27-2.04 (m, 2H), 1.77-1.48 (m, 5H), 1.21-1.00 (m, 3H). MS (EI) for C29H33N70: 473 (MH+).
250 Ή NMR (400 MHz, DMSO-d6) 510.33 (s, IH), 8.68 (s, IH), 8.67 (d,
IH), 8.20 (dd, IH), 8.09-8.02 (m, 2H), 7.32-7.26 (m, 2H), 7.15 (d, IH), 6.97 (d, IH), 5.00 (s, 2H), 4.06 (t, 2H), 3.93 (s, 3H), 3.16 (s, 3H), 3.03- 2.84 (m, 3H), 2.68 (s, 3H), 2.30-2.06 (m, 2H), 1.62 (s, 5H), 1.15 (s, 4H). MS (EI) for C32H36N602: 537 (MH+).
251 Ή NMR (400 MHz, methanol-d4): 8.61 (s, IH), 8.33 (s, IH), 8.17 (s,
IH), 8.14 (d, IH), 7.34-7.25 (m, 3H), 7.09 (d, IH), 5.00 (s, 2H), 4.73 (br s, IH), 4.12 (s,2H), 3.88 (brs, 1H),3.34 (m, IH), 3.20 (tr, 3H), 2.89 (d, 3H), 2.68 (s, 3H), 2.17 (br s, 1 H), 2.02 (br s, 1 H), 1.52 (br s, 2H), 1.05 (m, IH), 0.68 (m, 2H), 0.36 (m, 2H). MS (EI) for C32H35N702: 550 (MH+).
252 Ή NMR (400 MHz, methanol-d4): 8.58 (s, IH), 8.44 (s, IH), 8.17 (s,
IH), 8.13 (d, IH), 7.35-7.24 (m, 4H), 5.02 (s, 2H), 4.73 (brs, IH), 4.16 (s, 3H), 4.09 (s, 2H), 3.88 (br s, 1 H), 3.36 (br s, 1 H), 3.18 (br s, 3H), 2.90 (d, 3H), 2.67 (s, 3H), 2.19 (br s, 1 H), 2.05 (br s, 1 H), 1.56 (br s, 2H), 1.08 (br s, 1 H), 0.67 (m, 2H), 0.37 (m, 2H). MS (EI) for C33H37N702: 565 (MH+).
253 Ή NMR (400 MHz, DMSO-d6): δ 9.51 (s, IH), 8.66 (m, 2H), 8.18 (dd,
31 H), 8.05 (d, 1 H), 7.52 (m, 1 H), 7.15 (d, 1 H), 6.94 (d, 1 H), 4.94 (s, 2H), 4.13 - 3.95 (m, 2H), 3.89 (s, 3H), 3.05 (t, 2H), 2.67 (s, 3H), 2.55 (br s, 4H), 1.87 (s, 3H-OAc peak), 1.74 (br s, 4H), 1.19 (s, 6H); MS (EI) for C32H36N602: 537.1 (MH+).
254 Ή NMR (400 MHz, CD3OD) δ 8.64 (s, IH), 8.56 (d, IH), 8.28 (s, IH),
8.19 (d, IH), 7.32 (d, IH), 7.18 (d, IH), 7.13-7.03 (m, 2H), 5.02 (s, 2H), 4.21 - 4.11 (m, 5H), 3.15 (t, 3H), 2.90 (s, 3H), 2.74 (s, 3H). MS (EI) for C24H24N603S: 477 (MH+).
255 Ή NMR (400 MHz, DMSO-d6) δ 8.75 - 8.62 (m, 2H), 8.54 (m, IH),
8.06 (m, 1 H), 7.96 (s, 1 H), 7.77 (m, 1 H), 7.15 - 6.93 (m, 1 H), 4.49 - 3.99 (m, 2H), 3.23 - 3.04 (m, 2H), 2.91 (s, 5H), 2.67 (s, 3H), 1.96 - 1.71 (m, 3H), 1.49-1.26 (m, 2H). MS (EI) for C2iH24FN502S, found 430.1.
256 Ή NMR (400 MHz, DMSO-d6) δ 8.66 (s, IH), 8.53 (m, IH), 8.21 - 7.88 CMPD CHARACTERIZATION DATA
(m, 2H), 7.68 (s, 1 H), 7.59 (m, 1 H), 7.19 - 7.04 (m, I H), 4.35 (m, 2H), 3.21 (m, 2H), 2.92 (m, 5H), 2.67 (s, 3H), 2.57 (s, 3H), 1.98- 1.68 (m, 3H), 1.54 - 1.24 (m, 2H). MS (EI) for C22H27N502S, found 426.1.
257 Ή NMR (400 MHz, DMSO-d6) δ 8.66 (s, IH), 8.54 (s, IH), 8.32 (m,
IH), 8.04 (m, IH), 7.86 (m, IH), 7.49 (m, IH), 7.04 (m, IH), 4.30 (m, 2H), 3.96 (s, 3H), 3.24-3.03 (m, 2H), 2.90 (s, 5H), 2.65 (s, 3H), 1.99- 1.67 (m, 3H), 1.56 - 1.25 (m, 2H). MS (El) for C22H27N503S, found 442.1.
258 Ή NMR (400 MHz, DMSO-d6) δ 8.66 (s, IH), 8.28 (m, IH), 8.01 (m,
2H), 7.37 (m, IH), 7.17 (m, IH), 7.14- 7.04 (m, IH), 4.30 (m,2H),3.92 (s, 3H), 3.25 - 3.06 (m, 2H), 2.91 (s, 5H), 2.66 (s, 3H), 1.81 (m, 3H), 1.53 - 1.25 (m, 2H). MS (EI) for C22H27N503S, found 442.1.
259 Ή NMR (400 MHz, d6-DMSO): 8.68 (s, IH), 8.66 (d, IH), 8.19 (dd,
IH), 8.04 (s, 2H), 7.36 (s, IH), 7.32 (d, IH), 7.21 (d, IH), 6.96 (d, IH), 5.00 (s, 2H), 4.24 (br s, IH), 4.08 (t, 2H), 3.90 (s, 3H), 3.58 (br s, IH), 3.12 (t, IH), 3.00 (brs, IH), 2.92 (t, 3H), 2.71 (t, IH), 2.68 (s, 3H), 2.36 (m, IH), 2.20 (m, 2H), 1.80 (m, 4H), 1.32 (m, 2H). MS (EI) for
C34H36F2N602: 599 (MH+).
260 Ή NMR (400 MHz, DMSO-d6): 89.98 (s, IH), 8.70 (s, IH), 8.57 (s,
IH), 8.50-8.30 (m, 2H), 7.53 (s, IH), 7.39 (d, 2H), 7.18 (d, IH), 4.95 (s, 2H), 4.09 (s, 3H), 4.06 (br t, 2H), 3.07 (br t, 3H), 2.93 (m, 4H), 2.69 (s, 3H), 2.08 (s, 1 H), 1.91 (s, 1.5H-OAc peak); MS (EI) for C28H29N702: 496.0 (MH+).
261 Ή NMR (400 MHz, methanol-d4): 8.69 (s, IH), 8.67 (s, IH), 8.36 (s,
IH), 8.23 (d, IH), 7.74 (d, IH), 7.35 (d, IH), 7.31 (s, IH), 7.27 (d, IH), 5.11 (s, 2H), 4.60 (m, 2H), 4.49 (m, IH), 4.19 (m, 2H), 3.78 (m, IH), 3.25 (m, 2H), 3.21-2.84 (m, 5H), 2.76 (s, 3H), 2.75 (s, 3H), 2.06 (m, IH), 1.92 (s, 12H), 1.35 (m, 2H). MS (EI) for C3,H34FN70: 540 (MH+).
262 Ή NMR (400 MHz, methanol-d4): 9.08 (s, IH), 8.71 (s, IH), 8.67 (s,
IH), 8.35 (s, IH), 8.18 (s, IH), 7.35 (d, IH), 7.32 (s, IH), 7.27 (d, IH), 5.12 (s, 2H),4.61 (m, 2H), 4.50 (m, IH), 4.19 (m, 2H), 3.79 (m, IH), 3.24 (m, 2H), 3.20-2.84 (m, 5H), 2.76 (s, 3H), 2.52 (s, 3H), 2.06 (m, IH), 1.93 (s, 12H), 1.36 (m, 2H). MS (EI) for C3iH34FN70: 540 (MH+).
263 Ή NMR (400 MHz, DMSO-d6) δ 8.68 (s, IH), 8.55 (s, IH), 8.42 (dd,
IH), 8.35 (d, IH), 7.38 (d, IH), 6.95 (d, IH), 6.49 (dd, IH), 6.46 (d, IH), 5.30-5.20 (m, IH), 4.87 (s, 2H), 4.11 (s, 3H), 4.02 (t, 2H), 3.61-3.52 (m, 4H), 3.15-3.04 (m, 2H), 2.97 (t, 2H), 2.68 (s, 3H), 2.47 (t, 2H), 2.42-2.35 (m, 4H). MS (EI) for C29H33N702: 512 (MH+).
264 Ή NMR (400 MHz, DMSO-d6): 59.58 (s, IH), 8.70 (s, IH), 8.56 (s,
IH), 8.44 (s, IH), 8.37 (d, IH), 7.56 (s, IH), 7.44 (d, IH), 7.39 (d, IH), 7.18 (d, 1 H), 4.95 (s, 2H), 4.12 (s, 3H), 4.05 (br t, 2H), 3.20 (m, 2H), 3.07 (br t, 2H), 2.95 (d, 1 H), 2.69 (s, 3H), 2.50 (m, 2H), 1.89 (s, 3H-OAc peak), 1.77 (m, 2H), 1.43 (m, 4H); MS (EI) for C29H3|N702: 510.0 (MH+).
265 Ή NMR (400 MHz, DMSO-d6): δ 8.63 (s, IH), 8.62 (d, IH), 8.17 (dd, CMPD CHARACTERIZATION DATA
IH), 8.02 (s, IH), 6.97 (d, IH), 6.89 (d, IH), 6.44 (m, 2H), 4.91 (brs, 2H), 4.80 (br s, 2H), 3.99 (br t, 2H), 3.93 (s, 3H), 2.94 (br t, 2H), 2.67 (s, 3H); MS (EI) for C24H23N5O: 398.2 (MH+).
266 Ή NMR (400 MHz, CD3OD) δ 8.62 (s, IH), 8.56 (s, IH), 8.27 (s, IH),
8.18 (d, 1 H), 7.31 (d, 1 H), 6.98 (d, 1 H), 6.67 - 6.58 (m, 2H), 4.93 (s, 2H), 4.17 (s, 3H), 4.11 (t, 2H), 3.06 (t, 2H), 2.74 (s, 3H). MS (EI) for C23H22N60: 399 (MH+).
267 Ή NMR (400 MHz, methanol-d): 9.20 (d, IH), 8.73 (s, IH), 8.67 (s,
IH), 8.38 (s, IH), 8.34 (d, IH), 7.86 (dd, IH), 7.35 (d, IH), 7.31 (s, IH), 7.27 (d, IH), 5.12 (s, 2H), 4.60 (m, 2H), 4.48 (m, IH), 4.20 (m, 2H), 3.78 (m, IH), 3.25 (m, 2H), 3.20-2.82 (m, 5H), 2.76 (s, 3H), 2.05 (m, IH), 1.91 (s, 12H), 1.33 (m, 2H). MS (EI) for C30H32FN7O: 526 (MH+).
268 Ή NMR (400 MHz, methanol-d4): 8.71 (s, IH), 8.67 (s, IH), 8.35 (m,
2H), 7.92 (d, 1 H), 7.35 (d, I H), 7.31 (s, 1 H), 7.27 (d, IH), 5.11 (s, 2H), 4.63 (m,2H), 4.51 (m, IH), 4.19 (m, 2H), 3.80 (m, 1H),3.24 (m, 2H), 3.17-2.85 (m, 5H), 2.75 (s, 3H), 2.08 (m, IH), 1.95 (s, 3H), 1.36 (m, 2H). MS (EI) for C3oH3iC]FN70: 560 (MH+).
269 Ή NMR (400 MHz, methanol-d4): 9.22 (s, 2H), 9.20 (s, IH), 8.67 (s,
IH), 8.24 (s, IH), 8.06 (s, IH), 7.34 (d, IH), 7.30 (s, IH), 7.26 (d, IH), 5.10 (s, 2H), 4.61 (m, 2H), 4.49 (m, IH), 4.18 (m, 2H), 3.78 (m, IH), 3.23 (m, 2H), 3.19-2.83 (m, 5H), 2.75 (s, 3H), 2.06 (m, IH), 1.92 (s, 9H), 1.34 (m, 2H). MS (EI) for C30H32FN7O: 526 (MH+).
270 Ή NMR (400 MHz, DMSO) δ 9.35 (s, IH), 8.73 (s, IH), 8.60 (m, 3H),
8.39 (s, 1 H), 6.90 (dd, 1 H), 6.49 - 6.35 (m, 2H), 5.05 (bs, 1 H), 4.82 (s, 2H), 3.98 (t, 2H), 3.50 (m, 2H), 3.05 (m, 2H), 2.84 (m, 2H), 2.63 (s, 3H), 2.55 - 2.37 (m, 4H), 0.90 (qt, 6H); MS (EI) for C28H33N7: 468.3 (MH+).
271 Ή NMR (400 MHz, DMSO-d6) δ 13.21-12.88 (m, IH), 8.60 (s, IH),
8.42-8.30 (m, IH), 8.12-8.02 (m, IH), 7.99 (s, 2H), 6.94 (d, IH), 6.48 (dd, IH), 6.45 (d, IH), 5.16 (t, IH), 4.81 (s, 2H), 3.95 (t, 2H), 3.08-3.00 (m, 2H), 2.98 (t, 2H), 2.63 (s, 3H), 2.58-2.52 (m, 2H), 2.53-2.44 (m, 4H), 0.95 (t, 6H). MS (EI) for C27H33N7: 456 (MH+).
272 Ή NMR (400 MHz, CD3OD) S 8.61 (s, IH), 8.56 (d, IH), 8.25 (s, IH),
8.14 (d, 1 H), 7.29 (d, 1 H), 6.98 (d, 1 H), 6.54 (dd, 1 H), 6.49 (d, 1 H), 4.94 (s, 2H), 4.17 (s, 3H), 4.11 (t, 2H), 3.01 (dt, 5H), 2.78-2.68 (m, 3H), 2.67 - 2.51 (m, 1 H), 1.93 - 1.86 (m, 7H). MS (EI) for C29H33N70: 496 (MH+).
273 Ή NMR (400 MHz, d6-DMSO): 8.68 (s, IH), 8.64 (d, IH), 8.33 (d, IH),
8.14 (d, IH), 8.09 (d, IH), 7.77 (m, IH), 7.30 (m, 2H), 7.19 (dd, IH), 5.06 (s, 2H), 4.12 (t, 2H), 4.00 (s, 3H), 3.26 (br s, 2H), 3.18 (m, 2H), 3.00 (m, 2H), 2.70 (s, 3H), 2.68 (m, IH), 2.41 (d, 2H), 1.78 (m, 2H), 1.20 (m, 2H), 0.84 (m, IH), 0.40 (m, IH), 0.10 (m, 2H). MS (El) for
C34H38N602: 563 (MH+).
274 Ή NMR (400 MHz, DMSO-d6): δ 8.73 - 8.57 (m, 2H), 8.26 - 8.09 (dd,
IH), 8.03 (s, IH), 6.94 (d, IH), 6.92 (d, IH), 6.44 (m, IH), 5.53-5.36 (m, 0.5H), 4.83 (s, 2H), 3.99 (br t, 2H), 3.92 (s, 3H), 2.95 (m, 2H), 2.82 CMPD CHARACTERIZATION DATA
(m, 2H), 2.67 (s, 3H), 1.86 (s, 2H-OAc peak), 1.80 - 1.72 (m, 4H), 1.67 - 1.46 (m, 2H), 1.11 (m, IH); MS (EI) for C3oH34N60: 495.3 (MH+).
275 Ή NMR (400 MHz, DMSO-d6) δ 8.79 (s, IH), 8.69 (s, IH), 8.63 (m,
IH), 7.91 (m, IH), 7.81 (m, IH), 7.63 (m, IH), 7.18-6.98 (m, IH), 4.30 (m, 2H), 3.27 - 3.04 (m, 2H), 2.95 - 2.81 (m, 5H), 2.66 (s, 3H), 1.98 - 1.71 (m, 3H), 1.49 - 1.23 (m, 2H). MS (EI) for C2iH24CIN502S, found 446.1.
276 Ή NMR (400 MHz, DMSO) δ 9.21 (d, 2H), 8.65 (s, IH), 8.60 (s, IH),
8.43 (d, IH), 8.34 (dd, IH), 7.79 (m, IH), 6.92 (dd, IH), 6.44 (m, 2H), 6.39 (m, IH), 5.02 (bs, IH), 4.85 (s, 2H), 4.00 (t, 2H), 3.01 (t, 2H), 2.93 (t, 2H), 2.66 (s, 3H), 2.52 (m, 2H), 2.43 (m, 2H), 0.91 (t, 6H); MS (EI) for C28H33N7: 468.3 (MH+).
277 Ή NMR (400 MHz, DMSO) δ 9.23 (dt, IH), 8.68 (s, IH), 8.64 (t, IH),
8.48 (t, IH), 8.37 (dt, IH), 7.81 (dt, IH), 6.93 (t, IH), 6.52-6.45 (m, 2H), 5.17 (bs, IH), 4.89 (s, 2H), 4.04 (t, 2H), 3.59 - 3.54 (m, 4H), 3.10 (t, 2H), 2.97 (t, 2H), 2.71 (s, 3H), 2.48 (m, 2H), 2.39 (m, 4H); MS (EI) for C28H3|N70: 482.3 (MH+).
