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WO2024059186A1 - N-((isoquinolin-6-yl)methyl)-1h-pyrazole-4-carboxamid derivatives as plasma kallikrein inhibitors for the treatment of hereditary angioedema - Google Patents

N-((isoquinolin-6-yl)methyl)-1h-pyrazole-4-carboxamid derivatives as plasma kallikrein inhibitors for the treatment of hereditary angioedema Download PDF

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Publication number
WO2024059186A1
WO2024059186A1 PCT/US2023/032723 US2023032723W WO2024059186A1 WO 2024059186 A1 WO2024059186 A1 WO 2024059186A1 US 2023032723 W US2023032723 W US 2023032723W WO 2024059186 A1 WO2024059186 A1 WO 2024059186A1
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Prior art keywords
methyl
amino
compound
dimethylisoquinolin
optionally substituted
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French (fr)
Inventor
Nikolaos PAPAIOANNOU
Sarah Jocelyn FINK
Jeremy Mark Travins
John Mark Ellard
Alastair Rae
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Priority to EP23786841.9A priority Critical patent/EP4587434A1/en
Priority to JP2025515757A priority patent/JP2025531207A/en
Publication of WO2024059186A1 publication Critical patent/WO2024059186A1/en
Anticipated expiration legal-status Critical
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    • 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
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • C07D401/14—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
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Plasma Kallikrein (PKa) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor Xlla, and contributes to the innate inflammatory response and intrinsic cascade of blood coagulation.
  • the mechanisms that lead to the activation of this pathway in vivo include interactions with polyphosphates released from activated platelets and deficiency of Cl inhibitor (Cl -INH), the primary physiological inhibitor of PKa.
  • Cl inhibitor Cl inhibitor
  • PKa- mediated cleavage of high-molecular weight kininogen generates the potent vasodilator and pro- inflammatory nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor.
  • Bl and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers. Activation of Bl and B2 receptors causes vasodilation and increases vascular permeability.
  • PKa is also associated with a number of disorders, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx.
  • HAE hereditary angioedema
  • Prevalence for HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons without known differences among ethnic groups.
  • HAE is caused by deficient (Type I) or dysfunctional (Type II) levels of Cl -INH, which inhibits PKa, bradykinin, and other serine proteases in the blood.
  • HAE hereditary angioedema
  • the present disclosure is based on, at least in part, the development of a number of compounds which bind to plasma kallikrein and effectively inhibit its activity. Accordingly, provided herein are compounds and uses thereof for targeting plasma kallikrein and/or treating plasma kallikrein-mediated diseases and disorders. [0004] In some embodiments, the present invention provides a compound of Formula (I): Cy B — L'— Cy A — L— Cy c
  • the present invention provides a compound of Formula (I): Cy B — U— Cy A — L— Cy c
  • the present invention also provides methods of using compounds of Formulae (I)-(XVI-c).
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • the term “aryl” may be used interchangeably with the term “aryl ring”.
  • an 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring.
  • “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 7t electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a bivalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/7- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heterocyclyl As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2//-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in A-substitutcd pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocyclyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • a bivalent carbocycle is “carbocycylene”
  • a bivalent aryl ring is “arylene”
  • a bivalent benzene ring is “phenylene”
  • a bivalent heterocycle is “heterocyclylene”
  • a bivalent heteroaryl ring is “heteroarylene”
  • a bivalent alkyl chain is “alkylene”
  • a bivalent alkenyl chain is “alkenylene”
  • a bivalent alkynyl chain is “alkynylene”
  • compounds of the invention may, when specified, contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are in a polycyclic ring system, substituents may, unless otherwise indicated, replace a hydrogen on any individual ring (e.g., ).
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o- 2 R*, -(haloR*), -(CH 2 )o- 2 OH, -(CH 2 )o- 2 OR*, -(CH 2 )o- 2 CH(OR*) 2 ; -O(haloR’), - CN, -N3, -(CH 2 )O- 2 C(0)R*, -(CH 2 )O- 2 C(0)OH, -(CH 2 )O- 2 C(0)OR*, -(CH 2 )O- 2 SR*, -(CH 2 )O- 2 SH, - (CH 2 )O- 2 NH 2 , -(CH 2 )O- 2 NHR*, -(CH 2 )O- 2 NR* 2 , -NO 2 , -SiR*
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR # 2 ) 2 -3O-, wherein each independent occurrence of R # is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R # include halogen, -R*, - (haloR*), - OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R f , -NR’h, -C(O)R f , -C(O)OR f , -C(O)C(O)R f , -C(O)CH 2 C(O)R f , -S(O) 2 R f , - S(O) 2 NR T 2 , -CfSjNR’h, -C(NH)NR 1 ’2, or -N(R t )S(O)2R t ; wherein each R ?
  • Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R' are independently halogen, -R*, - (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • oxo means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.
  • a “dosing regimen” is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • a “reference” compound is one that is sufficiently similar to a particular compound of interest to permit a relevant comparison.
  • information about a reference compound is obtained simultaneously with information about a particular compound.
  • information about a reference compound is historical.
  • information about a reference compound is stored, for example in a computer-readable medium.
  • comparison of a particular compound of interest with a reference compound establishes identity with, similarity to, or difference of the particular compound of interest relative to the compound.
  • therapeutic agent refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject.
  • the term “therapeutically effective amount” refers to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease.
  • a therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple unit doses.
  • a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents.
  • the specific therapeutically effective amount (and/or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and/or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.
  • treatment refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • a substance e.g., provided compositions
  • Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
  • a provided compound is of Formula (I): Cy B — L'— Cy A — L— Cy c
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups; each R A is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO 2 , -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, -OC(O)R, -OC(O
  • L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each R z is independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group; wherein: each of R B1 and R B2 is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;
  • R B3 is hydrogen or C1-6 aliphatic
  • R B4 is -N(R X ) 2 ; each R x is independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. wherein no more than one of R B1 or R B2 is hydrogen; or wherein:
  • R B5 is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of R B6 and R B7 is independently hydrogen or an optionally substituted Ci-6 aliphatic;
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups; each L c is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each R c is independently selected from oxo, halogen, -CN, -C(O)R, -C(O) 2 R, -C(O)N(R)2,
  • a provided compound is of Formula (!'):
  • Cy A Cy A , Cy c , L, and L’ is defined and described in classes and subclasses herein, both singly and in combination; and Cy B is an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is phenylene, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is phenylene, wherein Cy A is substituted with 0-2 -R A groups. [0045] In some embodiments, Cy A is a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 6-membered monocyclic heteroarylene having 1-3 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 R A groups. In some embodiments, Cy A is a pyridinediyl substituted with 0-3 R A groups. In some embodiments, Cy A is a pyrimidinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a pyridazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a pyrazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a pyrazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a triazinediyl substitute
  • Cy A is a 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-2 -R A groups.
  • Cy A is thiazolediyl, wherein Cy A is substituted with 0-1 -R A groups.
  • Cy A is an unsubstituted thiadiazol ediyl.
  • Cy A is an unsubstituted oxadiazolediyl.
  • Cy A is an unsubstituted triazolediyl.
  • Cy A is pyrrolediyl, wherein Cy A is substituted with 0-2 -R A groups. In some embodiments, Cy A is pyrazolediyl, wherein Cy A is substituted with 0-2 -R A groups. In some embodiments, Cy A is imidazolediyl, wherein Cy A is substituted with 0-2 -R A groups. In some embodiments, Cy A is unsubstituted pyrazolediyl. In some embodiments, Cy A is unsubstituted imidazolediyl.
  • Cy A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9- to 10- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is an 8-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is an 8-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 9-membered bicyclic heteroarylene having 1-4 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 9-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9- membered bicyclic heteroarylene having 3 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 9-membered bicyclic heteroarylene having 4 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 10-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 10-membered bicyclic heteroarylene having 1 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 7- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A is substituted with 0-1 -R A groups.
  • Cy A is a 10-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A is substituted with 0-1 -R A groups.
  • Cy A is selected from the group consisting of:
  • Cy A is selected from the group consisting of wherein * represents the point of attachment to L’.
  • Cy A is selected from the group consisting of wherein * represents the point of attachment to L’.
  • Cy A is selected from the group consisting of wherein * represents the point of attachment to L’.
  • Cy A is selected from the group consisting of: wherein * represents the point of attachment to L’.
  • Cy A is: wherein * represents the point of attachment to L’.
  • Cy A is phenylene, 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of phenylene, thiazolediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadi azolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of:
  • Cy A is not a 6-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy A is not a 6-membered monocyclic heteroarylene having 1-2 nitrogen heteroatoms. In some embodiments, Cy A is not a pyridinediyl or pyrazinediyl substituted with 0-3 R A groups. In some embodiments, Cy A is not a pyridinediyl substituted with 0-3 R A groups. In some embodiments, Cy A is a not pyrazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is not some embodiments, Cy A is not some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments
  • Cy A is phenylene, 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of:
  • Cy A is not a 5-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy A is not a 5-membered monocyclic heteroarylene having 1 nitrogen and 1 sulfur heteroatoms. In some embodiments, Cy A is not a thiazolediyl or pyrazinediyl substituted with 0-3 R A groups.
  • Cy A is not
  • Cy A is substituted with 0 -R A groups (i.e., Cy A is unsubstituted).
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is not a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur substituted with 0-4 -R A groups.
  • each R A is independently selected from oxo, halogen, -CN, - C(O)R, -C(O) 2 R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, - OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O) 2 R, -S(O)N(R) 2 , -S(O) 2 N(R) 2 , or an optionally substituted group selected from C1-6 aliphatic,
  • each R A is independently selected from oxo, halogen, -CN, - C(O) 2 R, -N(R) 2 , -OR, -SR, -S(O)R, -S(O) 2 R, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • each R A is independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R) 2 , or an optionally substituted C1-6 aliphatic.
  • each R A is independently selected from halogen, -OR, or an optionally substituted C1-6 aliphatic. In some embodiments, each R A is independently selected from halogen or an optionally substituted C1-6 aliphatic. In some embodiments, each R A is independently selected from fluorine or methyl.
  • substituents on an optionally substituted R A group are independently halogen, -(CH2)o-40R°, or -(CH2)O--IN(R 0 )2, wherein each R° is independently as defined above and described in classes and subclasses herein.
  • each R° is independently hydrogen or methyl.
  • each R° is hydrogen.
  • references herein to embodiments in which “a single instance” of a substituent is defined are not limited to monosubstituted embodiments.
  • a single instance of R A is oxo includes embodiments in which at least one instance of R A is oxo and which may comprise one or more additional R A groups as defined herein.
  • a single instance of R A is oxo. In some embodiments, a single instance of R A is halogen. In some embodiments, a single instance of R A is fluorine. In some embodiments, a single instance of R A is chlorine. In some embodiments, a single instance of R A is -CN.
  • a single instance of R A is -C(O)2R. In some embodiments, a single instance of R A is -C(O)2R, wherein R is hydrogen, methyl, or ethyl. In some embodiments, a single instance of R A is -C(O)2H. In some embodiments, a single instance of R A is -C(O)2CHa. In some embodiments, a single instance of R A is -C(O)2CH2CH3. In some embodiments, a single instance of R A is -C(O)N(R)2. In some embodiments, a single instance of R A is -C(O)NH2.
  • a single instance of R A is -N(R)2. In some embodiments, a single instance of R A is -OR.
  • a single instance of R A is Ci-6 aliphatic substituted with halogen.
  • R A is -CHF2.
  • R A is -CF3.
  • a single instance of R A is Ci-6 aliphatic substituted with - (CH 2 )O-40R°, wherein R° is selected from hydrogen or C1-6 aliphatic.
  • a single instance of R A is -CH2OH.
  • a single instance of R A is -CH2OCH3.
  • a single instance of R A is C1-6 aliphatic substituted with -(CH2)o-4N(R°)2, wherein each R° is independently selected from hydrogen or C1-6 aliphatic.
  • a single instance of R A is -CH2NH2.
  • a single instance of R A is C1-6 aliphatic substituted with -(CH2)o-4C(0)OR°, wherein R° is selected from hydrogen or 0
  • a single instance of R A is j n some o embodiments, a single instance of R A is
  • a single instance of R A is methyl, ethyl, or propyl. In some embodiments, a single instance of R A is methyl.
  • a single instance of R A is optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of R A is optionally substituted cyclopropyl.
  • a single instance of R A is optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R A is optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen and nitrogen. In some embodiments, a single instance of R A is optionally substituted oxetanyl. In some embodiments, a single instance of R A is oxetanyl optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, a single instance of R A is pyrrolidinyl.
  • each R A is independently selected from halogen, -CN, - C(O)R, -C(O) 2 R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, - OC(O)R, -OC(O)N(R) 2 , -SR, -S(O)R, -S(O) 2 R, -S(O)N(R) 2 , -S(O) 2 N(R) 2 , or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or
  • R A is not oxo.
  • L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is a covalent bond.
  • L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, - NR Z -, -SO2-. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)- or -NR Z . In some embodiments, L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 methylene unit is replaced -NR Z .
  • L’ is an optionally substituted C1-3 hydrocarbon chain, wherein 1 methylene unit is replaced -NR Z .
  • L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 methylene unis is optionally and independently replaced with -NR Z -.
  • L’ is optionally substituted with halogen. In some embodiments, L’ is optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic and may be further substituted with halogen. In some embodiments, L’ is optionally substituted with -CF3.
  • L’ is selected from the group consisting of: and 0 , wherein # represents the point of attachment to Cy B .
  • L’ is selected from the group consisting of: , wherein # represents the point of attachment to Cy B .
  • L’ is wherein # represents the point of attachment to Cy B . In some embodiments, L’ is O , wherein # represents the point of attachment to Cy B .
  • L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is selected from the group consisting of:
  • L’ is not O , wherein # represents the point of attachment to Cy B .
  • L’ is a covalent bond or an optionally substituted C2-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is not -O-.
  • Cy B is an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy B is an optionally substituted 10-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, Cy B is optionally substituted isoquinolinyl. In some embodiments, Cy B is optionally substituted . in some embodiments, Cy B is optionally substituted with halogen; -(CH2)o-4R°; -(CH2)o-40R°; or -(CH2)o-4N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic.
  • Cy B wherein no more than one of R B1 or R B2 is hydrogen. In some embodiments, wherein R B1 is not hydrogen. In some embodiments, , wherein R B2 is not hydrogen. In some embodiments,
  • Cy B is , wherein R B1 and R B2 are not hydrogen.
  • R B1 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B1 is hydrogen or C1-6 aliphatic. In some embodiments, R B1 is hydrogen. In some embodiments, R B1 is C1-6 aliphatic. In some embodiments, R Bi is methyl. In some embodiments, R B1 is ethyl. In some embodiments, R B1 is methyl, optionally substituted with halogen. In some embodiments, R B1 is -CF3.
  • R B1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B1 is an optionally substituted cyclopropyl. In some embodiments, R B1 is cyclopropyl. In some embodiments, R B1 is cyclopropyl, optionally substituted with -(CH2)O-4R 0 , wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R Bi is In some embodiments, R B1 is methyl, ethyl, -CF3, or
  • R B2 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B2 is hydrogen or C1-6 aliphatic. In some embodiments, R B2 is hydrogen. In some embodiments, R B2 is C1-6 aliphatic. In some embodiments, R B2 is methyl. In some embodiments, R B2 is ethyl. In some embodiments, R B2 is methyl, optionally substituted with halogen. In some embodiments, R B2 is -CF3.