278 Ή NMR (400 MHz, DMSO) δ 9.37 (s, IH), 8.78 (s, IH), 8.67 (s, IH),
8.64 (dd, 2H), 8.43 (s, 1 H), 6.93 (t, 1 H), 6.52 - 6.44 (m, 2H), 5.17 (bs, IH), 4.89 (s, 2H), 4.04 (t, 2H), 3.60 - 3.53 (m, 4H), 3.10 (t, 2H), 2.97 (t, 2H), 2.69 (s, 3H), 2.47 (m, 2H), 2.39 (m, 4H); MS (EI) for C28H3,N70: 482.3 (MH+).
279 Ή NMR (400 MHz, DMSO-d6) δ 9.81 (s, IH), 8.69 (s, IH), 8.56 (d,
1 H), 8.41 (s, 1 H), 8.33 (d, 1 H), 7.48 (d, 1 H), 7.46 - 7.25 (m, 2H), 7.16 (d, IH), 4.94 (s, 2H), 4.12 (s, 3H), 4.06 (t, 2H), 3.06 (t, 2H), 2.70 (s, 3H), 2.02 (s, 3H). MS (EI) for C25H24N602: 441 (MH+).
280 Ή NMR (400 MHz, methanol-d4): 9.69 (s, IH), 9.27 (d, IH), 8.67 (s,
IH), 8.38 (s, IH), 8.16 (m, 2H), 7.35 (d, IH), 7.30 (s, IH), 7.26 (d, IH), 5.13 (s, 2H), 4.62 (m, 2H), 4.50 (m, IH), 4.19 (m, 2H), 3.78 (m, IH), 3.23 (m, 2H), 3.19-2.84 (m, 5H), 2.75 (s, 3H), 2.07 (m, IH), 1.93 (s, 6H), 1.36 (m, 2H). MS (EI) for C30H32FN7O: 526 (MH+).
281 Ή NMR (400 MHz, methanol-d4): 8.65 (s, IH), 8.56 (s, IH), 8.27 (s,
IH), 8.19 (d, IH), 7.37-7.23 (m, 4H), 5.88 (m, IH), 5.09 (s, 2H), 4.53 (m, IH), 4.17 (m, 5H), 3.75 (m, IH), 3.23 (m, 2H), 3.13 (m, IH), 2.97 (m, 3H), 2.80 (m, 1 H), 2.74 (s, 3H), 2.02 (m, 1 H), 1.94 (s, 6H), 1.85 (m, 1 H), 1.31 (m, 2H). MS (EI) for C3iH33F2N702: 574 (MH+).
282 Ή NMR (400 MHz, DMSO-d6) δ 8.71 (s, IH), 8.58-8.49 (m, IH), 8.43
(s, IH), 8.35 (d, IH), 7.35 (d, IH), 7.30 (d, IH), 7.25 (s, IH), 7.15 (dd, IH), 5.02 (s, 2H), 4.15-4.04 (m, 5H), 3.29 (br s, 2H), 3.18 (t, 3H), 2.81- 2.68 (m, 5H), 2.09 (br s, 3H), 1.90-1.48 (m, 7H), 1.07 (br s, 3H). MS (EI) for C32H37N702: 552 (MH+).
283 Ή NMR (400 MHz, DMSO-d6) δ 9.79-9.73 (m, IH), 9.31 (dd, IH), 8.67
(s, 1 H), 8.34 (d, 1 H), 8.24-8.18 (m, 1 H), 8.13 (dd, 1 H), 6.94 (d, 1 H), 6.52-6.45 (m, 2H), 5.16 (t, IH), 4.91 (s, 2H), 4.05 (t, 2H), 3.61-3.52 (m, 4H), 3.10 (q, 2H), 2.96 (t, 2H), 2.69 (s, 3H), 2.53-2.43 (m, 2H), 2.43-2.35 CMPD CHARACTERIZATION DATA
(m, 4H). MS (EI) for C28H31N7O: 482 (MH+).
284 Ή NMR (400 MHz, DMSO-d6): 58.67 (s, IH), 8.55 (s, IH), 8.42 (s,
IH), 8.35 (d, IH), 7.38 (d, IH), 6.93 (d, IH), 6.47 (d, IH), 6.41 (s, IH), 5.48 (br t, 1 H), 4.86 (s, 2H), 4.10 (s, 3H), 4.02 (t, 2H), 3.03 - 2.89 (m, 4H), 2.84 (t, 2H), 2.68 (s, 3H), 2.47 - 2.32 (m, 2H), 1.85 (s, 3H-Oac peak), 1.67 (m, 4H), 1.16- 0.90 (m, 2H); MS (EI) for C29H33N70: 496.3 (MH+).
285 Ή NMR (400 MHz, DMSO-d6): δ 8.70 (s, IH), 8.52 (s, IH), 8.43 (s,
IH), 8.40 (d, IH), 7.36 (d, IH), 6.90 (d, IH), 6.49 (d, IH), 6.44 (s, IH), 5.53 (br t, IH), 4.82 (s, 2H), 4.0 (br t, 2H), 2.95 (m, 4H), 2.70 (s, 3H), 2.67 (m, 1 H), 1.86 (s, 3H-OAc peak), 1.80 - 1.72 (m, 2H), 1.67 - 1.46 (m, 2H), 1.25 (m, 2H), 1.11 (m, 1 H); MS (EI) for C29H33 70: 496.2 (MH+).
286 Ή NMR (400 MHz, DMSO) δ 8.64 (s, IH), 8.59 (s, IH), 8.31 (d, IH),
8.10 (s, 1 H), 8.06 (s, 1 H), 7.71 (dd, 1 H), 6.90 (t, 1 H), 6.49 - 6.42 (m, 2H), 4.99 (bs, IH), 4.85 (s, 2H), 4.00 (t, 2H), 3.92 (d, 3H), 3.57 - 3.52 (m, 4H), 3.08 (t, 2H), 2.93 (t, 2H), 2.67 (s, 3H), 2.45 (d, 2H), 2.38 (m, 4H); MS (El) for C30H34N6O2: 511.3 (MH+).
287 Ή NMR (400 MHz, DMSO) δ 8.70 (s, IH), 8.58 (d, IH), 8.43 (m, IH),
8.35 (dd, IH), 8.09-7.58 (dd, IH), 7.73 (s, IH), 7.38 (d, IH), 7.34 (dd, IH), 5.05 (s, 2H), 4.18 (s, 3H), 4.09 (t, 2H), 3.91 (bs, IH), 3.78 (m, IH), 3.20 (m, 2H), 2.81 (m, 2H), 2.71 (s, 3H), 2.54 (m, 2H), 2.15 (m, 2H), 1.84 (m, IH), 1.73 (m, IH), 1.56 (m, IH), 1.38 (s, 9H)1.21 (m, IH); MS (EI) for C34H39N7O4: 610.3 (MH+).
288 Ή NMR (400 MHz, DMSO) δ 8.70 (s, IH), 8.56 (s, IH), 8.42 (s, IH),
8.35 (d, 1 H), 7.96 - 7.67 (m, 1 H), 7.72 (s, 1 H), 7.39 - 7.29 (m, 2H), 5.04 (d, 2H), 4.10 (s, 3H), 4.04 (m, 2H), 3.78 (bs, IH), 3.17 (m, 2H), 3.02 - 2.93 (m, 1 H), 2.85 - 2.75 (m, 1 H), 2.69 (s, 3H), 1.57 (m, 2H), 1.39 (m, 2H); MS (EI) for
Figure imgf000159_0001
510.3 (MH+).
289 Ή NMR (400 MHz, DMSO) δ 8.67 (s, IH), 8.65 (dd, IH), 8.18 (dd, IH),
8.09 - 7.58 (m, 2H), 7.74 (s, IH), 7.67 (dd, IH), 7.31 (dd, IH), 6.96 (d, IH), 5.04 (s, 2H), 4.15 (t, 2H), 3.98 (s, 3H), 3.91 (m, IH), 3.78 (m, 2H), 3.19 (m, 2H), 2.81 (m, 2H), 2.73 (s, 3H), 1.85 (m, 2H), 1.74 (m, 2H), 1.40 (m, 9H), 1.21 (m, 2H); MS (El) for C35H4oN604: 609.3 (MH+).
290 Ή NMR (400 MHz, DMSO) δ 8.67 (s, IH), 8.64 (t, IH), 8.30 (bs, IH),
8.19 (dd, IH), 8.05 (d, 2H), 7.82 (s, IH), 7.72 (d, IH), 7.32 (d, IH), 6.96 (d, IH), 5.03 (s, 2H), 4.07 (t, 2H), 3.93 (m, IH), 3.16 (s, 2H), 3.05-2.96 (m, 2H), 2.68 (d, 3H), 2.36 - 2.27 (m, 2H), 1.90 (m, 2H), 1.57 (m, 2H); MS (El) for C3oH32N602: 509.3 (MH+).
291 Ή NMR (400 MHz, DMSO-d5) δ 8.90 (d, IH), 8.73 (d, IH), 8.67 (s,
IH), 8.45-8.42 (m, IH), 7.62 (d, IH), 6.95 (d, IH), 6.50 (dd, IH), 6.46 (d, IH), 5.18 (t, IH), 4.88 (s, 2H), 4.06-3.99 (m, 5H), 3.60-3.53 (m, 4H), 3.24 (3, 4H), 3.10 (q, 2H), 2.97 (t, 2H), 2.67 (s, 3H), 2.52-2.44 (m, 2H), 2.42-2.35 (m, 4H). MS (EI) for C29H33 702: 512 (MH+).
292 Ή NMR (400 MHz, d6-DMSO): 8.67 (s, IH), 8.02 (d, 2H), 7.36 (s, IH), CMPD CHARACTERIZATION DATA
7.35 (dd, IH), 7.29 (m 2H), 7.19 (d, IH), 7.08 (d, IH), 4.97 (s, 2H), 4.04 (t, 2H), 3.90 (s, 2H), 3.82 (s, 6H), 3.16 (t, 2H), 3.00 (m, 2H), 2.69 (s, 3H), 2.65 (m, 1 H), 2.38 (d, 2H), 1.78 (m, 2H), 1.18 (m, 2H), 0.84 (m, IH), 0.36 (m, 2H), 0.09 (m, 2H). MS (El) for C36H41N5O3: 592 (MH+).
293 Ή NMR (400 MHz, d6-DMSO): 8.70 (s, IH), 8.53 (d, IH), 8.42 (s, IH),
8.34 (d, IH), 7.35 (d, IH), 7.32 (m, 2H), 7.24 (m, IH), 5.02 (s, 2H), 4.12 (s, 3H), 4.08 (t, 2H), 3.16 (m, 2H), 3.00 (m, 2H), 2.92 (t, 2H), 2.73 (m, IH), 2.69 (s, 3H), 2.38 (m, 2H), 2.20 (m, 2H), 1.78 (m, 2H), 1.34 (m, 2H). MS (EI) for C33H35F2N702: 600 (MH+).
294 Ή NMR (400 MHz, DMSO-d6): 58.64 - 8.52 (m, 2H), 8.12 (dd, IH),
7.98 (d, 2H), 7.50 (s, 1 H), 7.43 (d, 1 H), 7.10 (d, 1 H), 6.91 (d, 1 H), 4.87 (s, 2H), 3.97 (br t, 2H), 3.85 (s, 3H), 3.00 (br t, 2H), 2.57 (s, 3H), 1.83 (s, 2H-Oac peak), 1.20 (s, 6H); MS (EI) for C28H3oN602: 483.0 (MH+).
295 Ή NMR (400 MHz, DMSO-d6) δ 8.67 (s, IH), 8.54 (d, IH), 8.40 (s,
IH), 8.31 (d, IH), 7.35 (d, IH), 6.93 (d, IH), 6.53-6.36 (m, 2H), 5.15 (d, IH), 4.85 (s, 2H), 4.12 (s, 3H), 4.02 (t, 2H), 3.21-3.04 (m, IH), 2.96 (t, 2H), 2.73-2.60 (m, 5H), 2.15 (s, 3H), 2.02-1.91 (m, 2H), 1.90-1.77 (m, 2H), 1.43- 1.28 (m, 2H). MS (EI) for C29H33N70: 496 (MH+).
296 Ή NMR (400 MHz, d6-DMSO): 8.69 (s, IH), 8.54 (s, IH), 8.42 (s, IH),
8.32 (d, IH), 7.34 (d, IH), 7.14 (d, IH), 7.03 (m, 2H), 4.92 (s, 2H), 4.11 (s, 3H), 4.04 (t, 2H), 3.06 (t, 2H), 2.70 (s, 3H), 2.66 (s, 6H). MS (EI) for C25H27N703: 506 (MH+).
297 Ή NMR (400 MHz, d6-DMSO): 8.67 (s, IH), 8.63 (d, IH), 8.18 (dd,
2H), 8.03 (dd, 2H), 7.34 (s, IH), 7.29 (d, IH), 7.20 (d, IH), 6.94 (d, IH), 5.00 (s, 2H), 4.06 (t, 2H), 3.92 (s, 3H), 3.54 (m, 4H), 3.14 (2H), 2.90 (m, 2H), 2.69 (s, 3H), 2.44 (m, 4H), 2.38 (m, 1 H), 1.76 (m, 2H), 1.34 (m, 2H). MS (EI) for C34H38 603: 579 (MH+).
298 Ή NMR (400 MHz, d6-DMSO): 8.66 (s, IH), 8.64 (d, IH), 8.16 (dd,
IH), 8.04 (dd, 2H), 7.34 (s, IH), 7.29 (d, IH), 7.20 (d, IH), 6.96 (d, IH), 5.00 (s, 2H), 4.06 (t, 2H), 3.92 (s, 3H), 3.13 (m, 2H), 3.00 (m 2H), 2.68 (s, 3H), 2.46 (m, 5H) 2.23 (m, IH), 1.80 (m, 2H), 1.65 (m, 4H), 1.36 (m, 2H). MS (EI) for C34H38 602: 563 (MH+).
299 Ή NMR (400 MHz, DMSO-d6) δ 8.63 (s, IH), 7.99 (m, IH), 7.88 (m,
1 H), 7.81 (m, 1 H), 7.11 (m, 1 H), 6.54 (m, 1 H), 4.29 (m, 2H), 3.95 (m, 6H), 3.11 (m, 2H), 2.98 - 2.82 (m, 5H), 2.63 (s, 3H), 2.00 - 1.75 (m, 3H), 1.59- 1.14 (m, 2H). MS (EI) for C23H29N504S, found 472.1.
300 Ή NMR (400 MHz, DMSO-d6) δ 8.67 (s, IH), 7.67 (m, 3H), 7.08 (m,
IH), 6.76 (m, IH), 4.23 (m, 2H), 3.89 (s, 3H), 3.23 - 3.00 (m, 2H), 2.96 -2.78 (m, 5H), 2.65 (s, 3H), 2.44 (s, 3H), 1.93 - 1.66 (m, 3H), 1.51 - 1.23 (m, 2H). MS (EI) for C23H29N503S, found 456.1.
301 Ή NMR (400 MHz, DMSO-d6): 58.65 (s, IH), 8.51 (s, IH), 8.39 (s,
IH), 8.32 (d, IH), 7.35 (d, IH), 6.91 (d, IH), 6.45 (dd, IH), 6.39 (s, IH), 5.46 (t, 1 H), 4.84 (s, 2H), 4.09 (s, 3H), 4.00 (b t, 2H), 2.95 (br t, 2H), 2.83 (t, 2H), 2.74-2.61 (m, 5H), 2.09 (s, 3H), 1.83 - 1.58 (m, 4H), 1.44 (m, 1 H), 1.13 (m, 2H); MS (EI) for C3oH35 70: 10.3 (MH+). CMPD CHARACTERIZATION DATA
302 Ή NMR (400 MHz, DMSO-d6): 58.68 (s, IH), 8.54 (s, IH), 8.42 (s,
IH), 8.34 (s, IH), 7.37 (d, IH), 7.02 (d, IH), 6.55 (m, 2H), 4.86 (s, 2H), 4.11 (s, 3H), 4.02 (t, 2H), 3.18 (d, 4H), 3.00 (brt, 2H), 2.71 (m, 7H), 2.09 (s, 6H), 1.89 (s, IH-OAc peak), 1.69 (t, 4H), 1.54 (m, 6H), 1.18 (m, 4H); MS (EI) for
Figure imgf000161_0001
621.4 (MH+).
303 1 H NMR (400 MHz, CD3OD) 88.60 (s, 1 H), 8.54 (d, 1 H), 8.27 - 8.20
(m, IH), 8.13 (d, IH), 7.27 (d, IH), 6.97 (d, IH), 6.55 (dd, IH), 6.50 (d, IH), 4.93 (s, 2H), 4.17 (s, 3H), 4.10 (t, 2H), 3.08 (d, 2H), 3.04 (t, 2H), 3.00 - 2.83 (m, 2H), 2.84 - 2.67 (m, 3H), 2.67 - 2.35 (m, 4H), 2.23 - 1.96 (m, 2H), 1.89 (s, 3H). MS (EI) for C29H33N70: 496 (MH+).
304 Ή NMR (400 MHz, DMSO) δ 8.66 (s, IH), 8.36 (bs, IH), 8.05 (t, 2H),
7.97 (s, IH), 7.90 (s, IH), 7.73 (s, IH), 7.60 (m, IH), 7.30 (t, IH), 5.69 (s, 2H), 5.03 (d, 2H), 4.07 (d, 4H), 3.16 (s, 2H), 3.02 (bs, IH), 3.04 (bs, IH), 2.64 (s, 3H), 1.82 (m, 2H), 1.55 (bs, 2H); MS (EI) for C29H3oCIN70: 528.0 (MH+).
305 Ή NMR (400 MHz, DMSO) S 8.68 (s, IH), 8.65 (t, IH), 8.43 (d, IH),
8.18 (dt, IH), 8.07 (s, IH), 8.03 (d, IH), 7.82 (s, IH), 7.72 (d, IH), 7.33 (d, IH), 6.95 (m, IH), 5.02 (d, 2H), 4.13 (bs, IH), 4.06 (t, 2H), 3.92 (s, 3H), 3.17 (d, 2H), 2.82 (m, 2H), 2.67 (s, 3H), 2.44 (d, 2H), 1.65 (m, 2H), 1.68 (m, 2H); MS (EI) for C30H32N6O2: 509.3 (MH+).
306 Ή NMR (400 MHz, DMSO) 58.70 (s, IH), 8.57 (s, IH), 8.42 (d, IH),
8.34 (m, 1 H), 8.05 - 7.74 (dd, 1 H), 7.68 (t, 1 H), 7.39 - 7.28 (m, 2H), 5.04 (m, 2H), 4.10 (s, 3H), 4.05 (m, 2H), 3.88 (bs, IH), 3.18 (m, 2H), 2.90 (m, 2H), 2.90 (m, 2H), 2.69 (s, 3H), 1.83 (m, IH), 1.64 (m, IH), 1.48 (m, 2H); MS (EI) for C29H3IN702: 510.2 (MH+).
307 Ή NMR (400 MHz, DMSO) δ 8.62 (s, IH), 8.22 (m, 2H), 8.1 (m, IH),
8.01 (dd, IH), 7.75 (s, IH), 7.69 (d, 2H), 7.31 (dd, IH), 4.98 (d, 2H),
4.02 (t, 2H), 3.87 (bs, IH), 3.25 (m, 2H), 3.04 (m, 2H), 2.87 (m, 2H), 2.65 (s, 3H), 1.84 (m, IH), 1.69 (m, IH), 1.48 (m, 2H); MS (EI) for C27H29N70: 468.2 (MH+).
308 Ή NMR (400 MHz, DMSO) δ 8.66 (s, IH), 8.25 (d, IH), 8.19 (m, IH),
8.07 (d, IH), 7.93 (d, IH), 7.71 (d, IH), 7.65 (m, IH), 7.44 (dt, IH), 7.28 (t, IH), 7.24 (t, IH), 5.70 (d, IH), 5.02 (m, 2H), 4.05 (t, 2H), 3.91 (s, 3H), 3.78 (bs, IH), 3.15 (m, 2H), 2.88 (m, IH), 2.73 (m, IH), 2.65 (s, 3H), 2.52 (d, IH), 2.43 (s, IH), 1.87 (m, IH), 1.57 (s, IH), 1.37 (s, 2H); MS (EI) for C30H32N6O2: 509.3 (MH+).
309 Ή NMR (400 MHz, DMSO-d6) δ 8.71 (d, IH), 8.54 (s, IH), 8.43 (s,
IH), 8.34 (d, IH), 7.35 (d, IH), 7.31 (d, IH), 7.30 (s, IH), 7.20 (d, IH), 5.02 (s, 2H), 4.12 (s, 3H), 4.09 (m, 2H), 3.36 (t, 2H), 3.23 (s, 3H), 3.16 (m, 2H), 2.99 (m, 1 H), 2.71 (m, 2H), 2.67 (t, 2H), 2.49 (s, 3H), 1.76 (m, 2H), 1.20 (m, 2H). MS (ES) for C32H37N703: 568 (MH+).
310 Ή NMR (400 MHz, DMSO-d6) δ 8.71 (m, IH), 8.54 (d, IH), 8.45 (s,
IH), 8.37 (t, IH), 7.38 (d, IH), 7.33 (d, IH), 7.29 (s, IH), 7.23 (d, IH), 5.02 (s, 2H), 4.23 (m, IH), 4.11 (s, 3H), 4.08 (t, 2H), 3.60 (m, 2H), 3.16 (t, 2H), 2.95 (m, IH), 2.68 (s, 3H), 1.80 (m, 2H), 1.29 (m, 2H). MS (ES) CMPD CHARACTERIZATION DATA
for C29H30FN7O2: 528 (MH+).
31 1 Ή NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1 H), 8.54 (s, 1 H), 8.45 (s, 1 H),
8.38 (d, I H), 7.38 (d, 1 H), 7.32 (s, 1 H), 7.30 (s, 1 H), 7.21 (m, 1 H), 5.02 (s, 2H), 4.47 (m, 1 H), 4.1 1 (s, 3H), 4.09 (t, 2H), 3.72 (m, 2H), 3.16 (t, 2H), 2.86 (m, I H), 2.70 (s, 3H), 1.50 (m, 2H), 1.20 (m, 2H). MS (ES) for C29H30FN7O2: 528 (MH+).
312 Ή NMR (400 MHz, DMSO-d6) 5 8.71 (s, IH), 8.55 (s, I H), 8.45 (s, I H),
8.38 (d, I H), 7.38 (d, I H), 7.33 (m, I H), 7.30 (m, I H), 7.25 (s, I H), 5.40 (d, I H), 5.03 (s, 2H), 4.33 (m, I H), 4.1 1 (s, 4H), 4.08 (m, 2H), 3.77 (m, 2H), 3.19 (m, 2H), 2.71 (s, 3H), 2.67 (m, I H), 1.78 (m, 2H), 1.23 (m, 2H). MS (ES) for C^H^F eCb: 529 (MH+).
3 13 Ή NMR (400 MHz, methanol-d4): 8.66 (d, I H), 8.35 (s, I H), 8.03 (s,
I H), 7.72 (d, 2H), 7.66 (d, I H), 7.51 (d, I H), 7.16 (d, IH), 6.78 (s, I H), 4.60 (s, 2H), 3.72 (m, 2H), 3.41 (m, I H), 2.97 (m, 4H), 2.79 (s, 3H), 2.75 (s, 3H), 1 .99 (m, 2H), 1.92 (s, 6H), 1 .42 (m, 2H). MS (EI) for
C29H34N602S: 53 1 (MH+).
3 14 Ή NMR (400 MHz, methanol-d4): 8.44 (d, I H), 7.69 (s, I H), 7.65 (d,
I H), 7.50 (d, I H), 7.17 (s, I H), 7.07 (d, I H), 6.77 (s, I H), 4.50 (s, 2H), 3.79 (t, 2H), 3.62 (m, 4H), 3.41 (m, 2H), 3.24 (m, 2H), 2.96 (m, 4H), 2.75 (s, 3H), 2.72 (s, 3H), 2.56 (m, 2H), 2.00 (m, 2H), 1.91 (s, 6H), 1.42 (m, 2H). MS (EI) for C3oH37F2N502S: 570 (MH+).
Biological Examples
PI3K Biochemical Assays
[00262] PI3 a activity was measured as the percent of ATP consumed following the kinase reaction using luciferase-luciferin-coupled chemiluminescence. Reactions were conducted in 384-well white, medium binding microtiter plates (Greiner). Kinase reactions were initiated by combining test compounds, ATP, substrate (PIP2), and kinase in a 20 μL· volume in a buffer solution. The standard PI3Kalpha assay buffer was composed of 50 mM Tris, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 1 mM DTT, and 0.03% CHAPS. The standard assay concentrations for enzyme, ATP, and substrate were 1.5 nM, Ι μΜ, and 10 μΜ, respectively. The reaction mixture was incubated at ambient temperature for approximately 2 hours. Following the kinase reaction, a \ 0 μΐ. aliquot of luciferase-luciferin mix (Promega Kinase-Glo) was added, and the chemiluminescence signal was measured using a Victor2 plate reader (Perkin Elmer). Total ATP consumption was limited to 40-60%, and IC50 values of control compounds correlate well with literature references. Substituting P13Ka with ΡΙ3 β, ΡΙ3 Κγ, or PI3K.5, the inhibitory activity of the compounds for the other isoforms of I3K were measured. [00263) In one embodiment, the compound of the invention has a PI3 -alpha-inhibitory activity of about 2500 nM or less.
[00264] In one embodiment, the compound of the invention has a PI3 -alpha-inhibitory activity of about 1 500 nM or less, such as the compounds provided in Table 1.
[00265] In one embodiment, the compound has a PI3 -alpha-inhibitory activity of about 1000 nM or less.
[00266] In another embodiment, the compound has a PI3 -alpha-inhibitory activity of about 500 nM or less.
[00267] In another embodiment, the compound has a PI3K-alpha-inhibitory activity of about 250 nM or less.
[00268] In another embodiment, the compound has a PI3 -alpha-inhibitory activity of about 100 nM or less.
[00269] In another embodiment, the compound has a PI3 -alpha-inhibitory activity of about 50 nM or less.
[00270] In another embodiment, the compound has a PI3 -alpha-inhibitory activity of about 10 nM or less.
[00271] Table 3 summarizes the observed activities of compounds of formula I in the Assay. In the table, "+++" means an activity of (IC50 value) greater than 0 and less than 500 nM; " ++ " means an activity of 500 and less than 1000 nM; and "+" means an activity greater than 1000 nM.
Table 3
CMPD BINNED CMPD BINNED CMPD BINNED
DATA DATA DATA
1 +++ 56 +++ 98 +++
2 +++ 57 +++ 99 +++
16 +++ 58 +++ 100 +++
17 +++ 59 +++ 101 +
18 + 60 +++ 102 +
19 +++ 61 +++ 103 +++
20 +++ 62 +++ 104 +++
21 +++ 63 +++ 105 +++
22 +++ 64 +++ 106 ++
23 +++ 65 ++ 107 +++
24 +++ 66 +++ 108 +++
25 +++ 67 +++ 109 +++
26 +++ 68 +++ 1 10 +++
27 +++ 69 +++ 1 1 1 +++
28 +++ 70 +++ 1 12 +++
29 +++ 71 +++ 1 13 +++
30 +++ 72 +++ 1 14 +++
31 ++ 73 +++ 1 15 +++
32 +++ 74 +++ 1 16 +++
33 + 75 +++ 1 17 +++
34 +++ 76 +++ 1 18 +++
35 +++ 77 +++ 1 19 +++
36 ++ 78 +++ 120 +++
37 +++ 79 ++ 121 +++
38 +++ 80 +++ 122 +++
39 +++ 81 +++ 123 +++
40 +++ 82 +++ 124 +++
41 +++ 83 +++ 125 +++
42 +++ 84 +++ 126 +++
43 +++ 85 +++ 127 +
44 ++ 86 +++ 128 +++
45 +++ 87 +++ 129 +++
46 ++ 88 +++ 130 +++
47 +++ 89 +++ 13 1 +++
48 +++ 90 +++ 132 +++
49 +++ 91 +++ 133 +++
50 +++ 92 +++ 134 +++
51 +++ 93 +++ 135 +++
52 +++ 94 ++ 136 +++
53 +++ 95 +++ 137 +++
54 +++ 96 +++ 138 +++
55 ++ 97 +++ 139 +++ CMPD BINNED CMPD BINNED CMPD BINNED
DATA DATA DATA
140 +++ 182 ++ 224 +++
141 +++ 183 ++ 225 +++
142 +++ 1 84 +++ 226 +++
143 +++ 1 85 +++ 227 +++
144 +++ 186 +++ 228 +++
145 +++ 187 +++ 229 +++
146 +++ 188 +++ 230 +++
147 +++ 189 +++ 231 +++
148 ++ 190 +++ 232 +++
149 +++ 191 +++ 233 +++
150 +++ 192 +++ 234 +++
151 +++ 193 +++ 235 +++
152 +++ 194 +++ 236 +++
153 +++ 195 +++ 237 +++
1 54 +++ 196 +++ 238 +++
1 55 +++ 197 +++ 239 +++
1 56 +++ 198 +++ 240 ++
1 57 +++ 199 +++ 241 +++
158 +++ 200 +++ 242 +++
1 59 +++ 201 +++ 243 +++
160 +++ 202 +++ 244 +++
161 +++ 203 +++ 245 +++
162 +++ 204 +++ 246 +++
163 +++ 205 +++ 247 +++
164 +++ 206 +++ 248 +++
165 +++ 207 +++ 249 +++
166 +++ 208 +++ 250 +++
167 +++ 209 +++ 251 +++
168 +++ 210 +++ 252 +++
1 69 +++ 21 1 +++ 253 +++
170 +++ 212 +++ 254 +++
171 +++ 213 +++ 255 +++
1 72 +++ 214 +++ 256 +++
1 73 +++ 215 +++ 257 +++
174 +++ 216 +++ 258 +++
175 +++ 217 +++ 259 +++
1 76 +++ 218 +++ 260 +++
1 77 +++ 219 +++ 261 +++
178 +++ 220 +++ 262 +++
1 79 +++ 221 +++ 263 +++
1 80 +++ 222 +++ 264 +++
1 81 +++ 223 +++ 265 +++ CMPD BINNED CMPD BINNED CMPD BINNED DATA DATA DATA
266 +++ 283 +++ 300 +
267 +++ 284 +++ 301 +++
268 ++■ 285 +++ 302 +++
269 ■++ 286 +++ 303 +++
270 ■++ 287 +++ 304 +++
271 +++ 288 +++ 305 +++
272 +++ 289 +++ 306 +++
273 +++ 290 +++ 307 +++
274 +++ 291 +++ 308 +++
275 ++ 292 +++ 309 +++
276 +++ 293 +++ 310 +++
277 +++ 294 +++ 31 1 +++
278 +++ 295 +++ 312 +++
279 +++ 296 +++ 313 +++
280 +++ 297 +++ 314 +++
281 +++ 298 +++
282 +++ 299 +++ pS6 (S240/244) ELISA Assay
[00272] MCF-7 cells (ATCC) cells were seeded at 24000 cells per well in 96-well plates
(Corning, 3904) in DMEM (Cellgro) containing 10% FBS (Cellgro), 1% NEAA (Cellgro) and
1% penicillin-streptomycin (Cellgro). Cells were incubated at 37°C, 5% C02 for 48 h, and the growth medium was replaced with serum-free DMEM or in medium containing 0.4% BSA.
Serial dilutions of the test compound in 0.3% DMSO (vehicle) were added to the cells and incubated for 3h. To fix the cells, medium was removed and ΙΟΟμίΛνεΙΙ of 4% formaldehyde
(Sigma Aldrich, F8775) in TBS (20 mM Tris, 500 mM NaCl) was added to each well at RT for
30 min. Cells were washed 4 times with 200μΙ TBS containing 0.1% Triton X-100 (Sigma, catalog # T9284). Plates were blocked with Ι ΟΟμί Odyssey blocking buffer (Li-Cor Biosciences,
927-40000) for lh at RT. Anti-pS6 (S240/244) antibody (Cell Signaling Technology, 2215) and anti-total-S6 antibody (R&D systems, MAB5436) were diluted 1 :400 in Odyssey blocking buffer, and 50μΙ, of the antibody solution containing both antibodies was added to one plate to detect pS6 and total S6. After incubation overnight at 4°C, plates were washed 4 times with
200μί TBS containing 0.1 % Tween20 (Bio-Rad, catalog # 170-6351) (TBST). Goat anti-rabbit and Goat anti-mouse secondary antibody (Li-Cor Biosciences, catalog # 926-32221 and 926-
32210) conjugated to IRDye were diluted 1 :400 in Odyssey blocking buffer containing 0.1% Tween20. 50μΙ_, of antibody solution containing both antibodies was added to each well and incubated for lh at RT. Plates were washed 3 times with 200μΙ_ TBST and 2 times with 200μί TBS. Fluorescence was read on an Odyssey plate reader. IC50 values were determined based on the ratio of pS6 to total S6 signal for compound treated wells, normalized to the DMSO-treated control wells.
[00273] In one embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 1.0 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.5 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.25 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.2 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.15 μΜ or less.
DAKT (T308) ELISA Assay
[00274] MCF-7 cells (ATCC) cells were seeded at 24000 cells per well in 96-well plates (Corning, 3904) in DMEM (Cellgro) containing 10% FBS (Cellgro), 1% NEAA (Cellgro) and 1% penicillin-streptomycin (Cellgro). Cells were incubated at 37°C, 5% C02 for 48 h, and the growth medium was replaced with serum-free DMEM or in medium containing 0.4% BSA. Serial dilutions of the test compound in 0.3% DMSO (vehicle) were added to the cells and incubated for 3h. At the end of the incubation period, cells were stimulated for 10 minutes by the addition of L-IGF (Sigma, 1-1271 ) at a final concentration of l OOng/ml. Afterwards, media was discarded from cell plates and 1 1 Ομΐ/well of cold lysis buffer (see table below) were added. Cell plates were incubated on ice and then put on shaker in 4°C cold room for lh. Two capture plates (Thermo Scientific, Reacti-bind plate, 15042) were prepared for each cell plate by pre-coating with capture Akt antibody from the two sandwich ELISA antibody pairs used (Cell Signaling Technology 7142 and 7144). The Akt capture antibodies were diluted 1 : 100 in PBS and ΙΟΟμΙ of diluted capture antibody was added per well. Capture plates were incubated at 4C overnight. Prior to use, capture plates were washed 3 times in TBS containing 0.1% Tween20 (Bio-Rad, 170-6351) (TBST) and blocked in blocking buffer (Thermo Scientific, Starting Block T20, 37543) for 1 - 2 h at room temperature. After lh of cell lysis, 85μ1 of cell lysate/well was transferred to the capture plate for detection of pAkt(T308). 15μ1 of cell lysate was transferred from same well to the second capture plate for detection of total Aktl . After incubation overnight at 4°C, plates were washed 3 times with 200μί TBST. Primary antibodies, diluted 1 : 100 in blocking buffer, were added to the corresponding capture plates for pAkt(T308) (Cell Signaling Technology, 7144) and total Aktl (Cell Signaling Technology, 7142) detection and incubated at room temperature for lh. Plates were washed 3 times with 200μΙ_, of TBST. Goat anti-mouse secondary antibody (Cell Signaling Technology, 7076) conjugated to HRP was diluted 1 :1000 in blocking buffer and Ι ΟΟμΙ were added to each well and incubated for 30 minutes at room temperature. Plates were then washed 3 times with 200μΙ. of TBST. ΙΟΟμί of SuperSignal ELISA Femto stable peroxidase solution (Thermo Scientific, 37075) was added to each well. After 1 minute incubation, chemi luminescence was read on a Wallac Victor2 1420 multilabel counter. IC50 values were determined based on the ratio of pAkt(T308) to total Aktl signal for compound treated wells, normalized to the DMSO-treated control wells.