  • R B2 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B2 is an optionally substituted cyclopropyl. In some embodiments, R B2 is cyclopropyl. In some embodiments, R B2 is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R B2 is
  • R B1 and R B2 are the same. In some embodiments, R B1 and R B2 are different. In some embodiments, R B1 is hydrogen and R B2 is Ci-6 aliphatic. In some embodiments, R B1 is Ci-6 aliphatic and R B2 is hydrogen. In some embodiments, R B1 and R B2 are Ci-6 aliphatic. In some embodiments, R B1 is hydrogen and R B2 is methyl. In some embodiments, R B1 is methyl and R B2 is hydrogen. In some embodiments, R B1 and R B2 are methyl.
  • R B1 is methyl, ethyl, -CF3, or and R B2 is hydrogen, methyl, ethyl, -CF3, or In some embodiments, R B1 is hydrogen, methyl, ethyl, -CF3, or and R B2 is methyl, ethyl, -CF3, or In some embodiments, R B1 is methyl, ethyl, -CF3, or , and R B2 is methyl, ethyl, - .
  • the sizes of the R B1 and/or R B2 groups influence potency without loss of binding efficiency.
  • the relative size of a group can be determined from the van der Waals surface and/or molecular volume calculated for that group.
  • the van der Waals surface is a closed surface, and hence, it contains volume. This volume is called the molecular volume, or van der Waals volume, and is usually given in A 3 .
  • a straightforward way of calculating A-values on the computer is by numerical integration, i.e., by surrounding the van der Waals envelope with a grid of small bricks and summing up the bricks whose centers are within the van der Waals envelope of the molecule (i.e., are within a van der Waals radius from atom nucleus) (see, for example, Whitley, “Van der Waals surface graphs and molecular shape,” Journal of Mathematical Chemistry (1998) 23:377-397).
  • the relative size of a group can also be measured from the “A-value” for a given group.
  • the A-value is a measure of the effective size of a given group.
  • the “A-value” refers to the conformational energies (-G 0 values) as determined for a substituted cyclohexane and the relative axial-equatorial disposition of the substituent (see Table 1, provided below, and pages 695-697 of Eliel and Wilen, Chapter 11 entitled “Configuration and Confirmation of Cyclic Molecules” of Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New
  • R B1 is selected from a moiety with an A-value that is greater than about 1.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 1.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 1.70 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 2.0 kcal/mol (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value that is greater than about 2.25 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 2.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 2.75 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 3.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 4.0 kcal/mol (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value that is greater than about 1.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 1.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 1.70 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 2.0 kcal/mol (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value that is greater than about 2.25 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 2.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 2.75 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 3.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 4.0 kcal/mol (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1).
  • R B3 is hydrogen or Ci-6 aliphatic. In some embodiments, R B3 is hydrogen. In some embodiments, R B3 is Ci-6 aliphatic. In some embodiments, R B3 is methyl, ethyl, or propyl. In some embodiments, R B3 is methyl.
  • R B4 is -N(R x )i. In some embodiments, R B4 is -NH2. In some embodiments, R B4 is -NHR X .
  • each R x is independently selected from hydrogen, -C(O)R, - C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, each R x is hydrogen. In some embodiments, each R x is independently selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, one R x is hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic.
  • R x is -C(O)R. In some embodiments, R x is -C(O)R, wherein R is C1-6 aliphatic. In some embodiments, R x -C(O)CH3 In some embodiments, R x is -C(O)2R. In some embodiments, R x is -C(O)2R, wherein R is optionally substituted C1-6 aliphatic. In some embodiments, R x is -C(O)2R, wherein R is C1-6 aliphatic optionally substituted with -(CH2)o-4Ph. In some embodiments, R x is -C(O)2CH2Ph.
  • R x is -C(O)2R, wherein R is C1-6 aliphatic. In some embodiments, R x is -C(O)2R, wherein R is methyl, ethyl, isopropyl, or isobutyl. In some embodiments, R x is -C(O)2CH2CH3. In some embodiments, R x is - C(O)C(CH3)2. In some embodiments, R x is -C(O)CH2C(CH3)2. In some embodiments, R x is optionally substituted C1-6 aliphatic. In some embodiments, R x is C1-6 aliphatic. In some embodiments, R x is methyl, ethyl, or propyl. In some embodiments, R x is methyl.
  • Cy B is selected from the group consisting of:
  • Cy B is selected from the group consisting of: [0121] In some embodiments, Cy B is selected from the group consisting of:
  • R B5 is hydrogen or Ci-6 aliphatic or an optionally substituted
  • R B5 is hydrogen. In some embodiments, R B3 is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B5 is Ci-6 aliphatic. In some embodiments, R B5 is methyl, ethyl, or propyl. In some embodiments, R B5 is methyl. In some embodiments, R B5 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B3 is an optionally substituted cyclopropyl. In some embodiments, R B3 is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments,
  • R B6 is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, R B6 is hydrogen. In some embodiments, R B6 is an optionally substituted Ci-6 aliphatic. In some embodiments, R B6 is Ci-6 aliphatic or optionally substituted -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or Ci-6 aliphatic.
  • R B7 is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, R B7 is hydrogen. In some embodiments, R B7 is an optionally substituted Ci-6 aliphatic. In some embodiments, R B7 is Ci-6 aliphatic. In some embodiments, R B7 is C1-3 aliphatic. In some embodiments, R B7 is methyl, ethyl, or propyl. In some embodiments, R B7 is methyl.
  • Cy B is selected from the group consisting of:
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR 7 -, - N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a 5-membered saturated or partially unsaturated heterocyclene having 1 nitrogen heteroatom, optionally substituted with - (CH 2 )O-40R 0 or -OSiR°3, wherein R° is as defined above and described in classes and subclasses herein.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR 7 -, -N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a pyrrolidinediyl optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein each R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, each R° is independently hydrogen of C1-6 aliphatic.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, -N(N0)-, -S-, or an optionally substituted cyclopropylene.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, or -S-.
  • L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NR Z -, -N(NO)-, or -S-.
  • L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NR Z -, -N(N0)-, -S-, or an optionally substituted cyclopropylene.
  • L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NR Z -, or -S-. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, -O-, -NR Z -, -N(N0)-, or -S-.
  • L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -NR Z -, or -O-. In some embodiments, L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-.
  • L is a Ci hydrocarbon chain, optionally substituted with halogen; -(CH 2 )o-4R°; -(CH 2 )o-40R°; -(CH 2 )o-4C(0)OR°; -(CH 2 )o-4N(R°) 2 ; or -(CH 2 )o- 4N(R°)C(O)OR°, wherein each R° is independently hydrogen or C1-6 aliphatic.
  • L is . In some embodiments, L is . In some embodiments, L is a Ci hydrocarbon chain, substituted with halogen. In some embodiments, L is , . In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH 2 )o-4R°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, L is . In some embodiments, L is , wherein % represents the point of attachment to Cy c . In some embodiments, L is , wherein % represents the point of attachment to Cy c . In some embodiments, L is a Ci hydrocarbon chain, substituted with
  • L is . In some embodiments, L is In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, L is In some embodiments, L is In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or C1-6 aliphatic. In some embodiments, L is In some embodiments, L is a
  • Ci hydrocarbon chain substituted with -(CH2)o-4N(R°)C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic.
  • R° is hydrogen or Ci-6 aliphatic.
  • L is an optionally substituted C2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -NR Z -, -O-, -N(N0)-, -S-.
  • L is a C2 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is independently replaced with -NR Z -, -O-, -N(N0)-, -S-.
  • L is a C2 hydrocarbon chain optionally substituted with -
  • L is a C2 hydrocarbon chain optionally substituted with -
  • L is , wherein % represents the point of attachment to Cy c In some embodiments, L is wherein % represents the point of attachment to
  • L is wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment to Cy c . In some embodiments, L is , wherein % represents the point of attachment to
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -S-.
  • L is , wherein % represents the point of attachment to Cy c .
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or Ci-6 aliphatic, and wherein 1 methylene unit is replaced
  • L is , wherein % represents the point of attachment to Cy c .
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NR Z -.
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NR Z -, wherein R z is hydrogen, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group.
  • L is , wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment to
  • L is wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment ° ⁇ N to Cy c In some embodiments, L is wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment to i H r
  • L is i , wherein % represents the point of attachment to Cy c .
  • L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)-, -NR Z -, or -O-. In some embodiments, L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NR Z -. In some embodiments, L is a C3 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic and may be further substituted with halogen, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NR Z -. In some embodiments, L
  • O is H , wherein % represents the point of attachment to Cy c .
  • L is i , wherein % represents the point of attachment to Cy c .
  • L is CF 3 , wherein % represents the point of attachment to Cy c .
  • L is optionally substituted , wherein % represents the point of attachment to Cy c . In some embodiments, L is optionally substituted wherein % represents the point of attachment to Cy c . In some embodiments, optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point of attachment to Cy c . In some embodiments, L is optionally substituted , wherein % represents the point of attachment to Cy In some embodiments, L is optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point of attachment to Cy c .
  • % represents the point of attachment to Cy c .
  • L is not , wherein % represents the point of attachment to Cy .
  • L is not , wherein % represents the point of attachment to Cy
  • L is selected from the group consisting of:
  • L is selected from the group consisting of: wherein % represents the point of attachment to Cy c .
  • L is selected from the group consisting of:
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, - N(N0)- -S-, -SO-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6- membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • L is not -NHS(O)2- % , wherein % represents the point of attachment to Cy c .
  • each R z is independently selected from hydrogen, -(CH2)o- 3OR, -(CH2)O-3C(0)OR, or an optionally substituted C1-6 aliphatic group.
  • R z is hydrogen.
  • R z is selected from -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group.
  • R z is -(CH2)o-30R.
  • R z is -(CH2)o-3C(0)OR.
  • R z is -C(O)OH.
  • R z is -C(O)OCH3.
  • R z is -C(O)OCH2CH3. In some embodiments, R z is an optionally substituted C1-6 aliphatic group. In some embodiments, R z is a Ci-6 aliphatic group optionally substituted with halogen. In some embodiments, R z is -CH2CF3. In some embodiments, R z is a C1-6 aliphatic group. In some embodiments, R z is methyl, ethyl, or propyl. In some embodiments, R z is methyl.
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is phenyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is 5-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is 5-membered heteroaryl having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is 5-membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is 5-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyrazolyl or thiazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyrazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is thiazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is 6-membered heteroaryl having 1-3 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is 6-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyridinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyrimidinyl, wherein Cy c is substituted with 0-3 -L c -R c groups. In some embodiments, Cy c is pyrazinyl, wherein Cy c is substituted with 0-3 -L c -R c groups. In some embodiments, Cy c is pyridazinyl, wherein Cy c is substituted with 0-3 -L c -R c groups.
  • Cy c is selected from the group consisting of:
  • Cy c is not
  • Cy c is an 8- to 10-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is an 8-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 10-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is indazolyl, benzotriazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro-2//-benzo[/>][l,4]oxazinyl, or dihydro-2//- benzo[Z>][l,4]oxazinonyl, substituted with 0-6 -L c -R c groups.
  • Cy c is indazolyl, substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is benzotriazolyl, substituted with 0-4 -L c -R c groups.
  • Cy c is naphthalenyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is quinolinyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is isoquinolinyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is quinoxalinyl, substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is quinazolinyl, substituted with 0-5 -L c -R c groups.
  • Cy c is tctrahydro-2//- benzo[Z>][l,4]oxazinyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is dihydro-277-benzo[£>][l,4]oxazinonyl, substituted with 0-6 -L c -R c groups.
  • Cy c is a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is a 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 2-3 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 9-membered heteroaryl having 1 nitrogen heteroatom, wherein Cy c is substituted with 0-6 -L c - R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 3 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c - R c groups.
  • Cy c is a 9-membered heteroaryl having 4 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1 oxygen heteroatom, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1 sulfur heteroatom, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 9-membered heteroaryl having 1 nitrogen and 1 sulfur heteroatoms, wherein Cy c is substituted with 0-6 -L c - R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1 nitrogen and 1 oxygen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is a 10-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a
  • Cy c is a 10-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is imidazopyridinyl, wherein Cy c is substituted with 0-5 - L c -R c groups.
  • Cy c is pyrazolopyridinyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is indazolyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is pyrrolopyridinyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is benzoimidazolyl, wherein Cy c is substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is triazolopyridinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is imidazopyridazinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is imidazopyrimidinyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is imidazopyrimidinonyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is benzotriazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is triazolopyrimidinyl, wherein Cy c is substituted with 0-3 -L c -R c groups. . In some embodiments, Cy c is triazolopyridazinyl, wherein Cy c is substituted with 0-3 -L c -R c groups.
  • Cy c is benzothiophenyl, wherein Cy c is substituted with 0-5 -L c - R c groups. In some embodiments, Cy c is benzothiozolyl, wherein Cy c is substituted with 0-4 - L c -R c groups. In some embodiments, Cy c is thienopyridinyl, wherein Cy c is substituted with 0-
  • Cy c is benzofuranyl, wherein Cy c is substituted with 0-
  • Cy c is benzooxazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is pyrazolopyrimidinyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is imidazopyrazinyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is quinolinyl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is isoquinolinyl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is quinazolinyl, wherein Cy c is substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is naphthyridinyl, wherein Cy c is substituted with 0-5 -L c - R c groups.
  • Cy c is selected from the group consisting of: [0167] In some embodiments, Cy c is selected from the group consisting of:
  • Cy c is selected from the group consisting of:
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is not T (LC - RC)C - 5
  • Cy c is pyrazolopyridinyl, indazolyl, pyrrol opyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is not imidazopyridinyl substituted with 0-6 -L c -R c groups.
  • Cy c is selected from the group consisting of:
  • each L c is independently selected from a covalent bond or an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-.
  • a single instance of L c is a covalent bond.
  • a single instance of L c is an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-.
  • a single instance of L c is an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O- or -NR-.
  • L c is optionally substituted with -(CH2)o-4R°, wherein R° is independently as defined above and described in classes and subclasses herein.
  • R° is hydrogen or Ci-6 aliphatic.
  • a single instance of L c is selected from the group consisting of: *-NH-, *-NCHs-, *-O-, *-CH 2 -, *-CH 2 C(CH3) 2 -, *-CH 2 CH 2 -, *-CH 2 C(O)N(CH3)-, *-CH 2 C(O)N(CH3)CH 2 -, *-CF 2 -, *-CH(CH 3 )-, *-OCH 2 -, *-OCF 2 -, *-OC(CH 3 ) 2 -, *-CH 2 C(O)-, *-OCH 2 C(O)-, *-CH 2 C(O)NH-,*-CH 2 C(O)NHCH 2 -,*-N(CH 3 )C(O)-, *-C(CH 2 CH3)-, *-C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-NCH3-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-O-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(CH3) 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 CH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(O)N(CH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(O)N(CH3)CH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CF 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH(CH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-OCH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *- OCF 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-OC(CH3) 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(O)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-OCH2C(O)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH2C(0)NH-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH2C(O)NHCH2-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-N(CH3)C(0)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-C(CH2CH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-C(CHCH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-C(FCH3)-, wherein * represents the point of attachment to Cy c .
  • each R c is independently selected from oxo, halogen, -CN, - C(O)R, -C(O) 2 R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O) 2 R, -S(O)N(R) 2 , -S(O) 2 N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membere
  • each R c is independently selected from oxo, halogen, -CN, - C(O)2R, -C(O)N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • a single instance of R c is selected from oxo, halogen, -CN, -C(O)2R, -OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • a single instance of R c is oxo. In some embodiments, a single instance of R c is halogen. In some embodiments, a single instance of R c is fluorine. In some embodiments, a single instance of R c is chlorine. In some embodiments, a single instance of R c is bromine. In some embodiments, a single instance of R c is -CN. In some embodiments, a single instance of R c is -C(O)2R. In some embodiments, a single instance of R c is -COOH. In some embodiments, a single instance of R c is -C(O)OCH3.