Figure imgf000168_0001
[00275] In one embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 1.5 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 1.0 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.75 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.5 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.25 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.2 μΜ or less. In another embodiment, the Compounds of the Invention tested in this assay in MCF-7 cells had an inhibitory activity of about 0.15 μΜ or less.
Pharmacodynamic xenograft tumor models
[00276) Female and male athymic nude mice (NCr) 5-8 weeks of age and weighing approximately 20-25 g are used in the following models. Prior to initiation of a study, the animals are allowed to acclimate for a minimum of 48 h. During these studies, animals are provided food and water ad libitum and housed in a room conditioned at 70-75°F and 60% relative humidity. A 12 h light and 12 h dark cycle is maintained with automatic timers. All animals are examined daily for compound-induced or tumor-related deaths.
MCF-7 Breast adenocarcinoma model
[00277] MCF7 human mammary adenocarcinoma cells are cultured in vitro in DMEM (Cellgro) supplemented with 10% Fetal Bovine Serum (Cellgro), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified 5% C02 atmosphere. On day 0, cells are harvested by trypsinization, and 5 x 106 cells in 100 μΐ, of a solution made of 50% cold Hanks balanced salt solution with 50% growth factor reduced matrigel (Becton Dickinson) implanted subcutaneously into the hindflank of female nude mice. A transponder is implanted into each mouse for identification and data tracking, and animals are monitored daily for clinical symptoms and survival.
[00278] Tumors are established in female athymic nude mice and staged when the average tumor weight reached 100-200 mg. A Compound of the Invention is orally administered as a solution/fine suspension in water (with 1 : 1 molar ratio of 1 N HCL) once-daily (qd) or twice-daily (bid) at 10, 25, 50 and 100 mg/kg for 14 days. During the dosing period of 14-19 days, tumor weights are determined twice-weekly and body weights are recorded daily.
Colo-205 colon model
[00279] Colo-205 human colorectal carcinoma cells are cultured in vitro in DMEM
(Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified, 5% C02 atmosphere. On day 0, cells are harvested by trypsinization, and 3xl06 cells (passage 10-15, >95% viability) in 0.1 mL ice-cold Hank's balanced salt solution are implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice. A transponder is implanted in each mouse for identification, and animals are monitored daily for clinical symptoms and survival.
[00280] Tumors are established in female athymic nude mice and staged when the average tumor weight reached 100-200 mg. A Compound of the Invention is orally administered as a solution/fine suspension in water (with 1 : 1 molar ratio of 1 N HCL) once-daily (qd) or twice-daily (bid) at 10, 25, 50 and 100 mg/kg for 14 days. During the dosing period of 14 days, tumor weights are determined twice-weekly and body weights are recorded daily.
PC-3 prostate adenocarcinoma model
[00281] PC-3 human prostate adenocarcinoma cells are cultured in vitro in DMEM
(Mediatech) supplemented with 20% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified 5% C02 atmosphere. On day 0, cells are harvested by trypsinization and 3xl 06 cells (passage 10-14, >95% viability) in 0.1 mL of ice-cold Hank's balanced salt solution are implanted subcutaneously into the hindflank of 5-8 week old male nude mice. A transponder is implanted in each mouse for identification, and animals are monitored daily for clinical symptoms and survival.
[00282] Tumors are established in male athymic nude mice and staged when the average tumor weight reached 100-200 mg. A Compound of the Invention is orally administered as a solution/fine suspension in water (with 1 : 1 molar ratio of 1 N HC1) once-daily (qd) or twice-daily (bid) at 10, 25, 50, or 100-mg/kg for 19 days. During the dosing period of 14-19 days, tumor weights are determined twice-weekly and body weights are recorded daily.
U-87 MG human glioblastoma model
[00283] U-87 MG human glioblastoma cells are cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and nonessential amino acids at 37 °C in a humidified 5% C02 atmosphere. On day 0, cells are harvested by trypsinization and 2xl06 cells (passage 5, 96% viability) in 0.1 mL of ice-cold Hank's balanced salt solution are implanted intradermally into the hindflank of 5-8 week old female nude mice. A transponder is implanted in each mouse for identification, and animals are monitored daily for clinical symptoms and survival. Body weights are recorded daily.
A549 human lung carcinoma model
[00284] A549 human lung carcinoma cells are cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and nonessential amino acids at 37 °C in a humidified 5% C02 atmosphere. On day 0, cells are harvested by trypsinization and lOxlO6 cells (passage 12, 99% viability) in 0.1 mL of ice-cold Hank's balanced salt solution are implanted intradermally into the hindflank of 5-8 week old female nude mice. A transponder is implanted in each mouse for identification, and animals are monitored daily for clinical symptoms and survival. Body weights are recorded daily.
A2058 human melanoma model
[00285] A2058 human melanoma cells are cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and nonessential amino acids at 37 °C in a humidified, 5% C02 atmosphere. On day 0, cells are harvested by trypsinization and 3xl06 cells (passage 3, 95% viability) in 0.1 mL ice-cold Hank's balanced salt solution are implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice. A transponder is implanted in each mouse for identification, and animals are monitored daily for clinical symptoms and survival. Body weights are recorded daily.
WM-266-4 human melanoma model
[00286] WM-266-4 human melanoma cells are cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and nonessential amino acids at 37 °C in a humidified, 5% C02 atmosphere. On day 0, cells are harvested by trypsinization and 3xl06 cells (passage 5, 99% viability) in 0.1 mL ice-cold Hank's balanced salt solution are implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice. A transponder is implanted in each mouse for identification, and animals are monitored daily for clinical symptoms and survival. Body weights are recorded daily.
[00287] Tumor weight (TW) in the above models is determined by measuring perpendicular diameters with a caliper, using the following formula: tumor weight (mg) = [tumor volume = length (mm) x width2 (mm2)]/2
These data were recorded and plotted on a tumor weight vs. days post-implantation line graph and presented graphically as an indication of tumor growth rates. Percent inhibition of tumor growth (TGI) is determined with the following formula:
Figure imgf000172_0001
where X0 = average TW of all tumors on group day
Xf = TW of treated group on Day f
Yf = TW of vehicle control group on Day f
If tumors regress below their starting sizes, then the percent tumor regression is determined with the following formula:
Figure imgf000172_0002
Tumor size is calculated individually for each tumor to obtain a mean ± SEM value for each experimental group. Statistical significance is determined using the 2-tailed Student's t-test (significance defined as P<0.05).
[00288] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so
individually denoted.

Claims

Claims
1. A compound of Formula I:
Figure imgf000173_0001
or a pharmaceutically acceptable salt thereof, wherein:
X] and X2 are each independently N, C-H, C-Halo, C-(Ci-C6)alkyl, or C-(Ci-C6)alkoxy,
C-CN;
X2 is N, C-H, C-Halo, C-(C,-C6)alkyl, or C-(C,-C6)alkoxy, C-CN;
Rx and Ry are each independently H, (C|-C6)alkyl, halo(C) -C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3-C6)cycloalkyl, (CrC6)alkylene-(C3- C6)heterocycloalkyl, (Ci-C6)alkylene-(C3-C6)heteroaryl, (C|-C6)alkylene-(C3-C6)aryl, (Ci- C6)haloalkoxy, (C,-C6)alkylene-NH2, (Ci-C6)alkylene-NH(C,-C6)alkyl, (C,-C6)alkylene-NH(C,- C6)haloalkyl, (C,-C6)alkylene-N(Ci-C6)alkyl)2, (C,-C6)alkylene-OH, (C,-C6)alkylene-(Ci- C6)alkoxy, (C,-C6)alkylene-NHS02-(C|-C6)alkyl, (C1-C6)alkylene-NH(C=0)-(C,-C6)alkyl, or (Ci-C6)alkylene-(C=0)-(C| -C6)alkyl, any of which may be optionally substituted; or
Rx and Ry taken together with the atom to which they are attached form a 4-6 membered
ring represente
Figure imgf000173_0002
optionally containing an additional heteroatom selected from NH, N-(Ci-C6)alkyl, S, SO, or S02, and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano,
(C,-C6)alkyl, (C,-C6)alkoxy, halo(C,-C6)alkyl, (C|-C6)haloalkoxy, (Ci-C6)alkylene-NH2> (C,- C6)alkylene-NH(C|-C6)alkyl, (C-Ceialkylene-NHCd-Ceihaloalkyl, (Ci-C6)alkylene-N(C,- C6)alkyl)2, NH2, NH(C|-C6)alkyl, (C,-C6)alkylene-OH, (C,-C6)alkylene-(Ci-C6)alkoxy, NH(C C6)alky lene-NH2, NH(C i -C6)alky lene-NH(C , -C6)alkyl , NH(C , -C6)alkyleneN((C , -C6)alkyl)2, NH(Ci-C6)alkylene-(C3-C7)cyloalkyl, NH(CrC6)alkylene-(C3-C7)heterocyloalkyl, N((C,- C6)alky lene-(C3-C7)heterocycloalkyl)2, N((C , -C6)alkyl)(C , -C6)alky lene-(C3-C7)cyloalky 1, N((C , - C6)alky 1)(C , -C6)alky lene-(C3-C7)heterocyloalky 1, N((C , -C5)alky 1)2, (C i -C6)alky lene-NHS02- (C,-C6)alkyl, (Ci-C6)alkylene-NH(C=0)-(C,-C6)alkyl, -(C=0)-(C,-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(Ci-C6)alkyl, aryl, hetreroaryl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (CrC6)alkylene- (C3-C7)heterocycloalkyl, nitro, (C,-C6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(Ci-C6)alkyl, (C=0)-NRaRb, NH(C=0)-(C,-C6)alkylene-NH2, NH(C=0)-(C3-C7)cycloalkylene, NH(C=0)-(C3- C7)heterocycloalkylene, N((C,-C6)alkyl)(C=0)-(Ci-C6)alkylene-NH2, N((Ci-C6)alkyl)(C=0)- (C3-C7)cycloalkylene, N((Ci-C6)alkyl)(C=0)-(C3-C7)heterocycloalkylene, NH-S02-NRaRb, or S02-NRaRb, wherein Ra and Rb are each independently H, (C|-C6)alkyl, aryl, heteroaryl, (C3- C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)cycloalkyl, (Ci-C6)alkylene-(C3- C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (Ci-C6)alkylene-NH(C|-C6)alkyl), (Ci-C6)alkylene- N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, NH(C,-C6)alkoxy, NH(C,-C6)haloalkyl, N((Ci-C6)alkyl)2, (C=0)- ORa, -OH, (Ci-C6)alkyl, (C,-C6)haloalkyl, (C,-C6)alkylene-(C3-C7)cycloalkyl, (Ci-C6)alkylene- (C3-C7)heterocycloalkyl optionally substituted with 1-3 halo, (C3-C7)heterocycloalkyl optionally substituted with 1 -3 halo, (Ci-C6)alkoxy, or (C|-C6)haloalkoxy;
Rz is halo, cyano, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from halo, hydroxy, (C|-C6)alkyl, (Ci-C6)haloalkyl (C,-C6)alkoxy, halo(C,-C6)alkyl, (C,-C6)haloalkoxy, (C=0)-NH2, NH(C=0)-(C,-C6)alkyl, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)-N((C,- C6)alkyl)2; or
Rz is NR3R4, wherein R3 and R4 are each independently H or (C|-C6)alkyl optionally substituted with one , two, or three groups selected from halo, hydroxy, cyano, oxo, (Ci-C6)alkyl, (C,-C6)alkoxy, halo(C,-C6)alkyl, (C,-C6)haloalkoxy, S(0)-(C,-C6)alkyl, S02-(C,-C6)alkyl, (Cj- C6)alkylene-NH2, (C,-C6)alkylene-NH(C|-C6)alkyl, (C,-C6)alkylene-NH(C,-C6)haloalkyl, (C,- C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,-C6)alkylene-OH, (C-CsJalkylene-iQ- C6)alkoxy, NH(C|-C6)alkyleneNH2, NH(C,-C6)aIkylene-NH(Ci-C6)alkyl, NH(C,- C6)alkyleneN((C , -C6)alkyl)2, NH(C , -C6)alkylene-cyloalkyl, NH(C , -C6)alkylene- heterocyloalkyl, N((C,-C6)alkyl)2, (C|-C6)alky!ene-NHS02-(Ci-C6)alkyl, (C,-C6)alkylene- NH(C=0)-(C,-C6)alkyl, (C=0)-(C,-C6)alkyl, S(0)-(C C6)alkyl, S02-(C,-C6)alkyl, (C4- C7)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (CrC6)alkylene-CN, (d- C6)alkylene-OC(0)-(Ci-C6)alkyl,
Figure imgf000175_0001
or S02-NRcRd, wherein Rc and Ra are each independently are H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C,-C6)alkylene-(C3-C7)cycloalkyl, (C]-C6)alkylene-(C3-C7)heterocycloalkyl, (C,-C6)alkylene- NH2, (C,-C6)alkylene-NH(Ci-C6)alkyl), or (C,-C6)alkylene-N(CrC6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(CrC6)alkyl, N((C,-C6)alkyl)2, OH, (CrC6)alkyl, (C|-C6)alkoxy, or (C,-C6)haloalkoxy.
R3 and ^ together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from H, halo, hydroxy, cyano, oxo, (Ci-C6)alkyl, (C,-C6)alkoxy, halo(C,-C6)alkyl, (Ci-C6)haloalkoxy, (Ci-C6)alkylene-NH2, (C , -C6)alky lene-NH(C , -C6)alkyl, (C , -C6)alkylene-NH(C , -C6)haloalkyl, (C i -C6)alkylene-N(C i - C6)alkyl)2, S(0)-(CrC6)alkyl, S02-(C,-C6)alkyl, NH2, NH(CrC6)alkyl, (CrC6)alkylene-OH, (C , -C6)alky lene-(C , -C6)alkoxy, NH(C , -C6)alkyleneNH2, NH(C , -C6)alkylene-NH(C , -C6)alkyl, NH(C i -C6)alkyleneN((C , -C6)alkyl)2, NH(C , -C6)alkylene-cyloalkyl, NH(C ! -C6)alkylene- heterocyloalkyl, N((C,-C6)alkyl)2, (C|-C6)alkylene-NHS02-(C|-C6)alkyl, (C|-C6)alkylene- NH(C=0)-(C,-C6)alkyl, (C=0)-(C,-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(C,-C6)alkyl, (C4- C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (CrC6)alkylene-CN, (d- C6)alkylene-OC(0)-(C|-C6)alkyl,
Figure imgf000175_0002
or S02-NReRfj wherein Re and Rf are each independently H, (CrC6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C , -C6)alkylene-(C3-C7)cycloalkyl, (C , -C6)alkylene-(C3-C7)heterocycloalkyl, (C i -C6)alkylene- NH2, (Ci-C6)alkylene-NH(C|-C6)alkyl), or (C|-C6)alkylene-N(C|-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|-C6)alkyl, N((C|-C6)alkyl)2, OH, (C,-C6)alkyl, (C,-C6)alkoxy, or (C,-C6)haloalkoxy; and
R5 is H, halo, (C|-C6)alkyl, halo(C,-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2- C6)alkynyl, or (C|-C6)alkoxy.
2. The compound of claim 1, wherein X is N, C-H, C-Halo, or C-(Ci-C6)alkyl.
3. The compound of claim 1 , wherein X is N or C-H.
4. The compound of claim 1 , wherein R5 is (C|-C6)alkyl, halo-(Ci-C6)alkyl, (C2-C6)alkenyl, halo-(C2-C6)alkenyl, or (Ci-C6)alkoxy.
5. The compound of claim 1 , wherein X is N or C-H, and R5 is (C|-C6)alkyl.
6. The compound of claim 1 , wherein the compound of formula I is a compound of formula
IA:
Figure imgf000176_0001
IA
wherein ring
Figure imgf000176_0002
is a 6-membered saturated or partially saturated heterocycle optionally containing an additional heteroatom selected from NH, N-(Ci-C6)alkyl, S, SO, and S02, and that is additionally optionally fused to one or more saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic rings, any of which may be optionally substituted with 1 , 2, or 3 groups independently selected from halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci- C6)alkyl, (C,-C6)haloalkoxy, (C|-C6)alkylene-NH2, (C,-C6)alkylene-NH(C,-C6)alkyl, (C,- C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(Ci-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (C,- C6)alkylene-OH, (C|-C6)alkylene-(C,-C6)alkoxy, NH(C,-C6)alkylene-NH2, NH(C,-C6)alkylene- NH(C , -C6)alkyl, NH(C , -C6)alkyleneN((C , -C6)alkyl)2, NH(C , -C6)alkylene-(C3-C7)cyloalkyl, NH(Ci-C6)alkylene-(C3-C7)heterocyloalkyl, N((Ci-C6)alkylene-(C3-C7)heterocycloalkyl)2, N((C , -C6)alkyl)(C , -C6)alkylene-(C3-C7)cyloalkyl, N((C , -C6)alkyl)(C i -C6)alkylene-(C3- C7)heterocyloalkyl, N((C,-C6)alkyl)2, (C,-C6)alkylene-NHS02-(C1-C6)alkyl, (C,-C6)alkylene- NH(C=0)-(C,-C6)alkyl, -(C=0)-(C,-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(C,-C6)alkyl, aryl, hetreroaryl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)heterocycloalkyl, nitro, (C,-C6)alkylene-CN, (C|-C6)alkylene-OC(0)-(Ci-C6)alkyl, (C=0)- NRaRb, NH(C=0)-(Ci-C6)alkylene-NH2, NH(C=0)-(C3-C7)cycloalkylene, NH(C=0)-(C3- C7)heterocycloalky lene, N((C , -C6)alky 1)(C=0)-(C , -C6)alky lene-NH2, N((C i -C6)alky 1)(C=0)- (C3-C7)cycloalkylene, N((C,-C6)alkyl)(C=0)-(C3-C7)heterocycloalkylene, NH-S02-NRaRb, or S02-NRaRb, wherein Ra and Rb are each independently H, (Ci-C6)alkyl, aryl, heteroaryl, (C - C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C]-C6)alkylene-(C3-C7)cycloalkyl, (Ci-C6)alkylene-(C3- C7)heterocycloalkyl, (C|-C6)alkylene-NH2, (Ci-C6)alkylene-NH(C,-C6)alkyl), or (Cr
C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(CrC6)alkyl, NH(CrC6)alkoxy, NH(C,-C6)haloalkyl, N((C,- C6)alkyl)2, (C=0)-ORa, OH, (C,-C6)alkyl, (C,-C6)haloalkyl, (Ci-C6)alkylene-(C3-C7)cycloalkyl, or (C|-C6)alkylene-(C3-C7)heterocycloalkyl optionally substituted with 1-3 halo, (C3- C7)heterocycloalkyl optionally substituted with 1-3 halo, (Ci-C6)alkoxy, or (C|-C6)haloalkoxy.
7. The compound of claim 6, wherein the compound of formula I is a compound of formula IA-1 or IA-2:
Figure imgf000177_0001
IA-1 IA
wherein Κ(, is H, halo, hydroxy, cyano, (Ci-C6)alkyl, -(C|-C6)alkoxy, halo(Ci-C6)alkyl, (C|- C6)alkylene-NH2, (C|-C6)alkylene-NH(Ci-C6)alkyl, (Ci-C6)alkylene-NH(Ci-C6)haloalkyl, (Q- C6)alkylene-N(C,-C6)alkyl)2, (C,-C6)alkylene-NHS02Me,NH2, NH(C,-C6)alkyl, hydroxyalkyl, (C|-C6)alkylene-0(C|-C6)alkyl, NH(Ci-C6)alkylene-NH2, NH(d-C6)alkylene-cyloalkyl, NH(Ci- C6)alkylene-heterocyloalkyl, N((C|-C6)alkyl)2, (C,-C6)alkylene-NHS02-(C1-C6)alkyl, (C,- C6)alkylene-NH(C=0)-(C , -C6)alkyl, NH(C=0)-(C , -C6)alkylene-NH2, NH(C=0)-(C3- C7)cycloalkylene, NH(C=0)-(C3-C7)heterocycloalkylene, (CO)-(C,-C6)alkyl, NHS02-(Ci- C6)alkyl, N((C,-C6)alkyl)S02-(Ci-C6)alkyl, S(OHC,-C6)alkyl, S02-(C,-C6)alkyl, (C3- C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci-C6)alkylene-CN, NH(C , -C6)alky lene-NH(C , -C6)alky 1 , NH(C , -C6)alky lene-N((C , -C6)alkyl)2, (C i -C6)alky lene- OC(0)-(C,-C6)aIkyI, (C=0)-NR6aR6b, or S02-NR6aR6b, wherein R6a and Rsb are each
independently H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C )heterocycloalkyl, (C I -C6)alkylene-(C3-C6)cycloalky 1, (C i -C6)alkylene-(C3-C6)heterocycloalkyl, (C i -C6)alkylene- NH2, (Ci-C6)alkylene-NH(C,-C6)alkyl), or (Ci-C6)alkylene-N(C,-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)alkyl, N((C,-C6)alkyl)2, OH, (C,-C6)alkyl, (d-C6)alkoxy, or (C,-C6)haloalkoxy.
8. The compound of claim 6, wherein the compound of formula I is a compound of formula IA-3 or IA-4:
Figure imgf000178_0001
IA-3 IA-4
wherein Q is C=0, S=0, or S02 and Ri is OH or NR6aR6b, Rea and are each independently H, (CrC6)alkyl, halo(CrC6)alkyl, (Ci-C6)alkylene-NH2, (Ci-C6)alkylene-NH(C,-C6)alkyl, (C,- C6)alkylene-NH(C , -C6)haloalky 1, (C , -C6)alkylene-N(C , -C6)alky 1)2, (C , -C6)alkylene-OC(0)-(C , - C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci- C )alkylene-heteroaryI, (C[-C6)alkylene-(C3-C6)cycloalkyl, or (C|-C6)alkylene-(C3- C6)heterocycloalkyl, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, OH, (d-C6)alkyl, (d-C6)alkoxy, or (Ci-C6)haloalkoxy.
9. The compound of claim 6, wherein the compound of formula I is a compound of formula IA-5 or IA-6:
Figure imgf000179_0001
IA-5 IA-6 wherein Rz is halo, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from (Ci-C6)alkyl, (C|-C6)haloalkyl (C|-C6)alkoxy, halo(Ci- C6)alkyl, (C|-C6)haloalkoxy, (C=0)-NH2, NH(C=0)-(Ci-C6)alkyl, NH2, NH(Ci-C6)alkyl, N((C,- C6)alkyl)2, (CO)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)-N((CrC6)alkyl)2.
10. The compound of claim 1 -9, wherein Rz is optionally substituted phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indazolyl, pyridinyl, benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrazinyl, thienyl, or furanyl.
1 1. The compound of claim 1-9, wherein Rz is phenyl optionally substituted with hydroxy 1, fluoro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
12. The compound of claim 1 -9, wherein Rz is pyrazolyl optionally substituted with methyl, ethyl, or propyl.
13. The compound of claim 1 -9, wherein Rz is isoxazolyl, pyrimidinyl, or indazolyl, optionally substituted with amino or methyl.
14. The compound of claim 1 -9, wherein Rz is pyridinyl optionally substituted with fluoro, chloro, amino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, or (C=0)-NHMe,
15. The compound of claim 1 -9, wherein Rz is benzimidazolyl, thiazolopyridinyl, imidazolyl, thiazolyl, or triazolyl, optionally substituted with methyl or amino.
16. The compound of claim 1 -9, wherein Rz is pyridazinyl optionally substituted with hydroxyl, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
17. The compound of claim 1-9, wherein Rz is thienyl or furanyl optionally substituted with methyl.
18. The compound of claim 1 -9, wherein Rz is bromo, chloro, or fluoro.
19. The compound of claim 1-9, wherein Rz is NR3R4, wherein R3 and R4 are each independently (Ci-C6)alkyl optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (C|-C6)alkyl, (C| -C6)alkoxy, halo(Ci-C6)alkyl, (Ci-C6)haloalkoxy, (C|- C6)alkylene-NH2, (C,-C6)alkylene-NH(CrC6)alkyl, (CrC6)alkylene-NH(C|-C6)haloalkyl, (Ci- C6)alkylene-N(C|-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (Ci-C6)alkylene-OH, (Ci-C6)alkylene-(C,- C6)alkoxy, NH(C|-C6)alkyleneNH2, NH(C|-C6)alkylene-NH(Ci-C6)alkyl, NH(C|-
C5)alky leneN((C , -C6)al ky 1)2, NH(C , -C6)alky lene-cy loalky 1, NH(C , -C6)alky lene- heterocyloalkyl, N((d-C6)alkyl)2, (C,-C6)alkylene-NHS02-(C,-C6)alkyl, (d-C6)alkylene- NH(C=0)-(C,-C6)alkyl, -(C=0)-(C,-C6)alkyl, S(0)-(C|-C6)alkyl, S02-(C,-C6)alkyl, -(C4- C7)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (Ci-C6)alkylene-CN, (Ci- C6)alkylene-OC(0)-(C|-C6)alkyl, (C=0)-NRcRd> or SO NRcRa, wherein Rc and Rd are each independently are H, (C|-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (C 1 -C6)alky lene-(C3-C7)cycloalky 1, (C 1 -C6)alkylene-(C3-C7)heterocycloalkyl, (C 1 -C6)alky lene- NH2, (C|-C6)alkylene-NH(Ci-C6)alkyl), or (C|-C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C|-C6)alkyl, N((C,-C6)alkyl)2, OH, (C,-C6)alkyl, (Ci-C6)alkoxy, or (C|-C6)haloalkoxy.
20. The compound of claim 19, wherein R3 is H and R4 is methyl, ethyl, propyl, butyl, pentyl, CH2CH2-OCH3, or (C=0)-CH2-OH.
21. The compound of claim 19, wherein R3 and R4 together with the atoms to which they are attached form a 3- to 7-membered ring optionally substituted with one, two, or three groups selected from halo, hydroxy, cyano, (C|-C6)alkyl, (C|-C6)alkoxy, halo(Ci-C6)alkyl, (C|- C6)haloalkoxy, (C|-C6)alkylene-NH2, (C,-C6)alkylene-NH(C,-C6)alkyl, (Ci-C6)alkylene-NH(Ci- C6)haloalkyl, (C,-C6)alkylene-N(C,-C6)alkyl)2, NH2, NH(C|-C6)alkyl, (C,-C6)alkylene-OH, (C,- C6)alkylene-(CrC6)alkoxy, NH(Ci-C6)alkyleneNH2, NH(C|-C6)alkylene-NH(Ci-C6)alkyl, NH(C I -C6)alkyleneN((C , -C6)alky 1)2, NH(C , -C6)alkylene-cyloalkyl, NH(C , -C6)alkylene- heterocyloalkyl, N((C|-C6)alkyl)2, (C,-C6)alkylene-NHS02-(C|-C6)alkyI, (Ci-C6)alkylene- NH(C=0)-(C,-C6)alkyl, (C=0)-(C,-C6)alkyl, S(0)-(C,-C6)alkyl, S02-(C,-C6)alkyl, -(C4- C7)heterocycloalkyl, (C|-C6)alkylene-(C3-C7)heterocycloalkyl, nitro, (C|-C6)alkylene-CN, (C|- C6)alkylene-OC(0)-(Ci-C6)alkyl, (C=0)-NReRf, or S02-NReRf, wherein Re and Rf are each independently H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl,
(C 1 -C6)alkylene-(C3-C7)cycloalkyl, (C 1 -C6)alkylene-(C3-C7)heterocycloalkyl, (C 1 -C6)alkylene- NH2, (C,-C6)alkylene-NH(C|-C6)alkyl), or (C|-C6)alkylene-N(C,-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(Ci-C6)alkyl, N((C C6)alkyl)2, OH, (C|-C6)alkyl, (Ci-C6)alkoxy, or (C,-C6)haloalkoxy.
22. The compound of claim 1 -9, wherein Rz is
Figure imgf000181_0001
23. The compound of claim 6 and claims 10-22, wherein the compound of formula I is a compound of formula IA-7 or IA-8:
Figure imgf000182_0001
IA-7 IA-8
wherein Q is C=0 or S02; and
Ria and Rib are each independently H, (C|-C6)alkyl, halo(Ci-C6)alkyl, (C|-C6)alkylene- NH2, (C,-C6)alkylene-NH(C,-C6)alkyl, (C,-C6)alkylene-NH(C,-C6)haloalkyl, (CrC6)alkylene- N(Ci-C6)alkyl)2, (C|-C6)alkylene-OC(0)-(Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci-C6)alkylene-heteroaryl, (C|-C6)alkylene-(C3- C6)cycloalkyl, or (Ci-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C | -C6)alkyl, N((Ci-C6)alkyl)2, OH, (C|-C6)alkyl, (C,-C6)alkoxy, or (C,-C6)haloalkoxy.
24. The compound of claim 23, wherein:
Ria is H or (Ct-C6)alkyl;
R,b is H, (C,-C6)alkyl, halo(C|-C6)alkyl, (CrC6)alkylene-NH2, (CrC6)alkylene-NH(Ci- C6)alkyl, (C,-C6)alkylene-NH(C,-C6)haloalkyl, (C,-C6)alkylene-N(Ci-C6)alkyl)2, (Ct- C6)alkylene-OC(0)-(C|-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci-C6)alkylene-heteroaryl, (Ci-C6)alkylene-(C3-C6)cycloalkyl, or (Ci- C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted; and
R5 is methyl.
25. The compound of claim 23, wherein Ria is H, methyl, pyrrolidiny, piperidinyl, CH2- cyclopropyl, CH2-pyrrolidinyl, or CH2-piperidinyl.
The compound of claim 23, wherein Rib is H, methyl, ethyl, or fluoroethyl.
27. The compound of claim 23, wherein Ria is H, and Rib is H.
Figure imgf000183_0001
yl.
29. The compound of claim 23, wherein R|a and R^ are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, N¾, NH(Ci-C6)alkyl, N((C|-C6)alkyl)2, OH, (C,-C6)alkyl, (C,-C6)alkoxy, or (Ci-C6)haloalkoxy.
Figure imgf000183_0002
31. The compound of claim 29, wherein in a further embodiment, RiaRib is
Figure imgf000183_0003
, wherein:
Z is O, N or C;
R2a is absent when Z is O; or is H, OH, NH2, NH-(C2-C6)alkylene-0-(Ci-C6)alkyl, NH(C C6)haloalkyl, (Ci-C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(C|-C6)alkyl when Z is N or C;
R2b is absent when Z is N or 0; or is H, (CrC6)alkyl, or (C|-C6)haloalkyl when Z is C; each occurrence of R2c is independently halo, (C]-C )alkyl, or (Ci-C6)haloalkyl; and n is 0, 1, or 2.
32. The compound of claim 29, wherein in a further embodiment, RiaRib is
Figure imgf000184_0001
wherein:
Z is N or C;
R2a is H, OH, NH2, NH-(C2-C6)alkylene-0-(Ci-C6)alkyl, NH(C,-C6)haloalkyl, (C,- C6)alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(Ci-C6)alkyl;
R2b is absent when Z is N; or is H, (C]-C6)alkyl, or (Ci-C6)haloalkyl when Z is C; each occurrence of R2c is independently halo, (Ci-C6)alkyl, or (C|-C6)haloalkyl; and n is 0, 1, or 2.
The compound of claim 31 , wherein the compound of formula I is a compound of
Figure imgf000184_0002
IA-9 IA-10
wherein Q is C=0 or S02;
Z is N or C;
R2a is H, OH, NH2, NH-(C2-C6)alkylene-0-(C1-C6)alkyl> NH(Ci-C6)haloalkyl, (C,- C6)alkylene-(C3-C )cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alky lene-0-(C , -C6)alky 1;
R2b is absent when Z is N; or is H, (Ci-C6)alkyl, or (Ci-C6)haloalkyl when Z is C; each occurrence of R2c is independently halo, (C|-C6)alkyl, or (d-C6)haloalkyl; and n is 0, 1 , or 2.
34. The compound of claim 33, wherein the compound of formula IA-9 or IA-10 is a compound of formula IA-9a or IA-10a:
Figure imgf000185_0001
35. The compound of claim 34, wherein:
R2a is OH, NH2, NH-(C2-C6)alkylene-0-(C,-C6)alkyl, NH(C,-C6)haloalkyl, (C,- C )alkylene-(C3-C6)cycloalkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, or NH(C=0)NH-(C2-C6)alkylene-0-(C,-C6)alkyl;
R2b is absent H, (Ci-C6)alkyl, or (C|-C6)haloalkyl;
each occurrence of R2c is independently halo, (Ci-C6)alkyl, or (Ci-C6)haloalkyl; and n is 0, 1 , or 2.
Figure imgf000185_0002
Figure imgf000186_0001
37. The compound of claim 33, wherein the compound of formula I is a compound of formula I -9b or IA-10b:
Figure imgf000186_0002
38. The compound of claim 37, wherein R2a is H> methyl, ethyl, propyl, or butyl; R2c is methyl; and n is 1.
39. The compound of claim 38, wherein R5 is methyl.
40. The compound of claims 6 and 10-22, wherein the compound of formula I is a compound of formula IB-1 or IB-2:
Figure imgf000187_0001
IB-1 IB-2
wherein Q is CH2, C=0, S=0, or S02;
Rb is H, (CrC6)alkyl, (C|-C6)alkylene-NH(C|-C6)haloalkyl, (d-C5)alkylene-N(Ci- C6)alkyl)2, (C,-C6)alkylene-OC(0)-(C|-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, (C|-C6)alkylene-aryl, (Ci-C6)alkylene-heteroaryl, (C|-C6)alkylene-(C3- C6)cycloalkyl, (C|-C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C|-C6)alkyl)2, OH, (C,-C6)alkyl, (C,-C6)alkoxy, or (C|-C6)haloalkoxy; and
R, i is H, (C,-C6)alkyl, halo(C,-C6)alkyl, (C,-C6)alkylene-NH2, (CrC6)alkylene-NH(Ci- C6)alkyl, (C,-C6)alkylene-NH(Ci-C6)haloalkyl, (Ci-C6)alkylene-N(Ci-C6)alkyl)2, (C,- C6)alkylene-OC(0)-(Ci-C6)alkyl, aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-aryl, (Ci-C6)alkylene-heteroaryl, (Ci-C6)alkylene-(C3-C6)cycloalkyl, (Ci- C6)alkylene-(C3-C6)heterocycloalkyl, any of which may be optionally substituted with halo, NH2, NH(CrC6)alkyl, N((C,-C6)alkyl)2, OH, (Ci-C6)alkyl, (Ci-C6)alkoxy, or (C,-C6)haloalkoxy.
41. The compound of claim 40, wherein the compound of formula I is a compound of formula IB-3 or IB-4:
Figure imgf000188_0001
IB-3 IB-4
wherein Rz is halo, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl that is optionally substituted with 1 , 2, or 3 groups selected from (Ci-C6)alkyl, (C|-C6)haloalkyl (Ci-C6)alkoxy, halo(Ci- C6)alkyl, (C,-C6)haloalkoxy, -(C=0)-NH2, NH(C=0)-(CrC6)alkyl, NH2, NH(C,-C6)alkyl, N((C,-C6)alkyl)2, (C=0)-NH2, (C=0)-NH(C,-C6)alkyl, and (C=0)-N((C,-C6)alkyl)2.