  • a single instance of R c is -C(O)OCH2CH3. In some embodiments, a single instance of R c is -OR. In some embodiments, a single instance of R c is -OH. In some embodiments, a single instance of R c is -OMe. In some embodiments, a single instance of R c is -C(O)N(R)2. In some embodiments, a single instance of R c is -C(O)NH2. In some embodiments, a single instance of R c is -C(O)NHCH3. In some embodiments, a single instance of R c is -C(O)N(CH3)2. In some embodiments, a single instance of R c is -C(O)N(CH2CH3)2.
  • a single instance of R c is an optionally substituted Ci-6 aliphatic. In some embodiments, a single instance of R c is Ci-6 aliphatic optionally substituted with halogen. In some embodiments, a single instance of R c is Ci-6 aliphatic optionally substituted with fluorine. In some embodiments, a single instance of R c is -CF3. In some embodiments, a single instance of R c is -CHF2. In some embodiments, a single instance of R c is methyl. In some embodiments, a single instance of R c is ethyl. In some embodiments, a single instance of R c is isopropyl.
  • a single instance of R c is -CHCHCH3. In some embodiments, a single instance of R c is -CHC(CH3)2. In some embodiments, a single instance of R c is butyl. In some embodiments, a single instance of R c is n-butyl.
  • a single instance of R c is an optionally substituted phenyl. In some embodiments, a single instance of R c is phenyl.
  • a single instance of R c is an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of R c is an optionally substituted cyclopropyl. In some embodiments, a single instance of R c is cyclopropyl, optionally substituted with -(CH2)o-4R°, -(CH2)o-4N(R°)C(0)R°, or
  • R° is hydrogen or Ci-6 aliphatic (e.g., methyl).
  • R c is cyclopropyl.
  • R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In H ? some embodiments, a single instance of R c is A . In some embodiments, a single instance of R c is In some embodiments, Cy c is substituted with 1-6 -L c -R c groups, wherein a single instance of R c is cyclopropyl.
  • a single instance of R c is an optionally substituted 5- or 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of R c is an optionally substituted pyrazolyl.
  • a single instance of R c is pyrazolyl, optionally substituted with -(CH2)O-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is an optionally substituted imidazolyl.
  • a single instance of R c is imidazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom. In some embodiments, a single instance of R c is an optionally substituted thiazolyl. In some embodiments, a single instance of R c is thiazolyl. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxazolyl. In some embodiments, a single instance of R c is oxazolyl.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxadiazolyl. In some embodiments, a single instance of R c is oxadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of R c is oxadiazolyl.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 2 nitrogen heteroatoms and 1 sulfur heteroatom.
  • a single instance of R c is an optionally substituted thiadiazolyl.
  • a single instance of R c is thiadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is thiadiazolyl.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 3 nitrogen heteroatoms.
  • a single instance of R c is an optionally substituted triazolyl.
  • a single instance of R c is triazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is triazolyl.
  • a single instance of R c is an optionally substituted 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted pyridinyl.
  • a single instance of R c is pyridinyl, optionally substituted with halogen or -(CH2)o- 4R 0 ; wherein R° is C1-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of R c is an optionally substituted pyridinonyl.
  • a single instance of R c is pyridinonyl, optionally substituted with halogen or -(CH2)o-4R°; wherein R° is C1-6 aliphatic (e.g., methyl, ethyl, or cyclopropyl), wherein R° may be further substituted with halogen (e.g., fluorine).
  • a single instance of R c is pyridinonyl.
  • a single instance of R c is an optionally substituted pyrimidinyl. In some embodiments, a single instance of R c is pyrimidinyl. In some embodiments, a single instance of R c is an optionally substituted pyrazinyl. In some embodiments, a single instance of R c is pyrazinyl.
  • a single instance of R c is an optionally substituted 6- membered heteroaryl having 2 nitrogen heteroatoms.
  • a single instance of R c is selected from the group consisting of
  • a single instance of R c is an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • a single instance of R c is an optionally substituted 4- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted azetidinyl. In some embodiments, a single instance of R is x . In some embodiments, a single instance of R c is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom.
  • a single instance of R c is an optionally substituted pyrrolidinyl. In some embodiments, a single instance of R c is pyrrolidinyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl).
  • a single instance of R c is . In some embodiments, a single instance of R c is an optionally substituted pyrrolidinonyl. In some embodiments, a single instance of R c some embodiments, a single instance of R c is an optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted piperidinyl. In some embodiments, a single instance of R c is In some embodiments, a single instance of R c is an optionally substituted piperidinonyl. In some embodiments, a single instance of R c is
  • a single instance of R c is an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxetanyl. In some embodiments, a single instance of R c is oxetanyl, optionally substituted with halogen or -(CH2)o-40R°, wherein R° is hydrogen or Ci-6 aliphatic (e.g., methyl).
  • a single instance of R c is In some embodiments, a single instance
  • a single instance of R c is an optionally substituted 5- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxazolidinonyl. In some embodiments, a single instance of R c
  • a single instance of R c is an optionally substituted 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted morpholinyl. In some embodiments, a single instance of R c is . In some embodiments, a single instance of R is an optionally substituted morpholinonyl. In some embodiments, a single instance of R c is o
  • a single instance of R c is an optionally substituted 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.
  • a single instance of R c is an optionally substituted azabicyclo[3.1.0]hexanyl.
  • a single instance of R c is azabicyclo[3.1.0]hexanyl, optionally substituted with halogen, -(CH2)o-4R°, -(CH2)o-40R°,
  • R° is hydrogen or Ci-6 aliphatic (e g., methyl), wherein R° may be further substituted with halogen (e.g., fluorine).
  • a single instance of R c is In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is ’
  • a single instance of R c is N O ⁇ F i n some embodiments, a single H instance of R c is H . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c . In some embodiments, a single instance of R c . In some embodiments, a single instance of R c is . , some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance
  • a single instance of R c is an optionally substituted 7- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 7-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.
  • a single instance of R c is an optionally substituted 3- azabicyclo[3.1.1]heptanyl. In some embodiments, a single instance of R is
  • a single instance of R c is an optionally substituted 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of R c is an optionally substituted 5- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of R c is an optionally substituted 5- membered saturated bicyclic carbocyclyl. In some embodiments, a single instance of R c is bicycle[l. l.l]pentanyl. In some embodiments, a single instance of R c is
  • a single instance of R c is an optionally substituted 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a single instance of R c is an optionally substituted 9-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a single instance of R c is an optionally substituted 9-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of R c is an optionally substituted imidazopyridinyl.
  • a single instance of R c is [0209]
  • a provided compound is of Formula (Il-a) or (Il-b): or a pharmaceutically acceptable salt thereof, wherein each of Cy A , Cy c , L, L’, R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and R B7 is defined and described in classes and subclasses herein, both singly and in combination.
  • a provided compound is of Formula (Ill-a), (Ill-b), (III-c), or
  • a provided compound is of Formula (III-a-1), (III-a-2), or (III- a-3):
  • a provided compound is of Formula (III-b-1), (III-b-2), or (III- b-3):
  • a provided compound is of Formula (IV), (IV-a), (IV-b), or
  • a provided compound is of Formula (V-a), (V-b), or (V-c):
  • a provided compound is of Formula (Vl-a), (Vl-b), or (VI-c):
  • a provided compound is of Formula (Vll-a), (Vll-b), or (VII- c):
  • a provided compound is of Formula (Vlll-a), (VIILb), or (VIII-c):
  • a provided compound is of Formula (IX-a), (IX-b), or (IX-c):
  • a provided compound is of Formula (X-a), (X-b), or (X-c): or a pharmaceutically acceptable salt thereof, wherein each of Cy A , Cy c , L’, R B1 , and R B2 is defined and described in classes and subclasses herein, both singly and in combination. It will be understood that the connection between Cy A and Cy c in each of Formula (X-a), (X-b), and (X-c) is a methylene.
  • a provided compound is of Formula (Xl-a), (Xl-b), or (XI-c): or a pharmaceutically acceptable salt thereof, wherein each of Cy A , Cy c , L’, R B1 , and R B2 is defined and described in classes and subclasses herein, both singly and in combination.
  • a provided compound is of Formula (Xll-a), (Xll-b), or (XII- c):
  • a provided compound is of Formula (Xlll-a), (XIILb), or (XIII-c):
  • a provided compound is of Formula (XlV-a), (XlV-b), or (XIV-c):
  • a provided compound is of Formula (XVI-a), (XVI-b), or (XVI-c):
  • a compound is 2-((2S,4R)-4-amino-l-(6-chloroimidazo[l,2- a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • a compound is not 2-((2S,4R)-4-amino-l-(6- chloroimidazo[l,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin- 6-yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • a compound is selected from:
  • a compound is selected from:
  • the present invention provides pharmaceutical compositions comprising a compound of Formulae (I)-(XVI-c) or a compound of Formulae (I)-(XVI-c) in combination with a pharmaceutically acceptable excipient (e.g., carrier).
  • a pharmaceutically acceptable excipient e.g., carrier
  • the pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein.
  • a compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition may be covalently attached to a carrier moiety, as described above.
  • a compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition is not covalently linked to a carrier moiety.
  • a “pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent.
  • suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • the compounds of the invention can be administered alone or can be coadministered to the subject. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
  • test agent as described herein can be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and described herein for provided compounds.
  • Compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms.
  • the compounds of the present invention can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally).
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the invention.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit dosages.
  • the compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches.
  • Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as well-known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • such compositions when administered in methods to treat HAE, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g. inhibiting PKa and/or decreasing the amount of bradykinin in a subject).
  • the dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to PKa inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
  • the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing PKa enzymatic activity as measured, for example, using the methods described.
  • Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring PKa inhibition and adjusting the dosage upwards or downwards, as described above.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.
  • compounds provided herein display one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, ti/2, AUC, CL, bioavailability, etc.) when compared to a reference compound.
  • PK pharmacokinetic
  • a reference compound is a PKa inhibitor known in the art.
  • a reference compound is a PKa inhibitor selected from those disclosed in PCT Publication Number WO 2019/178129.
  • the present disclosure provides compounds for use in medicine.
  • the present disclosure further provides the use of any compounds described herein for inhibiting the activity of PKa, which would be beneficial to treatment of PKa-mediated diseases and conditions.
  • Exemplary PKa-mediated disorders include edema, which refers to swelling in the whole body of a subject or a part thereof due to inflammation or injury when small blood vessels become leaky and releases fluid into nearby tissues.
  • the edema is HAE.
  • the edema occurs in eyes, e.g., diabetic macular edema (DME).
  • DME diabetic macular edema
  • the present disclosure provides methods of inhibiting the activity of PKa.
  • the application provides a method of inhibiting the activity of PKa in vitro via contacting any of the compounds described herein with PKa molecules in a sample, such as a biological sample.
  • the application provides a method of inhibiting the activity of PKa in vivo via delivering an effective amount of any of the compounds described herein to a subject in need of the treatment through a suitable route.
  • the methods comprise administering to a subject in need thereof (e.g., a subject such as a human patient with edema) any of the compounds described herein or a pharmaceutically acceptable salt thereof.
  • the methods comprise administering a compound of Formulae (I)-(XVI-c), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof.
  • the method comprises administering a pharmaceutical composition comprising a compound of Formulae (I)- (XVI-c), or a pharmaceutically acceptable salt to a subject in need thereof.
  • the subject to be treated by any of the methods described herein is a human patient having, suspected of having, or at risk for edema, for example, HAE or diabetic macular edema (DME).
  • a subject having an edema can be identified by routine medical examination, e.g., laboratory tests.
  • a subject suspected of having an edema might show one or more symptoms of the disease/disorder.
  • a subject at risk for edema can be a subject having one or more of the risk factors associated with the disease, for example, deficiency in Cl -INH as for HAE.
  • provided herein are methods of alleviating one or more symptoms of HAE in a human patient who is suffering from an HAE attack. Such a patient can be identified by routine medical procedures. An effective amount of one or more of the provided compounds can be given to the human patient via a suitable route, for example, those described herein.
  • the compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKa inhibitor (e.g., ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).
  • a Cl esterase inhibitor e.g., Cinryze® or Berinert®
  • PKa inhibitor e.g., ecallantide or lanadelumab
  • a bradykinin B2 receptor antagonist e.g., Firazyr®
  • a human HAE patient who is in quiescent stage can be identified based on various factors, including history of HAE attack.
  • An effective amount of one or more of the compounds can be given to the human patient via a suitable route, for example, those described herein.
  • the compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKa inhibitor (e.g, ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).
  • prophylactic treatment of HAE in human patients having risk to HAE attacks with one or more of the compounds described herein are human subjects suffering from HAE (e.g., having history of HAE attacks).
  • patients suitable for such prophylactic treatment are human subjects where a physician determines a history of HAE attacks warrants a prophylactic approach (e.g., human subjects experiencing more than a particular average number of attacks over a time period, including by way of nonlimiting example, one, two, or more attacks per month).
  • patients suitable for the prophylactic treatment may be human subjects having no HAE attack history but bearing one or more risk factors for HAE (e.g, family history, genetic defects in Cl -INH gene, etc.)
  • prophylactic treatment may involve the compounds described herein as the sole active agent, or involve additional anti-HAE agents, such as those described herein.
  • a subject e.g., a human patient
  • the human patient is a diabetic having, suspected of having, or at risk for diabetic macular edema (DME).
  • DME is the proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leak, and retinal thickening in diabetes mellitus due to leaking of fluid from blood vessels within the macula.
  • an effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof may be delivered into the eye of the subject where treatment is needed.
  • the compound may be delivered topically, by intraocular injection, or intravitreal injection.
  • a subject may be treated with the compound as described herein, either as the sole active agent, or in combination with another treatment for DME.
  • treatment for DME include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and/or anti-PDGF agents.
  • the methods disclosed herein comprise administering to the subject an effective amount of a compound of Formulae (I)-(VLb), or a pharmaceutically acceptable salt or composition thereof.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the subject being treated is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject is a mammal.
  • the subject being treated is a human.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • a rodent e.g., mouse, rat
  • dog e.g., dog
  • pig e.g., dog
  • non-human primate e.g., non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal.
  • Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein.
  • the additional pharmaceutical agent(s) may be administered at the same time as the compound of Formulae (I)- (XVI-c), or at different times than the compound of Formulae (I)-(XVI-c).
  • the compound of Formulae (I)-(XVl-c) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules.
  • All or some doses of the compound of Formulae (I)-(XVI-c) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof.
  • the timing of administration of the compound of Formulae (I)-(XVI-c) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.
  • the additional pharmaceutical agent comprises an agent useful in the treatment of an edema, such as HAE or DME. Examples of such agents are provided herein.
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups; each R A is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, -OC(O)R, -OC(O)N
  • L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each R z is independently selected from hydrogen, -(CH 2 )o-30R, -(CH 2 )o-3C(0)OR, or an optionally substituted C1-6 aliphatic group; wherein: each of R B1 and R B2 is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;
  • R B3 is hydrogen or C1-6 aliphatic
  • R B4 is -N(R X ) 2
  • each R x is independently selected from hydrogen, -C(O)R, -C(O) 2 R, or optionally substituted C1-6 aliphatic. wherein no more than one of R B1 or R B2 is hydrogen; or wherein:
  • R B5 is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of R B6 and R B7 is independently hydrogen or an optionally substituted Ci-6 aliphatic;
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups; each L c is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each R c is independently selected from oxo, halogen, -CN, -C(O)R,
  • VIILa (Vlll-b), or (VIILc):
  • each R x is independently selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.