2. The compound of claim 41 , wherein Ru-Q-NH is
Figure imgf000188_0002
Figure imgf000188_0003
43. The compound of claim 40, wherein R5 is methyl.
44. The compound of claims 1 and 6-22, wherein the compound of formula I is a compound of formula IC:
Figure imgf000189_0001
IC
wherein R^ is halo, hydroxy, cyano, (Ci-C6)alkyl, (Ci-C6)alkoxy, halo(C|-C6)alkyl, (Cj- C6)haloalkoxy, (Ci-C6)alkylene-NH2, (Ci-C6)alkylene-NH(C|-C6)alkyl} (CrC6)alkylene-NH(C|- C6)haloalkyl, (C,-C6)alkylene-N(Ci-C6)alkyl)2, NH2, NH(C,-C6)alkyl, (CrC6)alkylene-OH, (C,- C6)alky lene-(C , -C6)alkoxy, NH(C , -C6)alkylene-NH2, NH(C , -C6)alkylene-NH(C , -C6)alkyl, NH(C , -C6)alkyleneN((C , -C6)alkyl)2, NH(C , -C6)alkylene-(C3-C7)cyloalkyl, NH(C , -C6)alkylene- (C3-C7)heterocyloalkyl, N((C|-C6)alkyl)(Ci-C6)alkylene-(C3-C7)cyloalkyl, N((Ci-C6)alkyl)(Ci- C6)alkylene-(C3-C7)heterocyloalkyl, N((C , -C6)alkyl)2, (C i -C6)alkylene-NHS02-(C , -C6)alkyl, (C,-C6)alkylene-NH(C=0)-(C,-C6)alkyl, (C=0)-(C,-C6)alkyl, S(0)-(CrC6)alkyl, SC Q- C6)alkyl, aryl, hetreroaryl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, (Ci-C6)alkylene-(C3- C7)heterocycloalkyl, nitro, (C,-C6)alkylene-CN, (Ci-C6)alkylene-OC(0)-(C C6)alkyl, (C=0)- NRaRb, or S02-NRaRb, wherein Ra and Rb are each independently H, (Ci-C6)alkyl), aryl, heteroaryl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, (Ci-C6)alkylene-(C3-C7)cycloalkyl, (C|- C6)alkylene-(C3-C7)heterocycloalky 1, (C , -C6)alkylene-NH2, (C , -C6)alkylene-NH(C , -C6)alkyl), or (Ci-C6)alkylene-N(Ci-C6)alkyl))2, any of which may be optionally substituted; or any of which are taken together with the atom to which they are attached to form a 3-7 membered ring optionally substituted with halo, NH2, NH(C,-C6)alkyl, N((C|-C6)alkyl)2, OH, (CrC6)alkyl, (C,- C6)alkoxy, or (C|-C6)haloalkoxy.
45. A compound which is: 3-{4-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]piperazin-l-yl}-4H-l,2,4- benzothiadiazine 1 ,1 -dioxide;
N-[3-chloro-4-(methyloxy)phenyl]-4-[6-(3,3-difluoropyrrolidin-l-yl)-8- methylquinazolin-4-yl]piperazine-l -carboxamide;
l -({2-[6-(3,3-difluoropyrrolidin-l -yl)-8-methylquinolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl}sulfonyl)piperidin-4-amine;
l -({2-[6-(3,3-difluoropyrrolidin-l -yl)-8-methylquinolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
l-({2-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl}sulfonyl)-4-methylpiperidin-4-amine;
1 - ({2-[6-(3,3-difluoropyrrolidin-l -yl)-8-methylquinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)-4-methylpiperidin-4-amine;
6-(3,3-difluoropyrrolidin-l-yl)-8-methyl-4-{7-[(4-methylpiperazin-l-yl)carbonyl]-3,4- dihydroisoquinolin-2( 1 H)-y\ } quinazoline;
6-(3,3-difluoropyrrolidin-l -yl)-8-methyl-4-{7-[(4-methylpiperazin-l-yl)sulfonyl]-3,4- dihydroisoquinolin-2(lH)-yl}quinazoline;
2- [6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]-N-methyl-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]-N-methyl-N-[(l- methylpiperidin-4-yl)methyl]-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]-N-[2-(dimethylamino)ethyl]- N-methyl-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-[6-(3,3-difluoropyrroIidin-l-yl)-8-methylquinazolin-4-yl]-N-methyl-N-piperidin-4-yl- l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]-N-methyl-N-(l - methylpiperidin-4-yl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-[6-(3,3-difluoropyrrolidin-l -yl)-8-methylquin^^
l ,2,3,4-tetrahydroisoquinolin-7-amine;
jV-{2-[6-(3,3-difluoropyrrolidin-l -yI)-8-methylquinazolin-4-yl]-l, 2,3,4- tetrahydroisoquinolin-7-yl}-N,N-diethylethane- 1 ,2-diamine; 3-{4-[6-(3,3 -difluoropyrrol idin- 1 -y l)-8-methy lquinazolin-4-y 1] piperazin- 1 -yl } -4H- 1 ,2,4- benzothiadiazine 1 ,1 -dioxide;
N-[3-chloro-4-(methyloxy)phenyl]-4-[6-(3,3-difluoropyrrolidin-l-yl)-8- methylquinazolin-4-yl]piperazine- 1 -carboxamide;
6-(3,3-difluoropyrrolidin-l-yl)-N,N,8-trimethylquinazolin-4-amine;
N- [3 -chloro-4-(methy loxy )pheny 1] -4- [8 -methy l-6-( 1 H-pyrazol-5-yl)quinazolin-4- y 1 ]piperazine- 1 -carboxamide ;
3-{4-[8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]piperazin-l-yl}-4H- 1 ,2,4- benzothiadiazine 1 ,1 -dioxide;
N-methyl-2-[8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]-N-(piperidin-4-ylmethyl)- l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-(6-isoxazol-4-yl-8-methylquinazolin-4-yl)-N-methyl-N-(piperidin-4-ylmethyl)-l, 2,3,4- tetrahydroisoquinoline-7-sulfonamide;
l -({2-[8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7- yl}sulfonyl)piperidin-4-amine;
l-({2-[8-methyl-6-(l H-pyrazol-4-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7- yl}carbonyl)piperidin-4-amine;
l-({2-[8-methyl-6-(lH-pyrazol-5-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7- yl }carbonyl)piperidin-4-amine;
5-(4-{7-[(4-aminopiperidin-l-yl)carbonyl]-3,4-dihydroisoquinolin-2(lH)-yI}-8- methylquinazolin-6-yl)pyrimidin-2-amine;
1- ({2-[6-(l H-indazol-6-yl)-8-methylquinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7- yl}carbonyl)piperidin-4-amine;
1 -({2-[6-(l H-indazol-5-yl)-8-methylquinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7- y 1 } carbony l)piperidin-4-amine ;
N-[5-(4- { 7-[(4-aminopiperidin- 1 -yl)carbonyl]-3 ,4-dihydroisoquinolin-2( 1 H)-yl } -8- methylquinazolin-6-yl)-2-chloropyridin-3-yl]methanesulfonamide;
2- { 6- [( 1 ,2-dimethy lpropy l)amino] -8-methy lquinazolin-4-y 1 } -N-methy l-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
l-{[2-(8-methyl-6-{[2-(methyloxy)ethyl]oxy}quinazolin-4-yl)-l ,2,3,4- tetrahydroisoquinolin-7-yl]carbonyl}piperidin-4-amine; 4-{7-[(4-aminopiperidin-l-yl)carbonyl]-3,4-dihydroisoquinolin-2(lH)-yl}-8-methyl-N- [( 1 S)- 1 -methylpropyl]quinazolin-6-amine;
1 - (l -{[2-(8-methyl-6-{[2-(methyloxy)ethyl]amino}quinazolin-4-yl)-l , 2,3,4- tetrahydroisoquinolin-7-yl]carbonyl}piperidin-4-yl)-3-[2-(methyloxy)ethyl]urea
2- [6-(2-aminopyrimidin-5-yl)-8-methylquinazolin-4-yl]-N-methyl-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
1 - [(2- { 6- [5 -fluoro-6-(methy loxy)pyridin-3 -yl] -8-methy lquinazolin-4-yl } - 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
4-{7-[(4-aminopiperidin-l -yl)carbonyl]-3,4-dihydroisoquinolin-2(l H)-yl}-8-methyl-N- [2-(methyloxy)ethyl]quinazolin-6-amine;
1- ({2-[8-methyl-6-(2-methyl-l H-benzimidazol-5-yl)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
2- [6-(2-amino[l ,3]thiazolo[5,4-b]pyridin-6-yl)-8-methylquinazolin-4-yl]-N-methyl-N- (piperidin-4-ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-2-[8-methyl-6-(l -methyl- 1 H-pyrazol-4-yl)quinazolin-4-yl]-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
l-({2-[6-(3-fluorophenyl)-8-methylquinazolin-4-yl]-l,2,3,4-tetrahydroisoquinolin-7- y 1 } carbonyl)piperidin-4-amine;
1 -( { 2- [6-(4-fluoropheny l)-8-methy lquinazolin-4-y 1] - 1 ,2 ,3 ,4-tetrahydroisoquinolin-7- yl}carbonyl)piperidin-4-amine;
l-({2-[6-(2-fluorophenyl)-8-methylquinazolin-4-yl]-l,2,3,4-tetrahydroisoquinolin-7- y 1 } carbonyl)piperidin-4-amine;
3- (4- { 7-[(4-aminopiperidin- 1 -y l)carbonyl]-3 ,4-dihydroisoquinolin-2( 1 H)-y 1 } -8- methylquinazolin-6-yl)phenol;
l -({2-[6-(2,6-dichloropyndin-3-yl)-8-methylquinazolin-4-yl]-l, 2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
l -{[2-(8-methyl-6-phenylquinazolin-4-yl)-l,2,3,4-tetrahydroisoquinolin-7- yl]carbonyl}piperidin-4-amine;
l -[(2-{8-methyl-6-[3-(trifluoromethyl)phenyl]quinazolin-4-yl}- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine; l -{[2-(8-methyl-6-pyridin-2-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7- yl]carbonyl}piperidin-4-amine;
1 - { [2-(8-methy l-6-pyridin-4-ylquinazolin-4-yl)- 1 ,2,3 ,4-tetrahydroisoquinolin-7- yl]carbonyl } piperidin-4-amine;
N-methyl-2-[8-methyl-6-( 1 -methyl- 1 H-imidazol-4-yl)quinazolin-4-yl]-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-N-[( 1 -methylpiperidin-4-yl)methyl]-2-[8-methyl-6-(l H-pyrazol-5- yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
1 -( { 2-[6-( 1 ,5-dimethyl- 1 H-pyrazol-4-yl)-8-methy lquinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
1 -( { 2- [8-methy l-6-(3 -methyl- 1 H-pyrazol-4-yl)quinazolin-4-yl]- 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
1 -[(2- { 8-methy i-6-[ 1 -( 1 -methy lethyl)- 1 H-pyrazol-4-yl]quinazolin-4-yl } - 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
N-methyl-2-[8-methyl-6-(l ,3-thiazol-2-yl)quinazolin-4-yl]-N-(piperidin-4-ylmethyl)- l,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
1 - { [2-(8-methy 1-6-piperidin- 1 -ylquinazolin-4-yl)- 1 ,2,3,4-tetrahydroisoquinolin-7- yl]carbonyl}piperidin-4-amine;
l -{ [2-(8-methyl-6-mo holϊn-4-ylquinazolin-4-yl)-l,2,3,4-tetrahydroisoquinolin-7- yl]carbonyl}piperidin-4-amine;
1- {[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7- yl]carbonyl}piperidin-4-amine;
2- {6-[3,4-bis(methyloxy)phenyl]-8-methylquinazolin-4-yl}-N-methyl-N-(piperidin-4- ylmethyl)-l >2,3,4-tetrahydroisoquinoline-7-sulfonamide;
8-methyl-4-{7-[(4-methylpiperazin-l -yl)carbonyl]-3,4-dihydroisoquinolin-2(lH)-yl}-6- ( 1 H-pyrazol-5-yl)quinazoline;
N-methyl-4- { 8-methy 1-4- [7- { [methy l(piperidin-4-ylmethyl)amino]sulfonyl } -3 ,4- dihydroisoquinolin-2(l H)-yl]quinazolin-6-yl}pyridine-2-carboxamide;
N-methyl-2-[8-methyl-6-(2-methylpyridin-4-yl)quinazolin-4-yl]-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2-(6-cyano-8-methylquinazolin-4-yl)-N-methyl-N-(piperidin-4-ylmethyl)-l, 2,3,4- tetrahydroisoquinoline-7-sulfonamide;
l-({2-[8-methyl-6-(2H-l,2,3-triazol-2-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin- 7-yl}carbonyl)piperidin-4-amine;
l -({2-[6-(2-amino-l ,3-thiazol-5-yl)-8-methylquinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl } carbonyl)piperidin-4-amine;
3 -(4- { 7-[(4-aminopiperidin- 1 -yl)carbony l]-3 ,4-dihydroisoquinolin-2( 1 H)-y 1 } -8- methylquinazolin-6-yl)pyridin-2 -amine;
4- (4- { 7-[(4-aminopiperidin- 1 -y l)carbony 1] -3 ,4-dihydroisoquinolin-2( 1 H)-yl } -8- methylquinazolin-6-yl)pyridin-2-amine;
5- (4- { 7-[(4-aminopiperidin- 1 -yl)carbonyl]-3,4-dihydroisoquinolin-2( 1 H)-yl } -8- methylquinazolin-6-yl)-N,N-dimethylpyridin-2-amine;
1- {[2-(8-methyl-6-pyridazin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7- yl]carbonyl}piperidin-4-amine;
N-methyl-2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-N-(piperidin-4-ylmethyl)-l , 2,3,4- tetrahydroisoquinoline-7-sulfonamide;
2- [6-(3,5-dimethylisoxazol-4-yl)-8-methylquinazolin-4-yl]-N-methyl-N-(piperidin-4- ylmethyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
5-(4- { 7-[(4-aminopiperidin- 1 -yl)carbony l]-3 ,4-dihydroisoquinolin-2( 1 H)-yl } -8- methylquinazolin-6-yl)pyridin-2-amine;
1 - [(2- { 8-methy 1-6- [6-(methy loxy)pyridin-3 -y 1] quinazolin-4-y 1 } - 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
l-({2-[8-methyl-6-(l ,3-thiazol-2-yl)quinazolin-4-yl]-l >2,3,4-tetrahydroisoquinolin-7- yl}carbonyl)piperidin-4-amine;
l -({2-[6-(5-fluoropyridin-3-yl)-8-methylquinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin- 7-yl}carbonyl)piperidin-4-amine;
l-({2-[8-methyl-6-(l ,3-thiazol-5-yl)quinazolin-4-yl]-l,2,3,4-tetrahydroisoquinolin-7- yl}carbonyl)piperidin-4-amine;
N-methyl-2-(8-methyl-6-pyridin-4-ylquinazolin-4-yl)-N-(piperidin-4-ylmethyl)-l, 2,3,4- tetrahydroisoquinoline-7-sulfonamide; N-methyl-2-{8-methyl-6-[3-(methyloxy)phenyl]quinazolin-4-yl}-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methy 1-2- { 8-methy 1-6- [4-(methy loxy)phenyl]quinazolin-4-y 1 } -N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-2-[8-methyl-6-(3-methylphenyl)quinazolin-4-yl]-N-(piperidin-4-ylmethyl)- l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-2-[8-methyl-6-(l ,3-thiazol-5-yl)quinazolin-4-yl]-N-(piperidin-4-ylmethyl)- l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
4-[4-(lH-benzimidazol-2-yl)piperazin-l-yl]-6-bromo-8-methylquinazoline;
4- [4-(l H-benzimidazol-2-yl)piperazin-l-yl]-6-(3,3-difluoropyrrolidin-l-yl)-8- methylquinazoline;
N-methyl-N-[(l-methylpiperidin-4-yl)methyl]-2-(8-methyl-6-pyridin-4-ylquinazolin-4- yl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-N-[(l -methylpiperidin-4-yl)methyl]-2-[8-methyl-6-(l,3-thiazol-2- yl)quinazolin-4-yl]-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
5- (4- {7-[(4-aminopiperidin- 1 -yl)carbonyl]-3 ,4-dihydroisoquinolin-2( 1 H)-yl } -8- methylquinazolin-6-yl)pyridin-3-amine;
N-methyl-N-[(l -methylpiperidin-4-yl)methyl]-2-(8-methyl-6-pyridazin-3-ylquinazolin-4- yl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-niethyl-N-[(l-methylpiperidin-4-yl)methyl]-2-(8-methyl-6-pyridin-3-ylquinazolin-4- yl)- 1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-N-[(l-methylpiperidin-4-yl)methyl]-2-[8-methyl-6-(l H-pyrazol-4- yl)quinazolin-4-yl]-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-N-[(l-methylpiperidin-4-yl)methyl]-2-(8-methyl-6-pyrimidin-5-ylquinazolin- 4-yl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
1- ({2-[8-methyl-6-(5-methylpyridin-3-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin- 7-yl } carbonyl)piperidin-4-amine;
2- [6-(l,5-dimethyl-lH-pyrazol-4-yl)-8-methylquinazolin-4-yl]-N-methyl-N-(piperidin-4- ylmethyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-[6-(l ,5-dimethyl-l H-pyrazol-4-yl)-8-methylquinazolin-4-yl]-N-methyl-N-[(l- methylpiperidin-4-yl)methyl]-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide; N-methyl-N-[(l -methylpiperidin-4-yl)methyl]-2-[8-methyl-6-(l,3-thiazol-5- yl)quinazolin-4-yl]-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2-[6-(4-fluoro-3-hydroxyphenyl)-8-methylquinazolin-4-yl]-N-methyl-N-(piperidin-4- ylmethyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-rnethyl-2-{8-methyl-6-[3-(trifluoromethyl)phenyl]quinazolin-4-yl}-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-2-(8-methyl-6-{3-[(trifluoromethyl)oxy]phenyl}quinazolin-4-yl)-N-(piperidin- 4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-3-{8-methyl-4-[7-{[methyl(piperidin-4-ylmethyl)amino]sulfonyl}-3,4- dihydroisoquinolin-2(l H)-yl]quinazolin-6-yl}benzamide
N-methyl-2-{8-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]quinazolin-4-yl}-N-(piperidin- 4-ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-2-{8-methyl-6-[5-(trifluoromethyl)pyridin-3-yl]quinazolin-4-yl}-N-(piperidin- 4-ylmethyl)-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-2-[8-(methyloxy)-6-(2-methylpyridin-4-yl)quinazolin-4-yl]-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
l-{ l-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]piperidin-4-yl}-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;
1- { l-[8-methyl-6-(l,3-thiazol-2-yl)quinazolin-4-yl]piperidin-4-yl}-l,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;
N-methyl-N-[(l -methylpiperidin-4-yl)methyl]-2-[8-methyl-6-(l ,3-thiazol-5- yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-methyl-2-[8-methyl-6-(5-rnethylpyridin-3-yl)quinazolin-4-yl]-N-[(l-methylpiperidin- 4-yl)methyl]-l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2- [6-(5-fluoropyridin-3-yl)-8-methylquinazolin-4-yl]-N-methyl-N-[(l-methylpiperidin-4- yl)methyl]-l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N- { [ 1 -(6-bromo-8-methy lquinazolin-4-y l)piperidin-4-yl]methy 1 } benzenesulfonamide ;
N-methyl-2-[8-methyl-6-(l -methyl- 1 H-imidazol-5-yl)quinazolin-4-yl]-N-[(l- methylpiperidin-4-yl)methyl]-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
N-methyl-2-{8-methyI-6-[(methylsulfonyl)amino]quinazolin-4-yl}-N-[(l- methylpiperidin-4-yl)methyl]-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l,2,3,4-tetrahydroisoquinolin-7-amine;
N-[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)- 1 ,2,3 , 4-tetrahydroisoquinolin-7- yl]methanesulfonamide;
2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinoline-7- sulfonamide;
N-({ l-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinazolin-4-yl]piperidin-4- yl } methyl)benzenesulfonamide;
1 - { [2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)- 1 ,2,3 ,4-tetrahydroisoquinolin-7- yl]sulfonyl}piperidin-4-amine;
2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
N-( 1 -methylpiperidin-4-yl)-2-[8-methyl-6-( 1 ,3-thiazol-5-yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-amine;
2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N-methyl-2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N,N-dimethyl-2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinoline- 7-carboxamide;
N-{2-[8-methyl-6-(l,3-thiazol-5-yl)quinazolin-4-yl]-l,2,3,4-tetrahydroisoquinolin-7- y 1 } methanesulfonamide;
8-methyl-4-{7-[(4-methylpiperazin-l-yl)carbonyl]-3,4-dihydroisoquinolin-2(lH)-yl}-6- pyridin-3-ylquinazoline;
8-methyl-4-[7-(mo holin-4-ylcarbonyl)-3,4-dihydroisoquinolin-2(l H)-yl]-6-pyΓidin-3- ylquinazoline;
8-methyl-6-pyridin-3-yl-4-[7-(pytTolidin-l-ylcarbonyl)-3,4-dihydroisoquinolin-2(lH)- yljquinazoline;
N- { 8-methy 1-4- [7-( { methyl [( 1 -methy lpiperidin-4-y l)methy 1] amino } sulfony l)-3 ,4- dihydroisoquinolin-2(lH)-yl]quinazolin-6-yl}acetamide;
N,N-diethyl-N'-[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4- tetrahydroisoquinolin-7-yl]ethane-l ,2-diamine; N-[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l,2,3,4-tetrahydroisoquinolin-7- yl]acetamide;
N-{[l-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)piperidin-4- yl]methyl}benzenesulfonamide;
N-{ [l -(6-bromo-8-methylquinazolin-4-yl)piperidin-4-yl]methyl}methanesulfonamide;
N-{ [l-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)piperidin-4- yl]methyl}methanesulfonamide;
N-({ l -[6-(3,3-difluoropyirolidin-l-yl)-8-methylquinazolin-4-yl]piperidin-4- yl}methyl)methanesulfonamide;
N-(2-fluoroethyl)-l-{[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l , 2,3,4- tetrahydroisoquinolin-7-yl]sulfonyl}piperidin-4-amine;
8-methy l-6-[6-(methy loxy)py ridin-3 -y 1] -4- [7-(pyrrolidin- 1 -y lcarbony l)-3 ,4- dihydroisoquinolin-2(lH)-yl]quinazoline;
8-methy l-6-( 1 H-pyrazol-4-yl)-4-[7-(pyrrolidin-l -ylcarbonyl)-3,4-dihydroisoquinolin- 2(l H)-yl]quinazoline;
N,N-diethyl-N'-(2- {8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7-y l)ethane- 1 ,2-diamine;
N-[l -(2-fluoroethyl)piperidin-4-yl]-2-{8-methyl-6-[6-(methyloxy)pyridin-3- yl]quinazolin-4-yl}-l ,2,3,4-tetrahydroisoquinolin-7-amine;
4- { 7- [(4-aminopiperidin- 1 -y l)sulfonyl] -3 ,4-dihydroisoquinolin-2( 1 H)-y 1 } -6-pyridin-3- ylquinazolin-2-amine;
l-{[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7- yl]sulfonyl } -4-(trifluoromethyl)piperidin-4-ol
N-(2-fluoroethyl)-l -[(2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}- l ,2,3,4-tetrahydroisoquinolin-7-yl)sulfonyl]piperidin-4-amine;
N-(2-fluoroethyl)-l -[(2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}- l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
N,N,8-trimethyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-amine;
N-methyl-N-[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l,2,3,4-tetrahydroisoquinolin- 7-yl]acetamide; N-methyl-N-[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin- 7-yl]methanesulfonamide;
2-[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7-yl]propan-
2-ol
8-methyl-4-[7-(pyrrolidin-l -ylcarbonyl)-3,4-dihydroisoquinolin-2(lH)-yl]-6-(l ,3-thiazol-
5- yl)quinazoline;
5- {8-methyl-4-[7-(pyrrolidin-l-ylcarbonyl)-3,4-dihydroisoquinolin-2(lH)-yl]quinazolin-
6- yl } pyrimidin-2-amine;
6- [5-fluoro-6-(methyloxy)pyridin-3-yl]-8-methyl-4-[7-(pyiTolidin-l-ylcarbonyl)-3,4- dihydroisoquinoIin-2(l H)-yl]quinazoline;
2-hydroxy-N-{8-methyl-4-[7-(pyrrolidin-l-ylcarbonyl)-3,4-dihydroisoquinolin-2(lH)- yl]quinazolin-6-yl}acetamide;
l -{8-methyl-4-[7-(pyrrolidin-l-ylcarbonyl)-3,4-dihydroisoquinolin-2(lH)-yl]quinazolin- 6-yl } pyrrolidin-2-one;
5 - { 8 -methyl-4- [7-(pyrrol idin- 1 -y lcarbonyl)-3 ,4-dihydroisoquinolin-2( 1 H)-yl]quinazolin- 6-yl}pyridin-2-ol
6-(4-fluoropyridin-3-yl)-8-methyl-4-[7-(pyrrolidin-l-ylcarbonyl)-3,4-dihydroisoquinolin- 2(lH)-yl]quinazoline;
N-{[l -(8-methyl-6-pyridin-3-ylquinazolin-4-yl)piperidin-4-yl]methyl}benzamide
N-[(l-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}piperidin-4- yl)methyl]methanesulfonamide;
N-[(l -{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}piperidin-4- yl)methyl]benzenesulfonamide;
l-{[2-(8-fluoro-6-pyridin-3-ylquinazolin-4-yl)-l,2,3,4-tetrahydroisoquinolin-7- yl]sulfonyl}piperidin-4-amine;
N-[2-(methyloxy)ethyl]-l-{ [2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l,2,3,4- tetrahydroisoquinolin-7-yl]sulfonyl}piperidin-4-amine;
l-[(2-{6-[5-fluoro-6-(methyloxy)pyridin-3-yl]-8-methylquinazolin-4-yl}-l, 2,3,4- tetrahydroisoquinolin-7-yl)sulfonyl]-N-[2-(methyloxy)ethyl]piperidin-4-amine;
l -[(2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)sulfonyl]-N-[2-(methyloxy)ethyl]piperidin-4-amine; N-methyl- 1 - { [2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)- 1 ,2,3 ,4-tetrahydroisoquinolin- 7-yl]sulfonyl}piperidin-4-amine;
8-methyl-6-[6-(methyloxy)pyridin-3-yl]-4-{7-[(4-methylpiperazin-l-yl)carbonyl]-3,4- dihydroi soquinolin-2( 1 H)-y 1 } quinazoline;
Ν,Ν-dimethyl - 1 - { [2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)- 1 ,2,3,4- tetrahydroisoquinolin-7-yl]carbonyl}pyrrolidin-3-amine;
N,N,8-trimethyl-6-pyridin-3-ylquinazolin-4-amine;
2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-N-piperidin-3-yl-l, 2,3,4- tetrahydroisoquinoline-7-sulfonamide;
4-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}piperazin-2-one;
2-methyl-N-[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7- yl]alaninamide;
4-[7-{[(3S)-3-fluoropyrrolidin-l-yl]carbonyl}-3,4-dihydroisoquinolin-2(lH)-yl]-8- methyl-6-pyridin-3-ylquinazoline;
(3 )-l-{[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l,2,3,4-tetrahydroisoquinolin-7- yl]carbonyl}pyrrolidin-3-ol
4-[7-{ [(3R)-3-fluoropyrrolidin-l-yl]carbonyl}-3,4-dihydroisoquinolin-2(lH)-yl]-8- methyl-6-pyridin-3-ylquinazoline;
6-(5-fluoropyridin-3-yl)-8-methyl-4-[7-(pyiTolidin-l-ylcarbonyl)-3,4-dihydroisoquinolin- 2(lH)-yl]quinazoline;
l-methyl-3-{[(3S)-l-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)piperidin-3-yl]methyl}urea
1 - {2-[(2- { 8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl } - 1 ,2,3,4- tetrahydroisoquinolin-7-yl)amino]ethyl}pyrrolidin-2-one;
l-{[2-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7- yl]sulfonyl}azetidin-3-amine;
N-methyl-N-[(l-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}piperidin-4- yl)methyl]methanesulfonamide;
N-methyl-N-{[l -(8-methyl-6-pyridin-3-ylquinazolin-4-yl)piperidin-4- yl]methyl}methanesulfonamide;
8-methyl-4-{7-[(4-methylpiperazin-l-yl)carbonyl]-3,4-dihydroisoquinolin-2(lH)-yl}-6- ( 1 H-pyrazol-4-yl)quinazoline; 5-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-4,5,6,7- tetrahydro[l ,3]thiazolo[5,4-c]pyridin-2-amine;
5-[8-methyl-6-(lH-pyrazol-4-yl)quinazolin-4-yl]-4,5,6,7-tetrahydro[l ,3]thiazolo[5,4- c]pyridin-2-amine;
5-[6-(6-aminopyridin-3-yl)-8-methylquinazolin-4-yl]-4,5,6,7-tetrahydro[l,3]thiazolo[5,4- c]pyridin-2-amine;
8-methyl-6-[6-(methyloxy)pyridin-3-yl]-N-[2-(lH-pyrazol-4-yl)ethyl]quinazolin-4- amine;
2- { 8-methyl-6-[6-(methy loxy)pyridin-3 -yl]quinazolin-4-yl } -N-(2-morpholin-4-ylethyl)- l ,2,3,4-tetrahydroisoquinolin-7-amine;
2-[8-methyl-6-(l H-pyrazol-4-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7-amine;
2-methyl-N-{2-[8-methyl-6-(l H-pyrazol-3-yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl}alaninamide;
2- methyl-N- {2-[8-methyl-6-(l H-pyrazol-4-yl)quinazolin-4-yl]-l ,2,3,4- tetrahydroisoquinolin-7-yl}alaninamide;
N-[(5-chloro-lH-benzimidazol-2-yl)methyl]-8-methyl-6-[6-(methyloxy)pyridin-3- yl]quinazolin-4-amine;
N-[(5-chloro-l H-benzimidazol-2-yl)methyl]-8-methyl-6-pyridin-3-ylquinazolin-4-amine;
3- chloro-N-[(l -{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}piperidin-4- yl)methyl]benzenesulfonamide;
2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-N-(2-piperidin-l-ylethyl)- l ,2,3,4-tetrahydroisoquinolin-7-amine;
2- { 8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl } -N-(2-pyrrolidin- 1 -ylethyl)- 1 ,2,3 ,4-tetrahydroisoquinol in-7-amine ;
N,N-diethyl-N'-[2-(6-isothiazol-5-yl-8-methylquinazolin-4-yl)-l ,2,3,4- tetrahydroisoquinolin-7-yl]ethane-l,2-diamine;
8-methyl-4- { 7- [(4-methy 1- 1 ,4-diazepan- 1 -y l)carbony l]-3 ,4-dihydroisoquinolin-2( 1 H)- yl}-6-[6-(methyloxy)pyridin-3-yl]quinazoline;
4- {7-[(4-ethylpiperazin-l-yl)carbonyl]-3,4-dihydroisoquinolin-2(lH)-yl}-8-methyl-6-[6- (methyloxy)pyridin-3-yl]quinazoline; 8-methy l-6-[6-(methy loxy)pyridin-3 -y 1] -4- [7- { [4-( 1 -methy lpropyl)piperazin- 1 - yl]carbonyl}-3,4-dihydroisoquinolin-2(lH)-yl]quinazoline;
8-methyl-6-[6-(methyloxy)pyridin-3-yl]-4-[7-{[4-(2-methylpropyl)piperazin-l- yl]carbonyl}-3,4-dihydroisoquinolin-2(l H)-yl]quinazoline;
N-(cyclopropylmethyl)-l -[(2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}- l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
N-{2-[8-methyl-6-(lH-pyrazol-4-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7-yl}- 5-oxoprolinamide
1 - amino-N-{2-[8-methyl-6-(lH-pyrazol-4-yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl}cyclopropanecarboxamide;
N-[2-(3,3-difluoropyrrolidin-l -yl)ethyl]-2-{8-methyl-6-[6-(methyloxy)pyridin-3- y 1] quinazol in-4-y 1 } - 1 ,2 ,3 ,4-tetrahydroisoquinolin-7-amine;
N-(2,2-difluoroethy 1)- 1 - [(2- { 8-methy 1-6- [6-(methyloxy)pyridin-3 -y l]quinazolin-4-yl } - l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
8-methyl-6-[6-(methyloxy)pyridazin-3-yl]-4-{7-[(4-methylpiperazin-l-yl)carbonyl]-3,4- dihydroisoquinolin-2(l H)-yl}quinazoline;
phenylmethyl { [(3S)- 1 - { 8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4- yl}piperidin-3-yl]methyl} carbamate
1 - [(3 S)- 1 - { 8-methyl-6- [6-(methy loxy)pyridin-3 -yl]quinazolin-4-yl } piperidin-3 - yljmethanamine;
3-chloro-N-{[l-(8-methyl-6-pyridin-3-ylquinazolin-4-yl)piperidin-4- yl]methyl}benzenesulfonamide;
1 -methy 1 -3 - { [(3 S)- 1 - { 8-methy 1-6- [6-(methy loxy)pyridin-3 -y 1] quinazolin-4-yl } piperidin- 3-yl]methyl}urea
2- methyl-N-{[(3S)-l-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}piperidin- 3-yl]methyl}alaninamide;
6-[6-(ethyloxy)pyridin-3-yl]-8-methyl-4-{7-[(4-methylpiperazin-l-yl)carbonyl]-3,4- dihydroisoquinolin-2( 1 H)-yl}quinazoline;
N-[3-chloro-4-(methyloxy)phenyl]-4-{8-methyl-6-[6-(methyloxy)pyridin-3- yl]quinazolin-4-yl}piperazine-l -carboxamide; N,N-diethyl-N'-(2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7-yl)ethane- 1 ,2-diamine;
N-(2-fluoroethyl)-2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-N- piperidin-4-y I- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
8-methyl-4-[7- { [4-( 1 -methylethyl)piperazin- 1 -y l]carbony 1 } -3,4-dihydroisoquinolin- 2(l H)-yl]-6-[6-(methyloxy)pyridin-3-yl]quinazoline;
4- [7- { [(3 R)-3 ,4-dimethy Ipiperazin- 1 -yl]carbonyl } -3 ,4-dihydroisoquinolin-2( 1 H)-y l]-8- methyl-6-[6-(methyloxy)pyridin-3-yl]quinazoline;
4-[7- { [(3 S)-3 ,4-dimethy Ipiperazin- 1 -yl]carbony 1 } -3,4-dihydroisoquinolin-2( 1 H)-yl]-8- methyl-6-[6-(methyloxy)pyridin-3-yl]quinazoline;
8-methyl-6-[6-(methyloxy)pyridin-3-yl]-4-[7-(piperazin-l-ylcarbonyl)-3,4- dihydroisoquinolin-2( 1 H)-yl]quinazoline;
N,N-diethyl-N'-{2-[8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-y 1 } ethane- 1 ,2-diamine;
N,N-diethyl-N'-[2-(6-isothiazol-4-yl-8-methylquinazolin-4-yl)-l,2,3,4- tetrahydroisoquinolin-7-yl]ethane- 1 ,2-diamine;
2-methyl-N-(2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)alaninamide;
2-methyl-N-{2-[8-methyl-6-(l -methyl-l H-pyrazol-4-yl)quinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-yl}alaninamide;
N,N-diethyl-N'-[2-(8-methyl-6-pyridin-4-ylquinazolin-4-yl)-lJ2,3,4- tetrahydroisoquinolin-7-yl]ethane- 1 ,2-diamine;
N,N-diethyl-N'-{2-[8-methyl-6-(3-thienyl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin- 7-y 1 } ethane- 1 ,2-diamine;