  • R B5 is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl.
  • Cy A is a 5- to 6- membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of phenylene, thiazolediyl, pyridinediyl, pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadiazolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 10- membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 7- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • each R A is independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.
  • Cy c is indazolyl, benzotri azolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro- 2J/-benzo[Z>][l,4]oxazinyl, or dihydro-2/f-benzo[6][l,4]oxazinonyl, substituted with 0-6 -L c -R c groups.
  • Cy c is a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cy c is substituted with 0-6 -L c - R c groups.
  • L c is selected from the group consisting of: *-NH-, *-NCH 3 -, *-O-, *-CH 2 -, *-CH 2 C(CH 3 ) 2 -, *-CH 2 CH2-, *-CH 2 C(O)N(CH 3 )-, *-CH 2 C(O)N(CH 3 )CH 2 -, *-CF 2 -, *-CH(CH 3 )-, *-OCH 2 -, *-OCF 2 -, *-OC(CH 3 ) 2 -, *-CH 2 C(O)-, *-OCH 2 C(O)-, *-CH 2 C(O)NH-,*-CH 2 C(O)NHCH 2 -,*-N(CH 3 )C(O)-, *-C(CH 2 CH 3 )-, *- C(CHCH 3 )-, *-C(FCH 3 )-, wherein * represents the point of attachment
  • each R c is independently selected from oxo, halogen, -CN, -C(O)2R, -C(0)N(R)2, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3 - to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • a pharmaceutical composition comprising a compound of any one of the preceding embodiments.
  • composition comprising a compound of any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.
  • composition of embodiment 68 or 69, wherein the composition is suitable for oral administration.
  • a method of treating hereditary angioedema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.
  • 75. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.
  • the Examples describe compounds comprising one or more stereocenters, where a particular stereocenter is designated “S*” or “R* ”
  • a particular stereocenter is designated “S*” or “R* ”
  • the depiction of the generally indicates that the exact configuration is unknown (e.g., for a compound with a single stereocenter, the depiction R*- or S*- indicates that either the R- or S- isomer was isolated, but the configuration at the stereocenter of the particular isomer isolated was not determined).
  • a compound denoted “(1S*,2S*)-” or “(1R*,2R*)-” would be understood to refer specifically to either the “(1S,2S)-” or “(1R,2R)-” isomer, but not the “(1 S,2R)-” or “(1R,2S)-” isomers.
  • a compound denoted “rac-(lS*,2S*)-” or “rac-(lR*,2R*)-” would be understood to include a racemic mixture of the “(1S,2S)-” and “(1R,2R)-” isomers.
  • a compound denoted “(1S*,2R*)-” or “(1R*,2S*)-” would be understood to refer specifically to either the “(1R,2S)-” or “(1S,2R)-” isomer, but not the “(1S,2S)-” or “(1R,2R)-” isomers.
  • a compound denoted “rac-(lR*,2S*)-” or “rac-(lS*,2R*)-” would be understood to include a racemic mixture of the “(1R,2S)-” and “(1S,2R)-” isomers.
  • the Examples include schemes that depict compounds with one or more stereocenters.
  • the symbol followed by a number appears adjacent to a stereocenter.
  • it is understood to include a mixture of both configurations (e.g., R- and S-) at that position.
  • the term “or” followed by a number appears adjacent to a stereocenter. In such cases, it is understood to denote either an “R-” or “S-” isomer, but the particular isomer was not determined.
  • the numbering following the symbol or term “or” refers to one stereocenter’s relation to another stereocenter in that compound.
  • two stereocenters in a compound are each denoted with the same number (e.g., two instances of “&1”), it is understood that the configurations are relative to each other (e.g., if the structure is drawn as (S,S) and both stereocenters are denoted “&1”, it is understood to include a mixture of the (S,S) and (R,R) isomers, but not the (S,R) or (R,S) isomers).
  • each stereocenter is denoted with a different number (e.g., one instance of “&1” and one instance of “&2”)
  • the configurations may be independent to each other (e.g., if the structure is drawn (S,S) and one stereocenter is denoted “&1” and one is denoted “&2,” it is understood to include a mixture of the (S,S), (S,R), (R,S), and (R,R) isomers).

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Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics for the same.The present invention provides isoquinoline derivatives of formula (I), wherein CyB is formula (II) or formula (III) as plasma kallikrein (PKa) inhibitors for use in methods of treatment of hereditary angioedema (HAE) or diabetic macular edema (DME). Preferred compounds are e.g. N-((isoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide derivatives and similar compounds.

Description

INHIBITORS OF PLASMA KALLIKREIN
I. BACKGROUND OF THE INVENTION
[0001] Plasma Kallikrein (PKa) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor Xlla, and contributes to the innate inflammatory response and intrinsic cascade of blood coagulation. The mechanisms that lead to the activation of this pathway in vivo include interactions with polyphosphates released from activated platelets and deficiency of Cl inhibitor (Cl -INH), the primary physiological inhibitor of PKa. PKa- mediated cleavage of high-molecular weight kininogen generates the potent vasodilator and pro- inflammatory nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor.
Subsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the Bl receptor. Both Bl and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers. Activation of Bl and B2 receptors causes vasodilation and increases vascular permeability.
[0002] PKa is also associated with a number of disorders, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. Prevalence for HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons without known differences among ethnic groups. HAE is caused by deficient (Type I) or dysfunctional (Type II) levels of Cl -INH, which inhibits PKa, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) are deficient in Cl -INH and consequently undergo excessive bradykinin generation, which in turn cause painful, debilitating, and potentially fatal swelling attacks. If left untreated, HAE can result in a mortality rate as high as 40% primarily due to upper airway obstruction.
II. SUMMARY OF THE INVENTION
[0003] The present disclosure is based on, at least in part, the development of a number of compounds which bind to plasma kallikrein and effectively inhibit its activity. Accordingly, provided herein are compounds and uses thereof for targeting plasma kallikrein and/or treating plasma kallikrein-mediated diseases and disorders. [0004] In some embodiments, the present invention provides a compound of Formula (I): CyB— L'— CyA— L— Cyc
(I) or a pharmaceutically acceptable salt thereof, wherein each of CyA, CyB, Cyc, L, and L’ is defined and described in classes and subclasses herein, both singly and in combination. In certain embodiments, the present invention provides compounds of Formulae (I)-(XVI-c), as defined and described in classes and subclasses herein.
[0005] In some embodiments, the present invention provides a compound of Formula (I): CyB— U— CyA— L— Cyc
(F)
[0006] or a pharmaceutically acceptable salt thereof, wherein each of CyA, CyB, Cyc, L, and L’ is defined and described in classes and subclasses herein, both singly and in combination.
[0007] In some embodiments, the present invention also provides methods of using compounds of Formulae (I)-(XVI-c).
III. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
A. Definitions
[0008] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0009] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0010] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0011] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).
[0012] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.
[0013] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
[0014] The term “halogen” means F, Cl, Br, or I.
[0015] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, an 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
[0016] The terms “heteroaryl” and “heteroar-” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 7t electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a bivalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/7- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
[0017] As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in this context in reference to a ring atom, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2//-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in A-substitutcd pyrrolidinyl).
[0018] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 37/-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
[0019] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
[0020] As used herein and unless otherwise specified, the suffix “-ene” is used to describe a bivalent group. Thus, any of the terms above can be modified with the suffix “-ene” to describe a bivalent version of that moiety. For example, a bivalent carbocycle is “carbocycylene”, a bivalent aryl ring is “arylene”, a bivalent benzene ring is “phenylene”, a bivalent heterocycle is “heterocyclylene”, a bivalent heteroaryl ring is “heteroarylene”, a bivalent alkyl chain is “alkylene”, a bivalent alkenyl chain is “alkenylene”, a bivalent alkynyl chain is “alkynylene”, and so forth.
[0021] As described herein, compounds of the invention may, when specified, contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are
Figure imgf000008_0001
in a polycyclic ring system, substituents may, unless otherwise indicated, replace a hydrogen on any individual ring (e.g.,
Figure imgf000008_0002
). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
[0022] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CFUlo-rOR0; -0(CH2)o-4R°, - 0(CH2)O-4C(0)OR°; -0(CH2)O-40R°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CfUjcwPh, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(0)R0; -N(R°)C(S)R°; -(CH2)O- 4N(R°)C(0)NRO 2; -N(RO)C(S)NRO 2; -(CH2)O-4N(R0)C(0)OR°; -N(R°)N(R°)C(O)R°; - N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)O-4C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; - (CH2)O-4C(0)SR°; - (CH2)o-4C(0)OSiR°3; -(CH2)o-40C(0)R°; -OC(0)(CH2)o.4SR°, -SC(S)SR°; - (CH2)O-4SC(0)R°; -(CH2)O-4C(0)NR°2; -C(S)NRO 2; -C(S)SR°; -SC(S)SR°, -(CH2)O-40C(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(0)CH2C(0)R°; -C(NOR°)R°; -(CH2)o-4SSR°; -(CH2)o- 4S(O)2R°; -(CH2)O-4S(0)2OR°; -(CH2)O-40S(0)2R°; -S(0)2NRO 2; - (CH2)o.4S(0)R°; - N(R°)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO 2; -P(O)2RO; -P(O)RO 2; -OP(O)RO 2; - OP(O)(OR°)2; SiR°2; -0SiR°3, -(Ci-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0023] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o-2OH, -(CH2)o-2OR*, -(CH2)o-2CH(OR*)2; -O(haloR’), - CN, -N3, -(CH2)O-2C(0)R*, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR*, -(CH2)O-2SR*, -(CH2)O-2SH, - (CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR’i, -C(O)SR* -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci- 4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.
[0024] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR# 2, =NNHC(O)R#, =NNHC(0)0R#, =NNHS(O)2R#, =NR#, =N0R#, -O(C(R# 2))2-3O-, or -S(C(R# 2))2-3S-, wherein each independent occurrence of R# is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR# 2)2-3O-, wherein each independent occurrence of R# is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0025] Suitable substituents on the aliphatic group of R# include halogen, -R*, - (haloR*), - OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0026] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rf, -NR’h, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O)Rf, -S(O)2Rf, - S(O)2NRT 2, -CfSjNR’h, -C(NH)NR1’2, or -N(Rt)S(O)2Rt; wherein each R? is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0027] Suitable substituents on the aliphatic group of R' are independently halogen, -R*, - (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0028] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. [0029] In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
[0030] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
[0031] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.
[0032] The symbol “ ”, except when used as a bond to depict unknown or mixed stereochemistry, denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
[0033] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.
[0034] A “dosing regimen” (or “therapeutic regimen”), as that term is used herein, is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
[0035] As will be understood from context, a “reference” compound is one that is sufficiently similar to a particular compound of interest to permit a relevant comparison. In some embodiments, information about a reference compound is obtained simultaneously with information about a particular compound. In some embodiments, information about a reference compound is historical. In some embodiments, information about a reference compound is stored, for example in a computer-readable medium. In some embodiments, comparison of a particular compound of interest with a reference compound establishes identity with, similarity to, or difference of the particular compound of interest relative to the compound.
[0036] As used herein, the phrase “therapeutic agent” refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject.
[0037] As used herein, the term “therapeutically effective amount” refers to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease. A therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple unit doses. For any particular therapeutic agent, a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and/or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and/or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts. [0038] As used herein, the term “treatment” (also “treat” or “treating”) refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
B. Compounds
[0039] In some embodiments, a provided compound is of Formula (I): CyB— L'— CyA— L— Cyc
(I) or a pharmaceutically acceptable salt thereof, wherein:
CyA is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyA is substituted with 0-4 -RA groups; each RA is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, - SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur; each R is independently hydrogen or an optionally substituted Ci-6 aliphatic group;
L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each Rz is independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group;
Figure imgf000014_0001
wherein: each of RB1 and RB2 is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;
RB3 is hydrogen or C1-6 aliphatic;
RB4 is -N(RX)2; each Rx is independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. wherein no more than one of RB1 or RB2 is hydrogen; or
Figure imgf000014_0002
wherein:
RB5 is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of RB6 and RB7 is independently hydrogen or an optionally substituted Ci-6 aliphatic;
L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
Cyc is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups; each Lc is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each Rc is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl, or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
[0040] In some embodiments, a provided compound is of Formula (!'):
CyB— L'— CyA— L— Cyc
(F) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, and L’ is defined and described in classes and subclasses herein, both singly and in combination; and CyB is an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
[0041] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (I'), embodiments of variables CyA, Cyc, L, and L’ as defined above and described in classes and subclasses herein, also apply to compounds of Formula (I'), both singly and in combination
[0042] In some embodiments, CyA is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyA is substituted with 0-4 -RA groups.
[0043] In some embodiments, CyA is a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups.
[0044] In some embodiments, CyA is phenylene, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is phenylene, wherein CyA is substituted with 0-2 -RA groups. [0045] In some embodiments, CyAis a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups.
[0046] In some embodiments, CyAis a 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyAis a 6-membered monocyclic heteroarylene having 1-3 nitrogen heteroatoms, wherein CyA is substituted with 0-4 RA groups. In some embodiments, CyAis a pyridinediyl substituted with 0-3 RA groups. In some embodiments, CyA is a pyrimidinediyl substituted with 0-2 RA groups. In some embodiments, CyA is a pyridazinediyl substituted with 0-2 RA groups. In some embodiments, CyA is a pyrazinediyl substituted with 0-2 RA groups. In some embodiments, CyA is a triazinediyl substituted with 0-1 RA groups.
[0047] In some embodiments, CyAis a 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-2 -RA groups. In some embodiments, CyA is thiazolediyl, wherein CyA is substituted with 0-1 -RA groups. In some embodiments, CyAis an unsubstituted thiadiazol ediyl. In some embodiments, CyAis an unsubstituted oxadiazolediyl. In some embodiments, CyAis an unsubstituted triazolediyl. In some embodiments, CyA is pyrrolediyl, wherein CyA is substituted with 0-2 -RA groups. In some embodiments, CyA is pyrazolediyl, wherein CyA is substituted with 0-2 -RA groups. In some embodiments, CyA is imidazolediyl, wherein CyA is substituted with 0-2 -RA groups. In some embodiments, CyA is unsubstituted pyrazolediyl. In some embodiments, CyA is unsubstituted imidazolediyl.
[0048] In some embodiments, CyA is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-4 -RA groups.
[0049] In some embodiments, CyA is an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is an 8- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 9- to 10- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups.
[0050] In some embodiments, CyA is an 8-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is an 8-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is an 8-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups.
[0051] In some embodiments, CyA is a 9-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 9-membered bicyclic heteroarylene having 1-4 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 9-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 9- membered bicyclic heteroarylene having 3 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 9-membered bicyclic heteroarylene having 4 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups.
[0052] In some embodiments, CyA is a 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 10-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 10-membered bicyclic heteroarylene having 1 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups.
[0053] In some embodiments, CyA is a 7- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups. In some embodiments, CyA is a 9-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyA is substituted with 0-1 -RA groups. In some embodiments, CyA is a 10-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyA is substituted with 0-1 -RA groups.
[0054] In some embodiments, CyAis selected from the group consisting of:
Figure imgf000019_0001
Figure imgf000020_0001
wherein * represents the point of attachment to L’.
[0055] In some embodiments, CyA is selected from the group consisting of
Figure imgf000020_0002
wherein * represents the point of attachment to L’.
[0056] In some embodiments, CyA is selected from the group consisting of
Figure imgf000020_0003
Figure imgf000021_0001
wherein * represents the point of attachment to L’.
[0057] In some embodiments, CyA is selected from the group consisting of
Figure imgf000021_0002
wherein * represents the point of attachment to L’.
[0058] In some embodiments, CyA is selected from the group consisting of:
Figure imgf000021_0003
wherein * represents the point of attachment to L’.
[0059] In some embodiments, CyA is:
Figure imgf000021_0004
wherein * represents the point of attachment to L’.
[0060] In some embodiments, CyA is phenylene, 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein CyA is substituted with 0-4 -RA groups.
[0061] In some embodiments, CyA is selected from the group consisting of phenylene, thiazolediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadi azolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein CyA is substituted with 0-4 -RA groups. [0062] In some embodiments, CyA is selected from the group consisting of:
Figure imgf000022_0001
Figure imgf000023_0001
wherein * represents the point of attachment to L’.
[0063] In some embodiments, CyA is not a 6-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, CyA is not a 6-membered monocyclic heteroarylene having 1-2 nitrogen heteroatoms. In some embodiments, CyAis not a pyridinediyl or pyrazinediyl substituted with 0-3 RA groups. In some embodiments, CyAis not a pyridinediyl substituted with 0-3 RA groups. In some embodiments, CyA is a not pyrazinediyl substituted with 0-2 RA groups. In some embodiments, CyA is not
Figure imgf000023_0003
some embodiments, CyA is not
Figure imgf000023_0002
. In some embodiments, CyA is not
Figure imgf000023_0004
[0064] In some embodiments, CyA is phenylene, 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein CyA is substituted with 0-4 -RA groups.
[0065] In some embodiments, CyAis selected from the group consisting of:
Figure imgf000024_0001
Figure imgf000025_0001
[0066] In some embodiments, CyA is not a 5-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, CyA is not a 5-membered monocyclic heteroarylene having 1 nitrogen and 1 sulfur heteroatoms. In some embodiments, CyAis not a thiazolediyl or pyrazinediyl substituted with 0-3 RA groups.
In some embodiments, CyA is not
Figure imgf000025_0002
[0067] In some embodiments, CyA is substituted with 0 -RA groups (i.e., CyA is unsubstituted).
[0068] In some embodiments, CyA is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyA is substituted with 0-4 -RA groups.
[0069] In some embodiments, CyA is not a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur substituted with 0-4 -RA groups. [0070] In some embodiments, each RA is independently selected from oxo, halogen, -CN, - C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, - OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur.
[0071] In some embodiments, each RAis independently selected from oxo, halogen, -CN, - C(O)2R, -N(R)2, -OR, -SR, -S(O)R, -S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0072] In some embodiments, each RAis independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.
[0073] In some embodiments, each RA is independently selected from halogen, -OR, or an optionally substituted C1-6 aliphatic. In some embodiments, each RA is independently selected from halogen or an optionally substituted C1-6 aliphatic. In some embodiments, each RA is independently selected from fluorine or methyl.
[0074] In some embodiments, substituents on an optionally substituted RA group are independently halogen, -(CH2)o-40R°, or -(CH2)O--IN(R0)2, wherein each R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, each R° is independently hydrogen or methyl. In some such embodiments, each R° is hydrogen.
[0075] It will be appreciated that references herein to embodiments in which “a single instance” of a substituent is defined are not limited to monosubstituted embodiments. For example, “ [i]n some embodiments, a single instance of RA is oxo” includes embodiments in which at least one instance of RA is oxo and which may comprise one or more additional RA groups as defined herein.
[0076] In some embodiments, a single instance of RA is oxo. In some embodiments, a single instance of RA is halogen. In some embodiments, a single instance of RA is fluorine. In some embodiments, a single instance of RA is chlorine. In some embodiments, a single instance of RA is -CN.
[0077] In some embodiments, a single instance of RAis -C(O)2R. In some embodiments, a single instance of RAis -C(O)2R, wherein R is hydrogen, methyl, or ethyl. In some embodiments, a single instance of RAis -C(O)2H. In some embodiments, a single instance of RAis -C(O)2CHa. In some embodiments, a single instance of RAis -C(O)2CH2CH3. In some embodiments, a single instance of RAis -C(O)N(R)2. In some embodiments, a single instance of RAis -C(O)NH2.
[0078] In some embodiments, a single instance of RA is -N(R)2. In some embodiments, a single instance of RAis -OR.
[0079] In some embodiments, a single instance of RAis Ci-6 aliphatic substituted with halogen. In some embodiments, RA is -CHF2. In some embodiments, RA is -CF3.
[0080] In some embodiments, a single instance of RA is Ci-6 aliphatic substituted with - (CH2)O-40R°, wherein R° is selected from hydrogen or C1-6 aliphatic. In some embodiments, a single instance of RA is -CH2OH. In some embodiments, a single instance of RA is -CH2OCH3. In some embodiments, a single instance of RA is C1-6 aliphatic substituted with -(CH2)o-4N(R°)2, wherein each R° is independently selected from hydrogen or C1-6 aliphatic. In some embodiments, a single instance of RA is -CH2NH2. In some embodiments, a single instance of RA is C1-6 aliphatic substituted with -(CH2)o-4C(0)OR°, wherein R° is selected from hydrogen or 0
C 1-6 aliphatic.. In some embodiments, a single instance of RA is
Figure imgf000027_0001
jn some o embodiments, a single instance of RA is
Figure imgf000027_0002
[0081] In some embodiments, a single instance of RAis methyl, ethyl, or propyl. In some embodiments, a single instance of RAis methyl.
[0082] In some embodiments, a single instance of RAis optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of RAis optionally substituted cyclopropyl.
[0083] In some embodiments, a single instance of RAis optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of RA is optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen and nitrogen. In some embodiments, a single instance of RA is optionally substituted oxetanyl. In some embodiments, a single instance of RA is oxetanyl optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, a single instance of RA is pyrrolidinyl.
[0084] In some embodiments, each RA is independently selected from halogen, -CN, - C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, - OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur.
[0085] In some embodiments, RA is not oxo.
[0086] In some embodiments, L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
[0087] In some embodiments, L’ is a covalent bond. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
[0088] In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, - NRZ-, -SO2-. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)- or -NRZ. In some embodiments, L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 methylene unit is replaced -NRZ. In some embodiments, L’ is an optionally substituted C1-3 hydrocarbon chain, wherein 1 methylene unit is replaced -NRZ. [0089] In some embodiments, L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 methylene unis is optionally and independently replaced with -NRZ-.
[0090] In some embodiments, L’ is optionally substituted with halogen. In some embodiments, L’ is optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic and may be further substituted with halogen. In some embodiments, L’ is optionally substituted with -CF3.
[0091] In some embodiments, L’ is selected from the group consisting of:
Figure imgf000029_0001
and 0 , wherein # represents the point of attachment to CyB.
[0092] In some embodiments, L’ is selected from the group consisting of:
Figure imgf000029_0002
, wherein # represents the point of attachment to CyB.
[0093] In some embodiments, L’ is
Figure imgf000029_0003
wherein # represents the point of
Figure imgf000029_0004
attachment to CyB. In some embodiments, L’ is O , wherein # represents the point of attachment to CyB.
[0094] In some embodiments, L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene. [0095] In some embodiments, L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
[0096] In some embodiments, L’ is selected from the group consisting of:
Figure imgf000030_0001
0 , wherein # represents the point of attachment to CyB.
Figure imgf000030_0002
[0097] In some embodiments, L’ is not O , wherein # represents the point of attachment to CyB.
[0098] In some embodiments, L’ is a covalent bond or an optionally substituted C2-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
[0099] In some embodiments, L’ is not -O-.
[0100] In some embodiments, CyB is an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, CyB is an optionally substituted 10-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, CyB is optionally substituted isoquinolinyl. In some embodiments, CyB is optionally substituted
Figure imgf000030_0003
. in some embodiments, CyB is optionally substituted with halogen; -(CH2)o-4R°; -(CH2)o-40R°; or -(CH2)o-4N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic.
[0101] In some embodiments,
Figure imgf000030_0004
some embodiments, CyB
Figure imgf000030_0005
, wherein no more than one of RB1 or RB2 is hydrogen. In some embodiments,
Figure imgf000031_0001
wherein RB1 is not hydrogen. In some embodiments,
Figure imgf000031_0002
, wherein RB2 is not hydrogen. In some embodiments,
CyB is
Figure imgf000031_0003
, wherein RB1 and RB2 are not hydrogen.
[0102] In some embodiments, RB1 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB1 is hydrogen or C1-6 aliphatic. In some embodiments, RB1 is hydrogen. In some embodiments, RB1 is C1-6 aliphatic. In some embodiments, RBi is methyl. In some embodiments, RB1 is ethyl. In some embodiments, RB1 is methyl, optionally substituted with halogen. In some embodiments, RB1 is -CF3. In some embodiments, RB1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB1 is an optionally substituted cyclopropyl. In some embodiments, RB1 is cyclopropyl. In some embodiments, RB1 is cyclopropyl, optionally substituted with -(CH2)O-4R0, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, RBi is
Figure imgf000031_0004
In some embodiments, RB1 is methyl, ethyl, -CF3, or
Figure imgf000031_0005
[0103] In some embodiments, RB2 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB2 is hydrogen or C1-6 aliphatic. In some embodiments, RB2 is hydrogen. In some embodiments, RB2 is C1-6 aliphatic. In some embodiments, RB2 is methyl. In some embodiments, RB2 is ethyl. In some embodiments, RB2 is methyl, optionally substituted with halogen. In some embodiments, RB2 is -CF3. In some embodiments, RB2 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB2 is an optionally substituted cyclopropyl. In some embodiments, RB2 is cyclopropyl. In some embodiments, RB2 is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, RB2 is
Figure imgf000032_0001
[0104] In some embodiments, RB1 and RB2 are the same. In some embodiments, RB1 and RB2 are different. In some embodiments, RB1 is hydrogen and RB2 is Ci-6 aliphatic. In some embodiments, RB1 is Ci-6 aliphatic and RB2 is hydrogen. In some embodiments, RB1 and RB2 are Ci-6 aliphatic. In some embodiments, RB1 is hydrogen and RB2 is methyl. In some embodiments, RB1 is methyl and RB2 is hydrogen. In some embodiments, RB1 and RB2 are methyl. In some embodiments, RB1 is methyl, ethyl, -CF3, or
Figure imgf000032_0002
and RB2 is hydrogen, methyl, ethyl, -CF3, or
Figure imgf000032_0003
In some embodiments, RB1 is hydrogen, methyl, ethyl, -CF3, or
Figure imgf000032_0004
and RB2 is methyl, ethyl, -CF3, or
Figure imgf000032_0006
In some embodiments, RB1 is methyl, ethyl, -CF3, or
Figure imgf000032_0005
, and RB2 is methyl, ethyl, -
Figure imgf000032_0007
.
[0105] Without wishing to be bound by any particular theory, it is believed that the sizes of the RB1 and/or RB2 groups influence potency without loss of binding efficiency. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB1 and/or RB2 position. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB1 position. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB2 position. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB1 and RB2 positions.
[0106] The relative size of a group (e.g., in this instance, RB1 and RB2) can be determined from the van der Waals surface and/or molecular volume calculated for that group. For a single molecule (i.e., a molecule for which there is a path between any two atoms along covalent bonds), the van der Waals surface is a closed surface, and hence, it contains volume. This volume is called the molecular volume, or van der Waals volume, and is usually given in A3. A straightforward way of calculating A-values on the computer is by numerical integration, i.e., by surrounding the van der Waals envelope with a grid of small bricks and summing up the bricks whose centers are within the van der Waals envelope of the molecule (i.e., are within a van der Waals radius from atom nucleus) (see, for example, Whitley, “Van der Waals surface graphs and molecular shape,” Journal of Mathematical Chemistry (1998) 23:377-397).
[0107] The relative size of a group can also be measured from the “A-value” for a given group. The A-value is a measure of the effective size of a given group. The “A-value” refers to the conformational energies (-G0 values) as determined for a substituted cyclohexane and the relative axial-equatorial disposition of the substituent (see Table 1, provided below, and pages 695-697 of Eliel and Wilen, Chapter 11 entitled “Configuration and Confirmation of Cyclic Molecules” of Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New
York: 1994, incorporated herein by reference). More detailed tabulations have been compiled by Hirsch, “Table of Conformational Energies”, Top. Stereochem. (1967) 1 : 199; Jensen and Bushweller, “Conformational Preferences in Cyclohexanes and Cyclohexenes”, Adv. Alicycl. Chem. (1971) 3: 139; and Schnieder and Hoppen “Carbon-13 Nuclear Magnetic Resonance
Substituent-induced Shieldings and Conformational Equilibria in Cyclohexanes”, J. Org. Chem.
(1978) 43:3866.
Table 1. Exemplary A-values.
Figure imgf000033_0001
Figure imgf000034_0001
[0108] In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 1.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 1.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 1.70 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 2.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 2.25 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 2.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 2.75 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 3.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value that is greater than about 4.0 kcal/mol (e.g., as shown in Table 1).
[0109] In some embodiments, RB1 is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).
[0110] In some embodiments, RB1 is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB1 is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1).
[0111] In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 1.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 1.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 1.70 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 2.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 2.25 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 2.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 2.75 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 3.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value that is greater than about 4.0 kcal/mol (e.g., as shown in Table 1).
[0112] In some embodiments, RB2 is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).
[0113] In some embodiments, RB2 is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB2 is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1). [0114] In some embodiments, RB3 is hydrogen or Ci-6 aliphatic. In some embodiments, RB3 is hydrogen. In some embodiments, RB3 is Ci-6 aliphatic. In some embodiments, RB3 is methyl, ethyl, or propyl. In some embodiments, RB3 is methyl.
[0115] In some embodiments, RB4 is -N(Rx)i. In some embodiments, RB4 is -NH2. In some embodiments, RB4 is -NHRX.
[0116] In some embodiments, each Rx is independently selected from hydrogen, -C(O)R, - C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, each Rx is hydrogen. In some embodiments, each Rx is independently selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, one Rx is hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic.
[0117] In some embodiments, Rx is -C(O)R. In some embodiments, Rx is -C(O)R, wherein R is C1-6 aliphatic. In some embodiments, Rx -C(O)CH3 In some embodiments, Rx is -C(O)2R. In some embodiments, Rx is -C(O)2R, wherein R is optionally substituted C1-6 aliphatic. In some embodiments, Rx is -C(O)2R, wherein R is C1-6 aliphatic optionally substituted with -(CH2)o-4Ph. In some embodiments, Rx is -C(O)2CH2Ph. In some embodiments, Rx is -C(O)2R, wherein R is C1-6 aliphatic. In some embodiments, Rx is -C(O)2R, wherein R is methyl, ethyl, isopropyl, or isobutyl. In some embodiments, Rx is -C(O)2CH2CH3. In some embodiments, Rx is - C(O)C(CH3)2. In some embodiments, Rx is -C(O)CH2C(CH3)2. In some embodiments, Rx is optionally substituted C1-6 aliphatic. In some embodiments, Rx is C1-6 aliphatic. In some embodiments, Rx is methyl, ethyl, or propyl. In some embodiments, Rx is methyl.