4- { 7-[(3 ,5-dimethylpiperazin- 1 -yl)carbonyl]-3,4-dihydroisoquinolin-2( 1 H)-yl } -8-methyl- 6-[6-(methyloxy)pyridin-3-yl]quinazoline;
l-methyl-N-{2-[8-methyl-6-(l H-pyrazol-4-yl)quinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-yl}-L-prolinamide
N- { 2- [8 -methy l-6-( 1 H -pyrazol-4-y 1 )quinazolin-4-y 1] - 1 ,2,3 ,4-tetrahydroisoquinolin-7-yl} - L-alaninamide; 2-methyl-N-{2-[8-methyl-6-(5-methyl-lH-pyrazol-4-yl)quinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-yl } alaninamide;
N-{2-[8-methyl-6-(l H-pyrazol-4-yl)quinazolin-4-yl]-l,2,3,4-tetrahydroisoquinolin-7-yl}- D-prolinamide
N-{2-[8-methyl-6-(lH-pyrazol-4-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7-yl}- L-prolinamide
l-amino-N-{2-[8-methyl-6-(l H-pyrazol-4-yl)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl}cyclobutanecarboxamide;
l-amino-N-{2-[8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]-l, 2,3,4- tetrahydroisoquinolin-7-yl}cyclobutanecarboxamide;
l-amino-N-{2-[8-methyl-6-(lH-pyrazol-4-yl)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl}cyclopentanecarboxamide;
1- amino-N-{2-[8-methyl-6-(lH-pyrazol-5-yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl } cyclopentanecarboxamide;
N-(2-fluoroethyl)-l -[(2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}- l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
2- [8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]-l ,2,3,4-tetrahydroisoquinolin-7-amine; N- { [ 1 -(8-methyl-6-pyridin-4-y lquinazolin-4-yl)piperidin-4- yl]methyl}methanesulfonamide;
l-[(2-{6-[5,6-bis(methyloxy)pyridin-3-yl]-8-methylquinazolin-4-yl}-l, 2,3,4- tetrahydroisoquinolin-7-yl)carbonyl]-N-(cyclopropylmethyl)piperidin-4-amine;
l -amino-N-{2-[8-methyl-6-(l H-pyrazol-4-yl)quinazolin-4-yl]-l , 2,3,4- tetrahydroisoquinolin-7-yl } cyclohexanecarboxamide;
1 -amino-N- {2-[8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl}cyclohexanecarboxamide;
l-[(2-{6-[5,6-bis(methyloxy)pyridin-3-yl]-8-methylquinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7-yl)carbonyl]-N-(2-fluoroethyl)piperidin-4-amine;
l-amino-N-{2-[8-methyl-6-(5-methyl-l H-pyrazol-4-yl)quinazolin-4-yl]-l, 2,3,4- tetrahydroisoquinolin-7-yl}cyclopentanecarboxamide;
N-[2-(6-isoxazol-4-yl-8-methylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7-yl]-2- methylalaninamide; 2-methyl-N-{2-[8-methyl-6-(l-methyl-l H-pyrazol-5-yl)quinazolin-4-yl]-l ,2,3,4- tetrahydroisoquinolin-7-yl}alaninamide;
2-methy l-N-(2- { 8-methyl-6- [6-(methy loxy)pyridazin-3 -yl]quinazolin-4-y 1 } - 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)alaninamide;
l-{[2-(6-bromo-8-methylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7-yl]carbonyl}- N-(2-fluoroethyl)piperidin-4-amine;
N-(2-fluoroethyl)-l -({2-[8-methyl-6-(lH-pyrazol-5-yl)quinazolin-4-yl]-l ,2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
1- {[2-(6-bromo-8-methylquinazolin-4-yl)-l ,2,3,4-tetrahydroisoquinolin-7-yl]carbonyl}- N-(cyclopropylmethyl)piperidin-4-amine;
N-(cyclopropylmethyl)-l-({2-[8-methyl-6-(lH-pyrazol-5-yl)quinazolin-4-yl]-l, 2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
N-({ 1 -[8-methyl-6-( 1 H-pyrazol-5-yl)quinazolin-4-yl]piperidin-4- yl } methyl)methanesulfonamide;
N-[(l -{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}piperidin-4- yl)methyl]methanesulfonamide;
2- methyl-N- { 2-[8-methy l-6-( 1 H-pyrazol-4-yl)quinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl}-2-pyrrolidin-l -ylpropanamide
3 ,3 -difluoro-N-methyl- 1 - [(2- { 8-methyl-6-[6-(methy loxy)pyridin-3-yl]quinazolin-4-yl } - l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
3,3-difluoro-l-[(2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
2-methyl-N-{2-[8-methyl-6-(lH-pyrazol-5-yl)quinazolin-4-yl]-l ,2,3,4- tetrahydroisoquinolin-7-yl } -2-pyrrolidin- 1 -ylpropanamide
3,3-difluoro- 1 -[(2- {8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-l, 2,3,4- tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-ol
N-ethyl-2-[8-methyl-6-(l H-pyrazol-5-yl)quinazolin-4-yl]-N-piperidin-4-yl-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-ethyl-2-{8-methyl-6-[6-(rnethyloxy)pyridin-3-yl]quinazolin-4-yl}-N-piperidin-4-yl- l ,2,3,4-tetrahydroisoquinoline-7-carboxamide; 6-{4-[7-({4-[(cyclopropylmethyl)amino]piperidin-l-yl}carbonyl)-3,4- dihydroisoquinolin-2(l H)-yl]-8-methylquinazolin-6-yl}pyridazin-3-ol
N-(cyclopropylmethyl)-l-[(2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4- yl }- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
2-methyl-N-(2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7-yl)-2-pyrrolidin- 1 -ylpropanamide
N-(2- { 8-methy l-6-[6-(methy loxy )pyridazin-3 -yl]quinazol in-4-y 1 } - 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)methanesulfonamide;
N-({ l-[6-(3-fluoropyridin-4-yl)-8-methylquinazolin-4-yl]piperidin-4- yl } methyl)methanesulfonamide;
N-({ l-[8-methyl-6-(2-methylpyridin-4-yl)quinazolin-4-yl]piperidin-4- yl } methy l)methanesulfonamide;
N-[( 1 - { 8-methyl-6-[3-(methyloxy)pyridin-4-yl]quinazolin-4-yl } piperidin-4- yl)methyl]methanesulfonamide;
N-[(l-{8-methyl-6-[2-(methyloxy)pyridin-4-yl]quinazolin-4-yl}piperidin-4- yl)methyl]methanesulfonamide;
4- [7- { [4-(3 ,3 -difluoropyrrol idin- 1 -y l)piperidin- 1 -y l]carbonyl } -3 ,4-dihydroisoquinolin- 2(l H)-yl]-8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazoline;
(3R)-N-(2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-l ,2,3,4- tetrahydroisoquinolin-7-yl)pyrrolidine-3-carboxamide;
N-(2-fluoroethy 1)- 1 -( { 2-[8 -methy l-6-(6-methylpyridazin-3 -yl)quinazolin-4-yl] -1 ,2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
N-(2-fluoroethyl)-l -({2-[8-methyl-6-(5-methylpyridazin-3-yl)quinazolin-4-yl]-l, 2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)piperidin-4-amine;
2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N-(2-mo holin-4- ylethyl)-l ,2,3,4-tetrahydroisoquinolin-7-amine;
(2 S)-N-(2- { 8-methy 1 -6- [6-(methy loxy)pyridazin-3-y l]quinazolin-4-yl } - 1 ,2,3 ,4- tetrahydroisoquinolin-7-yl)piperidine-2-carboxamide;
2- { 8-methyl-6-[6-(methyloxy)pyridin-3-y l]quinazolin-4-yl } - 1 ,2,3 ,4- tetrahydroi soquinolin-7-amine ; 2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7-amine;
N-(2-fluoroethyl)-l -{ [2-(8-methyl-6-pyridazin-3-ylquinazolin-4-yl)-l , 2,3,4- tetrahydroisoquinolin-7-yl]carbonyl}piperidin-4-amine;
1 - ({2-[6-(6-chloropyridazin-3-yl)-8-methylquinazolin-4-yl]- 1 ,2,3,4- tetrahydroisoquinolin-7-yl}carbonyl)-N-(2-fluoroethyl)piperidin-4-amine;
N-(2-fluoroethy 1)- 1 - { [2-(8-methy 1 -6-pyrimidin-5 -ylquinazolin-4-y 1)- 1 ,2 ,3 ,4- tetrahydroisoquinolin-7-yl]carbonyl}piperidin-4-amine;
N,N-diethyl-N'-[2-(8-methyl-6-pyrazin-2-ylquinazolin-4-yl)-l,2,3,4- tetrahydroisoquinolin-7-yl]ethane- 1 ,2-diamine;
N,N-diethyl-N'-{2-[8-methyl-6-(lH-pyrazol-4-yl)quinazolin-4-yl]-l,2,3,4- tetrahydroisoquinolin-7-yl} ethane- 1,2-diamine;
2- { 8-methy 1 -6- [6-(methy loxy)pyridazin-3 -y l]quinazolin-4-y 1 } -N-(piperidin-3 -y Imethy 1)- l ,2,3,4-tetrahydroisoquinolin-7-amine;
N-(cyclopropylmethy 1)- 1 -[(2- { 8-methy l-6-[5-(methy loxy)pyridin-3 -yl]quinazolin-4-y 1 } - l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-N-(piperidin-3-ylmethyl)- l ,2,3,4-tetrahydroisoquinolin-7-amine;
N-({ l -[6-(3-chloropyridin-4-yl)-8-methylquinazolin-4-yl]piperidin-4- yl } methyI)methanesulfonamide;
N,N-diethyl-N,-[2-(8-methyl-6-pyridazin-3-ylquinazolin-4-yl)-l, 2,3,4- tetrahydroisoquinolin-7-yl]ethane- 1 ,2-diamine;
2-(8-methyl-6-pyridazin-3-ylquinazolin-4-yl)-N-(2-morpholin-4-ylethyl)-l , 2,3,4- tetrahydroisoquinolin-7-amine;
2-(8-methyl-6-pyrazin-2-ylquinazolin-4-yl)-N-(2-morpholin-4-ylethyl)-l , 2,3,4- tetrahydroisoquinolin-7-amine;
N-(2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)acetamide;
N-(2-fluoroethyl)-l-{[2-(8-methyl-6-pyridazin-4-ylquinazolin-4-yl)-l,2,3,4- tetrahydroisoquinolin-7-yl]carbonyl}piperidin-4-amine; N-(2,2-difluoroethyl)- 1 -[(2- { 8-methy l-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl } - l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
N-ethyl-2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N-(l- methylpiperidin-4-yl)-l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(8-methyl-6-pyri dazin-4-ylquinazolin-4-yl)-N-(2-mo holϊn-4-ylethyl)-l , 2,3,4- tetrahy droi soquinol in-7-amine ;
2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N-(piperidin-4-ylmethyl)- l ,2,3,4-tetrahydroisoquinolin-7-amine;
2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N-(piperidin-2-ylmethyl)- l ,2,3,4-tetrahydroisoquinolin-7-amine;
2-{8-methyl-6-[5-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-N-(2-morpholin-4-ylethyl)- l ,2,3,4-tetrahydroisoquinolin-7-amine;
1 , 1 -dimethy lethy 1 (3 R)-3 - { [(2 - { 8-methy 1-6- [6-(methy loxy)pyridazin-3 -y l]quinazolin-4- yl}-l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]amino}piperidine-l-carboxylate
2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N-[(3R)-piperidin-3-yl]- l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
1 , 1 -dimethy lethy 1 (3 R)-3 - { [(2- { 8-methy 1-6- [6-(methy loxy)pyridin-3-yl]quinazol in-4-yl } - 1 ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]amino}piperidine- 1 -carboxylate
2-{8-methyl-6-[6-(methyloxy)pyridin-3-yl]quinazolin-4-yl}-N-[(3R)-piperidin-3-yl]- l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-{8-methyl-6-[6-(methyloxy)pyrimidin-4-yl]quinazolin-4-yl}-N-(2-morpholin-4- ylethyl)-l,2,3,4-tetrahydroisoquinolin-7-amine;
1- [(2-{6-[3,4-bis(methyloxy)phenyl]-8-methylquinazolin-4-yl}-l,2,3,4- tetrahydroisoquinolin-7-yl)carbonyl]-N-(cyclopropylmethyl)piperidin-4-amine;
4-[7-{[4-(3,3-difluoropyrrolidin-l-yl)piperidin-l -yl]carbonyl}-3,4-dihydroisoquinolin- 2(l H)-yl]-8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazoline;
2- {6-[3,4-bis(methyloxy)phenyl]-8-methylquinazolin-4-yl}-N-ethyl-N-(l- methylpiperidin-4-yl)-l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2- { 8-methy l-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl } -N-( 1 -methylpiperidin-4- yl)-l ,2,3,4-tetrahydroisoquinolin-7-amine; 8-methyl-6-[6-(methyloxy)pyridin-3-yl]-4-{7-[(4-mo holin-4-ylρiperidin-l- yl)carbonyl]-3,4-dihydroisoquinolin-2(l H)-yl}quinazoline;
8-methyl-6-[6-(methyloxy)pyridin-3-yl]-4-{7-[(4-pyrrolidin-l-ylpiperidin-l- yl)carbonyl]-3,4-dihydroisoquinolin-2(l H)-yl}quinazoline;
N,N-dimethyl-N'-(2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7-yl)sulfamide
N-[(l -{6-[2,6-bis(methyloxy)pyridin-4-yl]-8-methylquinazolin-4-yl}piperidin-4- yl)methyl]methanesulfonamide;
N-[(l -{8-methyl-6-[2-methyl-6-(methyloxy)pyridin-4-yl]quinazolin-4-yl}piperidin-4- yl)methyl]methanesulfonamide;
2- { 8-methyl-6-[6-(methy loxy)pyridazin-3-yl]quinazolin-4-yl } -N-[( 1 -methylpiperidin-4- yl)methyl]- 1 ,2,3,4-tetrahydroisoquinolin-7-amine;
2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N,N-bis[(l- methylpiperidin-4-yl)methyl]-l ,2,3,4-tetrahydroisoquinolin-7-amine;
2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N-[(l-methylpyiTolidin-3- y l)methy 1] - 1 ,2,3 ,4-tetrahydroisoquinol in-7-amine ;
2-[6-(5-amino-6-chloropyridin-3-yl)-8-methylquinazolin-4-yl]-N-[(3R)-piperidin-3-yl]- l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2- { 8-methy l-6-[6-(methy loxy)pyridin-3 -yl]quinazolin-4-yl } -N-[(3 S)-piperidin-3-yl]- l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-N-[(3S)-piperidin-3-yl]- l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-[8-methyl-6-(lH-pyrazol-4-yl)quinazolin-4-yl]-N-[(3S)-piperidin-3-yl]-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-{8-methyl-6-[2-(methyloxy)pyridin-4-yl]quinazolin-4-yl}-N-[(3S)-piperidin-3-yl]- l ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
l-[(2-{8-methyl-6-[6-(methyloxy)pyridazin-3-yl]quinazolin-4-yl}-l , 2,3,4- tetrahydroisoquinolin-7-yl)carbonyl]-N-[2-(methyloxy)ethyl]piperidin-4-amine;
(3 S,4 S)-3 -fluoro- 1 - [(2- { 8-methy 1-6- [6-(methy loxy )pyridazin-3 -y l]quinazolin-4-yl } - l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine; (3 R,4S)-3 -fluoro- 1 - [(2- { 8-methy 1-6- [6-(methy loxy)pyridazin-3 -yl]quinazolin-4-y 1 } - l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-amine;
(3 R,4S)-3 -fluoro- 1 -[(2- { 8-methy l-6-[6-(methyloxy)py ridazin-3 -y l]quinazol in-4-y 1 } - l ,2,3,4-tetrahydroisoquinolin-7-yl)carbonyl]piperidin-4-ol
N-methyl-2-[8-methyl-6-(l H-pyrazol-5-yl)quinolin-4-yl]-N-(piperidin-4-ylmethyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide; or
2-[6-(3,3-difluoropyrrolidin-l-yl)-8-methylquinolin-4-yl]-N-methyl-N-(piperidin-4- ylmethyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide.
46. A pharmaceutical composition comprising a compound of claims 1-45 admixed with a pharmaceutical carrier, excipient, or diluent.
47. A method for treating a disease, disorder, or syndrome which method comprises administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of claims 1-46.
48. The method of claim 47, wherein the disease is cancer.
49. The method of claim 47, wherein the cancer is breast cancer, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, NPM/ALK- transformed anaplastic large cell lymphoma, diffuse large B cell lymphoma, rhabdomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, non-small cell lung carcinoma, small cell lung carcinoma, adenocarcinoma, colon cancer, rectal cancer, gastric carcinoma, hepatocellular carcinoma, melanoma, pancreatic cancer, prostate carcinoma, thyroid carcinoma, anaplastic large cell lymphoma, hemangioma, glioblastoma, or head and neck cancer.
50. A process for making a compound of formula I, comprising process for making a compound of formula I, comprising reacting a compound of formula F with NHR3R4 to provide a compound of formula I:
Figure imgf000211_0001
wherein:
NRxRy is as defined in claim 1 ; and
X, R3, R4, and R5 are as defined in claim 1.
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