[0118] In some embodiments, CyB is selected from the group consisting of:
Figure imgf000037_0001
Figure imgf000038_0001
[0119] In some embodiments, CyB is selected from the group consisting of:
Figure imgf000038_0002
[0121] In some embodiments, CyB is selected from the group consisting of:
Figure imgf000039_0001
[0122]
Figure imgf000039_0002
[0123] In some embodiments,
Figure imgf000039_0003
[0124] In some embodiments, RB5 is hydrogen or Ci-6 aliphatic or an optionally substituted
3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB5 is hydrogen. In some embodiments, RB3 is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB5 is Ci-6 aliphatic. In some embodiments, RB5 is methyl, ethyl, or propyl. In some embodiments, RB5 is methyl. In some embodiments, RB5 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB3 is an optionally substituted cyclopropyl. In some embodiments, RB3 is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments,
Figure imgf000039_0004
[0125] In some embodiments, RB6 is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, RB6 is hydrogen. In some embodiments, RB6 is an optionally substituted Ci-6 aliphatic. In some embodiments, RB6 is Ci-6 aliphatic or optionally substituted -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or Ci-6 aliphatic.
[0126] In some embodiments, RB7 is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, RB7 is hydrogen. In some embodiments, RB7 is an optionally substituted Ci-6 aliphatic. In some embodiments, RB7 is Ci-6 aliphatic. In some embodiments, RB7 is C1-3 aliphatic. In some embodiments, RB7 is methyl, ethyl, or propyl. In some embodiments, RB7 is methyl.
[0127] In some embodiments, CyB is selected from the group consisting of:
Figure imgf000040_0001
[0128] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
[0129] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR7-, - N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
[0130] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a 5-membered saturated or partially unsaturated heterocyclene having 1 nitrogen heteroatom, optionally substituted with - (CH2)O-40R0 or -OSiR°3, wherein R° is as defined above and described in classes and subclasses herein. In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR7-, -N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a pyrrolidinediyl optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein each R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, each R° is independently hydrogen of C1-6 aliphatic.
[0131] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(N0)-, -S-, or an optionally substituted cyclopropylene. In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, or -S-.
[0132] In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NRZ-, -N(NO)-, or -S-. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NRZ-, -N(N0)-, -S-, or an optionally substituted cyclopropylene. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NRZ-, or -S-. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, -O-, -NRZ-, -N(N0)-, or -S-.
[0133] In some embodiments, L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -NRZ-, or -O-. In some embodiments, L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-. In some embodiments, L is a Ci hydrocarbon chain, optionally substituted with halogen; -(CH2)o-4R°; -(CH2)o-40R°; -(CH2)o-4C(0)OR°; -(CH2)o-4N(R°)2; or -(CH2)o- 4N(R°)C(O)OR°, wherein each R° is independently hydrogen or C1-6 aliphatic.
[0134] In some embodiments, L is
Figure imgf000041_0002
. In some embodiments, L is
Figure imgf000041_0001
. In some embodiments, L is a Ci hydrocarbon chain, substituted with halogen. In some embodiments, L is
Figure imgf000041_0003
, . In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, L is
Figure imgf000041_0004
. In some embodiments, L is
Figure imgf000041_0005
, wherein % represents the point of attachment to Cyc. In some embodiments, L is
Figure imgf000041_0006
, wherein % represents the point of attachment to Cyc. In some embodiments, L is a Ci hydrocarbon chain, substituted with
OH
-(CH2)O-40R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, L is
Figure imgf000041_0007
. In some embodiments, L is
Figure imgf000042_0001
In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, L is
Figure imgf000042_0002
In some embodiments, L is
Figure imgf000042_0003
In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or C1-6 aliphatic. In some embodiments, L is
Figure imgf000042_0004
In some embodiments, L is a
Ci hydrocarbon chain, substituted with -(CH2)o-4N(R°)C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments,
Figure imgf000042_0005
[0135] In some embodiments, L is an optionally substituted C2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -NRZ-, -O-, -N(N0)-, -S-. In some embodiments, L is a C2 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is independently replaced with -NRZ-, -O-, -N(N0)-, -S-. [0136] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with -
(CH2)O-4R°, wherein R° is hydrogen or CI-G aliphatic. In some embodiments, L is
Figure imgf000042_0006
[0137] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with -
(CH2)O-4R°, wherein R° is hydrogen or Ci-6 aliphatic, and wherein 1 methylene unit is replaced with -O-. In some embodiments, L is
Figure imgf000042_0007
, wherein % represents the point of attachment to Cyc In some embodiments, L is
Figure imgf000042_0008
wherein % represents the point of attachment to
Cyc In some embodiments, L is
Figure imgf000042_0009
wherein % represents the point of attachment to
Figure imgf000042_0010
Cyc. In some embodiments, L is , wherein % represents the point of attachment to Cyc. In some embodiments, L is
Figure imgf000043_0001
, wherein % represents the point of attachment to
Cyc.
[0138] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -S-. In some embodiments, L is
Figure imgf000043_0002
, wherein % represents the point of attachment to Cyc.
[0139] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or Ci-6 aliphatic, and wherein 1 methylene unit is replaced
° N with -N(N0)-. In some embodiments, L is
Figure imgf000043_0003
, wherein % represents the point of attachment to Cyc.
[0140] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NRZ-. In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NRZ-, wherein Rz is hydrogen, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group. In some embodiments, L is
Figure imgf000043_0004
, wherein % represents the point of attachment to
Cyc. In some embodiments, L is
Figure imgf000043_0005
, wherein % represents the point of attachment to
Cyc. In some embodiments, L is
Figure imgf000043_0006
wherein % represents the point of attachment to
Cyc. In some embodiments,
Figure imgf000043_0007
wherein % represents the point of attachment to
Cyc. In some embodiments, L is
Figure imgf000043_0008
, wherein % represents the point of attachment °^N to Cyc In some embodiments, L is
Figure imgf000044_0001
wherein % represents the point of attachment to
Figure imgf000044_0002
Cy r . In some embodiments, L is , wherein % represents the point of attachment to i H r | 7 %
Cy In some embodiments, L is i , wherein % represents the point of attachment to Cyc.
[0141] In some embodiments, L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)-, -NRZ-, or -O-. In some embodiments, L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NRZ-. In some embodiments, L is a C3 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic and may be further substituted with halogen, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NRZ-. In some embodiments, L
O
Figure imgf000044_0003
is H , wherein % represents the point of attachment to Cyc. In some embodiments,
O
Figure imgf000044_0004
L is i , wherein % represents the point of attachment to Cyc. In some embodiments,
Figure imgf000044_0005
L is CF3 , wherein % represents the point of attachment to Cyc.
Figure imgf000044_0006
[0142] In some embodiments, L is optionally substituted , wherein % represents
Figure imgf000044_0007
the point of attachment to Cyc. In some embodiments, L is optionally substituted wherein % represents the point of attachment to Cyc. In some embodiments,
Figure imgf000045_0001
optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point of
Figure imgf000045_0002
attachment to Cyc. In some embodiments, L is optionally substituted , wherein %
Figure imgf000045_0003
represents the point of attachment to Cy In some embodiments, L is optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point of attachment to Cyc.
In some embodiments,
Figure imgf000045_0004
wherein % represents the point of attachment to Cyc.
In some embodiments,
Figure imgf000045_0005
, wherein % represents the point of attachment to Cyc.
NH2
6 p
In some embodiments, L is not , wherein % represents the point of attachment to Cy . p
In some embodiments, L is not , wherein % represents the point of attachment to Cy
[0143] In some embodiments, L is selected from the group consisting of:
Figure imgf000046_0001
wherein % represents the point of attachment to Cyc.
[0144] In some embodiments, L is selected from the group consisting of:
Figure imgf000046_0002
wherein % represents the point of attachment to Cyc.
[0145] In some embodiments, L is selected from the group consisting of:
Figure imgf000046_0003
[0146] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, - N(N0)- -S-, -SO-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6- membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
[0147] In some embodiments, L is not -NHS(O)2-%, wherein % represents the point of attachment to Cyc.
[0148] In some embodiments, each Rz is independently selected from hydrogen, -(CH2)o- 3OR, -(CH2)O-3C(0)OR, or an optionally substituted C1-6 aliphatic group. In some embodiments, Rz is hydrogen. In some embodiments, Rz is selected from -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group. In some embodiments, Rz is -(CH2)o-30R. In some embodiments, Rz is -(CH2)o-3C(0)OR. In some embodiments, Rz is -C(O)OH. In some embodiments, Rz is -C(O)OCH3. In some embodiments, Rz is -C(O)OCH2CH3. In some embodiments, Rz is an optionally substituted C1-6 aliphatic group. In some embodiments, Rz is a Ci-6 aliphatic group optionally substituted with halogen. In some embodiments, Rz is -CH2CF3. In some embodiments, Rz is a C1-6 aliphatic group. In some embodiments, Rz is methyl, ethyl, or propyl. In some embodiments, Rz is methyl.
[0149] In some embodiments, Cyc is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0150] In some embodiments, Cyc is phenyl, wherein Cyc is substituted with 0-5 -Lc-Rc groups.
[0151] In some embodiments, Cyc is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 - Lc-Rc groups. In some embodiments, Cyc is 5-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 - Lc-Rc groups. In some embodiments, Cyc is 5-membered heteroaryl having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 - Lc-Rc groups. In some embodiments, Cyc is 5-membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is 5-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is pyrazolyl or thiazolyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is pyrazolyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is thiazolyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups.
[0152] In some embodiments, Cyc is 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 - Lc-Rc groups. In some embodiments, Cyc is 6-membered heteroaryl having 1-3 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is 6-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 - Lc-Rc groups.
[0153] In some embodiments, Cyc is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is pyridinyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is pyrimidinyl, wherein Cyc is substituted with 0-3 -Lc-Rc groups. In some embodiments, Cyc is pyrazinyl, wherein Cyc is substituted with 0-3 -Lc-Rc groups. In some embodiments, Cyc is pyridazinyl, wherein Cyc is substituted with 0-3 -Lc-Rc groups.
[0154] In some embodiments, Cyc is selected from the group consisting of:
Figure imgf000048_0001
[0155] In some embodiments, Cyc is not
Figure imgf000048_0002
Figure imgf000048_0003
[0156] In some embodiments, Cyc is an 8- to 10-membered bicyclic aryl, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is an 8-membered bicyclic aryl, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 9-membered bicyclic aryl, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 10-membered bicyclic aryl, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0157] In some embodiments, Cyc is indazolyl, benzotriazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro-2//-benzo[/>][l,4]oxazinyl, or dihydro-2//- benzo[Z>][l,4]oxazinonyl, substituted with 0-6 -Lc-Rc groups.
[0158] In some embodiments, Cyc is indazolyl, substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is benzotriazolyl, substituted with 0-4 -Lc-Rc groups.
[0159] In some embodiments, Cyc is naphthalenyl, substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is quinolinyl, substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is isoquinolinyl, substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is quinoxalinyl, substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is quinazolinyl, substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is tctrahydro-2//- benzo[Z>][l,4]oxazinyl, substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is dihydro-277-benzo[£>][l,4]oxazinonyl, substituted with 0-6 -Lc-Rc groups.
[0160] In some embodiments, Cyc is a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 - Lc-Rc groups. In some embodiments, Cyc is a 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0161] In some embodiments, Cyc is a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 - Lc-Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 2-3 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 1 nitrogen heteroatom, wherein Cyc is substituted with 0-6 -Lc- Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 3 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc- Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 4 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 1 oxygen heteroatom, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 1 sulfur heteroatom, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 1 nitrogen and 1 sulfur heteroatoms, wherein Cyc is substituted with 0-6 -Lc- Rc groups. In some embodiments, Cyc is a 9-membered heteroaryl having 1 nitrogen and 1 oxygen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0162] In some embodiments, Cyc is a 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 - Lc-Rc groups. In some embodiments, Cyc is a 10-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is a
10-membered heteroaryl having 1 nitrogen heteroatom, wherein Cyc is substituted with 0-6 -Lc- Rc groups. In some embodiments, Cyc is a 10-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0163] In some embodiments, Cyc is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0164] In some embodiments, Cyc is imidazopyridinyl, wherein Cyc is substituted with 0-5 - Lc-Rc groups. In some embodiments, Cyc is pyrazolopyridinyl, wherein Cyc is substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is indazolyl, wherein Cyc is substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is pyrrolopyridinyl, wherein Cyc is substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is benzoimidazolyl, wherein Cyc is substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is triazolopyridinyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is imidazopyridazinyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is imidazopyrimidinyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is imidazopyrimidinonyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is benzotriazolyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is triazolopyrimidinyl, wherein Cyc is substituted with 0-3 -Lc-Rc groups. . In some embodiments, Cyc is triazolopyridazinyl, wherein Cyc is substituted with 0-3 -Lc-Rc groups. In some embodiments, Cyc is benzothiophenyl, wherein Cyc is substituted with 0-5 -Lc- Rc groups. In some embodiments, Cyc is benzothiozolyl, wherein Cyc is substituted with 0-4 - Lc-Rc groups. In some embodiments, Cyc is thienopyridinyl, wherein Cyc is substituted with 0-
4 -Lc-Rc groups. In some embodiments, Cyc is benzofuranyl, wherein Cyc is substituted with 0-
5 -Lc-Rc groups. In some embodiments, Cyc is benzooxazolyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is pyrazolopyrimidinyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups. In some embodiments, Cyc is imidazopyrazinyl, wherein Cyc is substituted with 0-4 -Lc-Rc groups.
[0165] In some embodiments, Cyc is quinolinyl, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is isoquinolinyl, wherein Cyc is substituted with 0-6 -Lc-Rc groups. In some embodiments, Cyc is quinazolinyl, wherein Cyc is substituted with 0-5 -Lc-Rc groups. In some embodiments, Cyc is naphthyridinyl, wherein Cyc is substituted with 0-5 -Lc- Rc groups.
[0166] In some embodiments, Cyc is selected from the group consisting of:
Figure imgf000051_0001
[0167] In some embodiments, Cyc is selected from the group consisting of:
Figure imgf000052_0001
[0168] In some embodiments, Cyc is selected from the group consisting of:
Figure imgf000052_0002
[0169] In some embodiments,
Figure imgf000052_0003
[0170] In some embodiments, Cyc is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0171] In some embodiments, Cyc is not T (LC-RC)C-5
[0172] In some embodiments, Cyc is pyrazolopyridinyl, indazolyl, pyrrol opyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
[0173] In some embodiments, Cyc is not imidazopyridinyl substituted with 0-6 -Lc-Rc groups.
[0174] In some embodiments, Cyc is selected from the group consisting of:
Figure imgf000053_0001
[0175] In some embodiments, each Lc is independently selected from a covalent bond or an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-. [0176] In some embodiments, a single instance of Lc is a covalent bond. In some embodiments, a single instance of Lc is an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-. In some embodiments, a single instance of Lc is an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O- or -NR-.
[0177] In some embodiments, Lc is optionally substituted with -(CH2)o-4R°, wherein R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, R° is hydrogen or Ci-6 aliphatic.
[0178] In some embodiments, a single instance of Lc is selected from the group consisting of: *-NH-, *-NCHs-, *-O-, *-CH2-, *-CH2C(CH3)2-, *-CH2CH2-, *-CH2C(O)N(CH3)-, *-CH2C(O)N(CH3)CH2-, *-CF2-, *-CH(CH3)-, *-OCH2-, *-OCF2-, *-OC(CH3)2-, *-CH2C(O)-, *-OCH2C(O)-, *-CH2C(O)NH-,*-CH2C(O)NHCH2-,*-N(CH3)C(O)-, *-C(CH2CH3)-, *-C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cyc.
[0179] In some embodiments, a single instance of Lc is
Figure imgf000054_0001
wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-NCH3-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-O-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2C(CH3)2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2CH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2C(O)N(CH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2C(O)N(CH3)CH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CF2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH(CH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-OCH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *- OCF2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-OC(CH3)2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2C(O)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-OCH2C(O)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2C(0)NH-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-CH2C(O)NHCH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-N(CH3)C(0)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-C(CH2CH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-C(CHCH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lc is *-C(FCH3)-, wherein * represents the point of attachment to Cyc.
[0180] In some embodiments, each Rc is independently selected from oxo, halogen, -CN, - C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
[0181] In some embodiments, each Rc is independently selected from oxo, halogen, -CN, - C(O)2R, -C(O)N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
[0182] In some embodiments, a single instance of Rc is selected from oxo, halogen, -CN, -C(O)2R, -OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0183] In some embodiments, a single instance of Rc is oxo. In some embodiments, a single instance of Rc is halogen. In some embodiments, a single instance of Rc is fluorine. In some embodiments, a single instance of Rc is chlorine. In some embodiments, a single instance of Rc is bromine. In some embodiments, a single instance of Rc is -CN. In some embodiments, a single instance of Rc is -C(O)2R. In some embodiments, a single instance of Rc is -COOH. In some embodiments, a single instance of Rc is -C(O)OCH3. In some embodiments, a single instance of Rc is -C(O)OCH2CH3. In some embodiments, a single instance of Rc is -OR. In some embodiments, a single instance of Rc is -OH. In some embodiments, a single instance of Rc is -OMe. In some embodiments, a single instance of Rc is -C(O)N(R)2. In some embodiments, a single instance of Rc is -C(O)NH2. In some embodiments, a single instance of Rc is -C(O)NHCH3. In some embodiments, a single instance of Rc is -C(O)N(CH3)2. In some embodiments, a single instance of Rc is -C(O)N(CH2CH3)2.
[0184] In some embodiments, a single instance of Rc is an optionally substituted Ci-6 aliphatic. In some embodiments, a single instance of Rc is Ci-6 aliphatic optionally substituted with halogen. In some embodiments, a single instance of Rc is Ci-6 aliphatic optionally substituted with fluorine. In some embodiments, a single instance of Rc is -CF3. In some embodiments, a single instance of Rc is -CHF2. In some embodiments, a single instance of Rc is methyl. In some embodiments, a single instance of Rc is ethyl. In some embodiments, a single instance of Rc is isopropyl. In some embodiments, a single instance of Rc is -CHCHCH3. In some embodiments, a single instance of Rc is -CHC(CH3)2. In some embodiments, a single instance of Rc is butyl. In some embodiments, a single instance of Rc is n-butyl.
[0185] In some embodiments, a single instance of Rc is an optionally substituted phenyl. In some embodiments, a single instance of Rc is phenyl.
[0186] In some embodiments, a single instance of Rc is an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of Rc is an optionally substituted cyclopropyl. In some embodiments, a single instance of Rc is cyclopropyl, optionally substituted with -(CH2)o-4R°, -(CH2)o-4N(R°)C(0)R°, or
-(CH2)O-4N(R°)C(0)OR°; wherein R° is hydrogen or Ci-6 aliphatic (e.g., methyl). In some embodiments, a single instance of Rc is cyclopropyl. In some embodiments, a single instance of
Rc is
Figure imgf000057_0002
. In some embodiments, a single instance of Rc is
Figure imgf000057_0001
. In some embodiments, a single instance of Rc is
Figure imgf000057_0004
. In some embodiments, a single instance of Rc is
Figure imgf000057_0003
. In H ? some embodiments, a single instance of Rc is A . In some embodiments, a single instance of Rc is
Figure imgf000057_0005
In some embodiments, Cyc is substituted with 1-6 -Lc-Rc groups, wherein a single instance of Rc is cyclopropyl.
[0187] In some embodiments, a single instance of Rc is an optionally substituted 5- or 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0188] In some embodiments, a single instance of Rc is an optionally substituted 5- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 5-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of Rc is an optionally substituted pyrazolyl. In some embodiments, a single instance of Rc is pyrazolyl, optionally substituted with -(CH2)O-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rc is an optionally substituted imidazolyl. In some embodiments, a single instance of Rc is imidazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
[0189] In some embodiments, a single instance of Rc is an optionally substituted 5- membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom. In some embodiments, a single instance of Rc is an optionally substituted thiazolyl. In some embodiments, a single instance of Rc is thiazolyl. In some embodiments, a single instance of Rc is an optionally substituted 5-membered heteroaryl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted oxazolyl. In some embodiments, a single instance of Rc is oxazolyl.
[0190] In some embodiments, a single instance of Rc is an optionally substituted 5- membered heteroaryl having 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms and 1 oxygen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted oxadiazolyl. In some embodiments, a single instance of Rc is oxadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rc is oxadiazolyl.
[0191] In some embodiments, a single instance of Rc is an optionally substituted 5- membered heteroaryl having 2 nitrogen heteroatoms and 1 sulfur heteroatom. In some embodiments, a single instance of Rc is an optionally substituted thiadiazolyl. In some embodiments, a single instance of Rc is thiadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rc is thiadiazolyl.
[0192] In some embodiments, a single instance of Rc is an optionally substituted 5- membered heteroaryl having 3 nitrogen heteroatoms. In some embodiments, a single instance of Rc is an optionally substituted triazolyl. In some embodiments, a single instance of Rc is triazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rc is triazolyl.
[0193] In some embodiments, a single instance of Rc is an optionally substituted 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 6-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted pyridinyl. In some embodiments, a single instance of Rc is pyridinyl, optionally substituted with halogen or -(CH2)o- 4R0; wherein R° is C1-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rc is an optionally substituted pyridinonyl. In some embodiments, a single instance of Rc is pyridinonyl, optionally substituted with halogen or -(CH2)o-4R°; wherein R° is C1-6 aliphatic (e.g., methyl, ethyl, or cyclopropyl), wherein R° may be further substituted with halogen (e.g., fluorine). In some embodiments, a single instance of Rc is pyridinonyl.
[0194] In some embodiments, a single instance of Rc is an optionally substituted pyrimidinyl. In some embodiments, a single instance of Rc is pyrimidinyl. In some embodiments, a single instance of Rc is an optionally substituted pyrazinyl. In some embodiments, a single instance of Rc is pyrazinyl.
[0195] In some embodiments, a single instance of Rc is an optionally substituted 6- membered heteroaryl having 2 nitrogen heteroatoms.
[0196] In some embodiments, a single instance of Rc is selected from the group consisting
Figure imgf000059_0001
[0197] In some embodiments, a single instance of Rc is an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0198] In some embodiments, a single instance of Rc is an optionally substituted 4- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted
Figure imgf000059_0002
azetidinyl. In some embodiments, a single instance of R is x . In some embodiments, a single instance of Rc is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted pyrrolidinyl. In some embodiments, a single instance of Rc is pyrrolidinyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl).
In some embodiments, a single instance of Rc is
Figure imgf000060_0001
. In some embodiments, a single instance of Rc is an optionally substituted pyrrolidinonyl. In some embodiments, a single instance of Rc
Figure imgf000060_0002
some embodiments, a single instance of Rc is an optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted piperidinyl. In some embodiments, a single instance of Rc is
Figure imgf000060_0003
In some embodiments, a single instance of Rc is an optionally substituted piperidinonyl. In some embodiments, a single instance of Rc is
Figure imgf000060_0004
[0199] In some embodiments, a single instance of Rc is an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 oxygen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted oxetanyl. In some embodiments, a single instance of Rc is oxetanyl, optionally substituted with halogen or -(CH2)o-40R°, wherein R° is hydrogen or Ci-6 aliphatic (e.g., methyl).
In some embodiments, a single instance of Rc is
Figure imgf000060_0005
In some embodiments, a single instance
Figure imgf000060_0006
[0200] In some embodiments, a single instance of Rc is an optionally substituted 5- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted oxazolidinonyl. In some embodiments, a single instance of Rc
Figure imgf000061_0001
[0201] In some embodiments, a single instance of Rc is an optionally substituted 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of Rc is an optionally substituted morpholinyl. In some embodiments, a single instance of Rc is
Figure imgf000061_0002
. In some embodiments, a single instance of R is an optionally substituted
Figure imgf000061_0003
morpholinonyl. In some embodiments, a single instance of Rc is o
[0202] In some embodiments, a single instance of Rc is an optionally substituted 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.
[0203] In some embodiments, a single instance of Rc is an optionally substituted azabicyclo[3.1.0]hexanyl. In some embodiments, a single instance of Rc is azabicyclo[3.1.0]hexanyl, optionally substituted with halogen, -(CH2)o-4R°, -(CH2)o-40R°,
-(CH2)O-4C(0)OR°; wherein R° is hydrogen or Ci-6 aliphatic (e g., methyl), wherein R° may be further substituted with halogen (e.g., fluorine).
[0204] In some embodiments, a single instance of Rc is
Figure imgf000061_0004
In some embodiments, a single instance of Rc is
Figure imgf000061_0005
. In some embodiments, a single instance of Rc is ’
Figure imgf000061_0006
In some embodiments, a single instance of Rc is NO^F in some embodiments, a single H
Figure imgf000062_0001
instance of Rc is H . In some embodiments, a single instance of Rc is
Figure imgf000062_0002
. In some embodiments, a single instance of Rc is
Figure imgf000062_0003
. In some embodiments, a single instance of Rc is
Figure imgf000062_0005
. In some embodiments, a single instance of Rc
Figure imgf000062_0004
. In some embodiments, a single instance of Rc
Figure imgf000062_0006
. In some embodiments, a single instance of Rc is
Figure imgf000062_0007
. ,
Figure imgf000062_0008
some embodiments, a single instance of Rc is
Figure imgf000062_0009
. In some embodiments, a single instance
Figure imgf000062_0010
[0205] In some embodiments, a single instance of Rc is an optionally substituted 7- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rc is an optionally substituted 7-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.
[0206] In some embodiments, a single instance of Rc is an optionally substituted 3- azabicyclo[3.1.1]heptanyl. In some embodiments, a single instance of R is
Figure imgf000062_0011
[0207] In some embodiments, a single instance of Rc is an optionally substituted 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of Rc is an optionally substituted 5- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of Rc is an optionally substituted 5- membered saturated bicyclic carbocyclyl. In some embodiments, a single instance of Rc is bicycle[l. l.l]pentanyl. In some embodiments, a single instance of Rc is
Figure imgf000062_0012
[0208] In some embodiments, a single instance of Rc is an optionally substituted 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a single instance of Rc is an optionally substituted 9-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a single instance of Rc is an optionally substituted 9-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of Rc is an optionally substituted imidazopyridinyl. In some embodiments, a single instance of Rc is
Figure imgf000063_0001
[0209] In some embodiments, a provided compound is of Formula (Il-a) or (Il-b):
Figure imgf000063_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB1, RB2, RB3, RB4, RB5, RB6, and RB7 is defined and described in classes and subclasses herein, both singly and in combination.
[0210] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (Il-a) and (Il-b), embodiments of variables CyA, Cyc, L, L’, RB1, RB2, RB3, RB4, RB5, RB6, and RB7 as defined above and described in classes and subclasses herein, also apply to compounds of Formula (Il-a) and (Il-b), both singly and in combination.
[0211] In some embodiments, a provided compound is of Formula (Ill-a), (Ill-b), (III-c), or
(Ill-d):
Figure imgf000063_0003
or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB1, RB2, RB3, and RB4 is defined and described in classes and subclasses herein, both singly and in combination.
[0212] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Ill-a), (Ill-b), (III-c), and (Ill-d) embodiments of variables CyA, Cyc, L, L’, RB1, RB2, RB3, and RB4 as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Ill-a), (Ill-b), (III-c), and (Ill-d) both singly and in combination.
[0213] In some embodiments, a provided compound is of Formula (III-a-1), (III-a-2), or (III- a-3):
Figure imgf000064_0001
(III-a-3) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB2, RB4, and Rx is defined and described in classes and subclasses herein, both singly and in combination.
[0214] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (III-a-1), (III-a-2), and (III-a-3), embodiments of variables CyA, Cyc, L, L’, RB2, RB4, and Rx as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (III-a-1), (III-a-2), and (III-a-3), both singly and in combination.
[0215] In some embodiments, a provided compound is of Formula (III-b-1), (III-b-2), or (III- b-3):
Figure imgf000064_0002
(III-b-1) (III-b-2)
Figure imgf000065_0001
(III-b-3) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB1, RB4, and Rx is defined and described in classes and subclasses herein, both singly and in combination.
[0216] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (III-b-1), (III-b-2), and (III-b-3), embodiments of variables CyA, Cyc, L, L’, RB1, RB4, and Rx as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (III-b-1), (III-b-2), and (III-b-3), both singly and in combination.
[0217] In some embodiments, a provided compound is of Formula (IV), (IV-a), (IV-b), or
(IV-c):
Figure imgf000065_0002
(IV-b) (IV-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB3, RB4, and Rx is defined and described in classes and subclasses herein, both singly and in combination.
[0218] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (IV), (IV-a), (IV-b), and (IV-c), embodiments of variables CyA, Cyc, L, L’, RB3, RB4, and Rx as defined above and described in classes and subclasses herein, also apply to compounds of Formulae Formula (IV), (IV-a), (IV-b), and (IV-c), both singly and in combination.
[0219] In some embodiments, a provided compound is of Formula (V-a), (V-b), or (V-c):
Figure imgf000066_0001
(V-c) or a pharmaceutically acceptable salt thereof, wherein each of Cyc, L, L’, RB1, RB2, and RA is defined and described in classes and subclasses herein, both singly and in combination.
[0220] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (V-a), (V-b), and (V-c), embodiments of variables Cyc, L, L’, RB1, RB2, and RA as defined above and described in classes and subclasses herein, also apply to compounds of Formula (V-a), (V-b), and (V-c), both singly and in combination.
[0221] In some embodiments, a provided compound is of Formula (Vl-a), (Vl-b), or (VI-c):
Figure imgf000066_0002
(VI-c) or a pharmaceutically acceptable salt thereof, wherein each of Cyc, L, L’, RB1, RB2, and RA is defined and described in classes and subclasses herein, both singly and in combination.
[0222] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Vl-a), (Vl-b), and (VI-c), embodiments of variables Cyc, L, L’, RB1, RB2, and RA as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Vl-a), (Vl-b), and (VI-c), both singly and in combination.
[0223] In some embodiments, a provided compound is of Formula (Vll-a), (Vll-b), or (VII- c):
Figure imgf000067_0001
(VII-c) or a pharmaceutically acceptable salt thereof, wherein each of Cyc, L, L’, RB1, RB2, and RA is defined and described in classes and subclasses herein, both singly and in combination.
[0224] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Vll-a), (Vll-b), and (VII-c), embodiments of variables Cyc, L, L’, RB1, RB2, and RA as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Vll-a), (Vll-b), and (VII-c), both singly and in combination.
[0225] In some embodiments, a provided compound is of Formula (Vlll-a), (VIILb), or (VIII-c):
Figure imgf000068_0001
(VIII-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, RB1, and RB2 is defined and described in classes and subclasses herein, both singly and in combination.
[0226] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (VIII-a), (VIII-b), and (VIII-c), embodiments of variables CyA, Cyc, L, RB1, and RB2 as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (VIII-a), (VIII-b), and (VIII-c), both singly and in combination.
[0227] In some embodiments, a provided compound is of Formula (IX-a), (IX-b), or (IX-c):
Figure imgf000068_0002
(IX-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, RB1, and RB2 is defined and described in classes and subclasses herein, both singly and in combination. [0228] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (IX-a), (IX-b), and (IX-c), embodiments of variables CyA, Cyc, L, RB1, and RB2 as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (IX-a), (IX-b), and (IX-c), both singly and in combination.
[0229] In some embodiments, a provided compound is of Formula (X-a), (X-b), or (X-c):
Figure imgf000069_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L’, RB1, and RB2 is defined and described in classes and subclasses herein, both singly and in combination. It will be understood that the connection between CyA and Cyc in each of Formula (X-a), (X-b), and (X-c) is a methylene.
[0230] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (X-a), (X-b), and (X-c), embodiments of variables CyA, Cyc, L’, RB1, and RB2 as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (X-a), (X-b), and (X-c), both singly and in combination.
[0231] In some embodiments, a provided compound is of Formula (Xl-a), (Xl-b), or (XI-c):
Figure imgf000069_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L’, RB1, and RB2 is defined and described in classes and subclasses herein, both singly and in combination.
[0232] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Xl-a), (Xl-b), and (XI-c), embodiments of variables CyA, Cyc, L’, RB1, and RB2 as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Xl-a), (Xl-b), and (XI-c), both singly and in combination.
[0233] In some embodiments, a provided compound is of Formula (Xll-a), (Xll-b), or (XII- c):
Figure imgf000070_0001
(XII-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rc is defined and described in classes and subclasses herein, both singly and in combination.
[0234] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Xll-a), (Xll-b), and (XII-c), embodiments of variables CyA, L, L’, RB1, RB2, Lc, and Rc as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Xll-a), (Xll-b), and (XII-c), both singly and in combination.
[0235] In some embodiments, a provided compound is of Formula (Xlll-a), (XIILb), or (XIII-c):
Figure imgf000070_0002
(XIILa) (Xlll-b)
Figure imgf000071_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rc is defined and described in classes and subclasses herein, both singly and in combination.
[0236] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XIILa), (Xlll-b), and (XIII-c), embodiments of variables CyA, L, L’, RB1, RB2, LC, and Rc as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Xlll-a), (Xlll-b), and (XIII-c), both singly and in combination.
[0237] In some embodiments, a provided compound is of Formula (XlV-a), (XlV-b), or (XIV-c):
Figure imgf000071_0002
(XIV-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rc is defined and described in classes and subclasses herein, both singly and in combination.
[0238] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XlV-a), (XlV-b), and (XIV-c), embodiments of variables CyA, L, L’, RB1, RB2, Lc, and Rc as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (XlV-a), (XlV-b), and (XIV-c), both singly and in combination. [0239] In some embodiments, a provided compound is of Formula (XV-a), (XV-b), or (XV- c):
Figure imgf000072_0001
(XV-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rc is defined and described in classes and subclasses herein, both singly and in combination.
[0240] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XV-a), (XV-b), and (XV-c), embodiments of variables CyA, L, L’, RB1, RB2, LC, and Rc as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (XV-a), (XV-b), and (XV-c), both singly and in combination.
[0241] In some embodiments, a provided compound is of Formula (XVI-a), (XVI-b), or (XVI-c):
Figure imgf000072_0002
(XVI-a)
Figure imgf000073_0001
(XVI-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rc is defined and described in classes and subclasses herein, both singly and in combination.
[0242] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XVI-a), (XVI-b), and (XVI-c), embodiments of variables CyA, L, L’, RB1, RB2, LC, and Rc as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (XVI-a), (XVI-b), and (XVI-c), both singly and in combination.
[0243] In some embodiments, a compound is 2-((2S,4R)-4-amino-l-(6-chloroimidazo[l,2- a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
[0244] In some embodiments, a compound is not 2-((2S,4R)-4-amino-l-(6- chloroimidazo[l,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin- 6-yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
[0245] In some embodiments, a compound is selected from:
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methylisoquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-1);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-cyclopropyl-3-methylbenzyl)-lH- pyrazole-4-carboxamide (1-2); diisopropyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)iminodicarbonate (1-3); benzyl ((benzyloxy)carbonyl)(5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-4-carboxamido)methyl)isoquinolin-l-yl)carbamate (1-4); isobutyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)carbamate (1-5); isopropyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l -yl)carbamate (1-6); benzyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)carbamate (1-7);
N-(( 1 -acetamido-5,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-methylimidazo[ 1 ,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-8); ethyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)carbamate (1-9);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methylimidazo[l,2-a]pyri din-2- y 1 )methy 1 )- 1 H-py razol e-4-carb oxami de (I- 10) ;
(R*)-N-(( 1 -amino-5,7-dimethylisoquinolin-6-yl)m ethyl)- 1 -( 1 -(6-methylimidazo[ 1 ,2-a]pyri din-2 - yl)ethyl)-lH-pyrazole-4-carboxamide (1-11);
(R)-N-(( 1 -amino-5,7-dimethyli soquinolin-6-yl)methyl)- 1 -( 1 -(6-methylimidazo[ 1 ,2-a]pyridin-2- yl)ethyl)-lH-pyrazole-4-carboxamide (1-1 la);
(S*)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(l-(6-methylimidazo[l,2-a]pyri din-2- yl)ethyl)-lH-pyrazole-4-carboxamide (1-12);
(S)-N-(( 1 -amino-5, 7-dimethylisoquinolin-6-yl)methyl)- 1 -( 1 -(6-methylimidazo[ 1 ,2-a]pyri din-2 - yl)ethyl)- lH-pyrazole-4-carboxamide (I- 12a);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(l-(6-methylimidazo[l,2-a]pyri din-2- yl)ethyl)- lH-pyrazole-4-carboxamide (I- 13); methyl 2-(4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2-(6- methylimidazo[l,2-a]pyridin-2-yl)acetate (1-14);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-methyl-[ 1,2, 4]triazolo[l, 5-a]pyri din-2 - yl)methyl)-lH-pyrazole-4-carboxamide (1-15);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((2-methylquinazolin-7-yl)methyl)- 1H- pyrazole-4-carboxamide (1-16);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((5-chl oro-1 -methyl-2-oxo-l, 2- dihydropyridin-3-yl)oxy)benzyl)-lH-pyrazole-4-carboxamide (1-17); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((l-methyl-2-oxo-l,2-dihydropyridin-3- yl)oxy)benzyl)-lH-pyrazole-4-carboxamide (1-18); l-(4-(l-acetamidocyclopropyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-19);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)-3,5- dimethylbenzyl)- lH-pyrazole-4-carboxamide (1-20);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(N-methylpyrrolidine-l- carboxamido)benzyl)-lH-pyrazole-4-carboxamide (1-21);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l,3,3-trimethylureido)benzyl)-lH- pyrazole-4-carboxamide (1-22);
N-(( 1 -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- 1 -(4-(2-(dimethylamino)- 1 , 1 -difluoro-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-23);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-methylquinoxalin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-24); ethyl (4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)(methyl)carbamate (1-25);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)-3- methylbenzyl)-lH-pyrazole-4-carboxamide (1-26);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-methylquinolin-7-yl)methyl)-lH- pyrazole-4-carboxamide (1-27);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -((3 -cy clopropylquinolin-6-yl)methyl)- 1 H- pyrazole-4-carboxamide (1-28);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-cy cl opropylbenzyl)-lH-pyrazole-4- carboxamide (1-29);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((l-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)benzyl)-lH-pyrazole-4-carboxamide (1-30);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(3-cycl opropylbenzyl)-lH-pyrazole-4- carboxamide (1-31);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(2-cy anobenzyl)-lH-pyrazole-4- carboxamide (1-32); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(2 -methoxybenzyl)- lH-pyrazole-4- carboxamide (1-33);
(S)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(l-phenylethyl)-lH-pyrazole-4- carboxamide (1-34);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(4-methylbenzyl)- 1 H-py razole-4- carboxamide (1-35);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-methyl-3-(trifluoromethyl)benzyl)-lH- pyrazole-4-carboxamide (1-36);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(3, 5-dichlorobenzyl)-lH-pyrazole-4- carboxamide (1-37);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l -(2-fluorobenzyl)-lH-pyrazole-4- carboxamide (1-38);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(4-fluorobenzyl)- 1 H-pyrazole-4- carboxamide (1-39);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(2 -methylbenzyl)- lH-pyrazole-4- carboxamide (1-40);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l -(3 -methylbenzyl)- lH-pyrazole-4- carboxamide (1-41);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(2-(trifluoromethyl)benzyl)- IH-pyrazole- 4-carboxamide (1-42);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(3 -methoxybenzyl)- 1 H-pyrazole-4- carboxamide (1-43); l-(4-((l,3,4-oxadiazol-2-yl)methyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)- lH-pyrazole-4-carboxamide (1-44);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl )methy 1 )- 1 -(3 -fluorobenzyl )- 1 H-pyrazole-4- carboxamide (1-45);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-oxo-2H-[l,2'-bipyridin]-5'-yl)methyl)- lH-pyrazole-4-carboxamide (1-46);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)- 1 -((3 -methylb enzofuran-2-yl)methyl)- 1 H- pyrazole-4-carboxamide (1-47); l-(4-(2-(lH-pyrazol-l-yl)ethyl)benzyl)-N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-48);
N-(( 1 -amino-5, 7-dimethylisoquinolin-6-yl)m ethyl)- 1 -(4-(2-(2-oxopyridin- 1 (2H)- yl)ethyl)benzyl)-lH-pyrazole-4-carboxamide (1-49);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromobenzofuran-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-50);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-51);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l -methyl- lH-indazol-5-yl)methyl)-lH- pyrazole-4-carboxamide (1-52);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(imidazo[l,2-a]pyridin-2-ylmethyl)-lH- pyrazole-4-carboxamide (1-53);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((8-methylimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-54); ethyl 2-(4-((4-((( 1 -amino-5 ,7-dimethyli soquinolin-6-yl)methyl)carbamoy 1)- 1 H-pyrazol- 1 - yl)methyl)phenyl)acetate (1-55);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(naphthal en-2-ylmethyl)- lH-pyrazole-4- carb oxami de (1-56);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-fluorobenzofuran-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-57);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l-methyl-lH-benzo[d] [1,2, 3]triazol-5- y l)methy 1 )- 1 H-py razol e-4-carb oxami de (I- 58) ;
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l -methyl- lH-indazol-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-59);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(quinolin-6-ylmethyl)-lH-pyrazole-4- carboxamide (1-60);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((7-chloroquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-61);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((4-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-62); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)benzyl)- 1 H-pyrazole-4-carboxamide (1-63);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((2-methylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-64);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-65);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-(trifluoromethyl)benzo[b]thiophen-2- yl)methyl)- lH-pyrazole-4-carboxamide (1-66);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((2-methoxyquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-67);
N-(( 1 -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- 1 -(( 1 -(difluoromethyl)- 1H- benzo[d]imidazol-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-68);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((6-bromoquinolin-2-yl)m ethyl)- 1H- pyrazole-4-carboxamide (1-69);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromoquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-70);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((l-isopropyl-lH-benzo[d]imidazol-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-71);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((8-methylquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-72);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-chloro-8-methylquinolin-3-yl)methyl)- lH-pyrazole-4-carboxamide (1-73);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(isoquinolin-6-ylmethyl)-lH-pyrazole-4- carboxamide (1-74);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l -methyl-lH-benzo[d]imidazol-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-75);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(benzo[d]thi azol -2 -ylmethyl)-lH-pyrazole- 4-carboxamide (1-76);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(pyrimidin-5-ylmethyl)-lH-pyrazole-4- carboxamide (1-77); N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(pyridin-2-ylmethyl)-lH-pyrazole-4- carboxamide (1-78);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl )methy 1)- 1 -(quinoxalin-6-y Imethyl )- 1 H-pyrazole-4- carboxamide (1-79);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((3-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-80);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-81);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(benzofuran-2-ylmethyl)-lH-pyrazole-4- carboxamide (1-82);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(pyrimidin-2-y Imethyl)- lH-pyrazole-4- carb oxami de (1-83);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(benzo[b]thiophen-2-ylmethyl)-lH- pyrazole-4-carboxamide (1-84);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(benzo[d]oxazol -2 -ylmethyl)-lH-pyrazole- 4-carboxamide (1-85);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl )methyl)-l -(pyrazin-2-ylmethyl)-lH-pyrazole-4- carb oxami de (1-86);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(pyridin-4-ylmethyl)- lH-pyrazole-4- carb oxami de (1-87);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(pyridin-3 -ylmethyl)- 1 H-pyrazole-4- carboxamide (1-88);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -((3-chloroquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-89); l-((6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)pyridin-3-yl)methyl)-N-((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-90);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(4-methoxybenzyl)-lH-pyrazole-4- carboxamide (1-91);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-cy anobenzyl)-lH-pyrazole-4- carboxamide (1-92); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(trifluoromethyl)benzyl)-lH-pyrazole- 4-carboxamide (1-93);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl )methy 1)- 1 -(3 -cyanobenzyl)- 1 H-pyrazole-4- carboxamide (1-94);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(3,5-bis(trifluoromethyl)benzyl)-lH- pyrazole-4-carboxamide (1-95);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(3-chl oro-4-methylbenzyl)-lH-pyrazole-4- carboxamide (1-96);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(3-(trifluoromethyl)benzyl)- IH-pyrazole- 4-carboxamide (1-97);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l -(3 -chlorobenzyl)- lH-pyrazole-4- carboxamide (1-98);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-99);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((7-cy cl opropylimidazo[ l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (I- 100);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloroimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (I- 101 );
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- 1-((6, 7-dimethylimidazo[ l,2-a]pyri din-2 - yl)methyl)-lH-pyrazole-4-carboxamide (1-102);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((7-methylimidazo[l, 2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-103);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-methylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-105);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloro-5-methylimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-106);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((7-chloroquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-107);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-chloro-7-methoxyquinolin-3- yl)methyl)-lH-pyrazole-4-carboxamide (1-108); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-chloro-7-methoxyquinolin-3- yl)methyl)-lH-pyrazole-4-carboxamide (1-109);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((7-methoxyquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-110);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -((7 -methoxy quinolin-3 -yl)methyl)- 1 H- pyrazole-4-carboxamide (1-111); l-((5-(lH-pyrazol-l-yl)naphthalen-2-yl)methyl)-N-((l -amino-5, 7-dimethylisoquinolin-6- yl)methyl)-lH-pyrazole-4-carboxamide (1-112);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromonaphthalen-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-113);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((5-(pyridin-2-yl)naphthalen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-114);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-methylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-115);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)- 1 -(4-(3 -fluoro-2-methoxybenzyl)benzyl)- 1 H- pyrazole-4-carboxamide (1-116);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(4-((4-methyl-4H-l, 2, 4-triazol-3- yl)methyl)benzyl)-lH-pyrazole-4-carboxamide (1-117);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(2-cyclopropylbenzyl)-lH-pyrazole-4- carboxamide (1-118);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l -(dimethylamino)- 1 -oxopropan-2- yl)benzyl)-lH-pyrazole-4-carboxamide (1-119);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(l-(3-chloroquinolin-6-yl)ethyl)-lH- pyrazole-4-carboxamide (1-120);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-cyclopropylpyrazolo[l,5-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-121 );
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-y l)methy 1)- 1 -(4-( 1 -(pyrrolidine- 1 - carbonyl)cyclopropyl)benzyl)-lH-pyrazole-4-carboxamide (1-122);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-vinylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-123); N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3-ethylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-124);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-(2-oxopyridin-l(2H)-yl)naphthalen-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-125);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methoxyquinazolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-126);
(R)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)rnethyl)-l-(l -phenylethyl)- lH-pyrazole-4- carboxamide (1-127);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N-methyl-l-((6-methylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-128);
2-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2-(6- methylimidazo[l,2-a]pyridin-2-yl)acetic acid (1-129);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(2-hydroxy-l-(6-methylimidazo[l,2- a]pyridin-2-yl)ethyl)-lH-pyrazole-4-carboxamide (1-130);
2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetic acid (1-131); ethyl (6-((l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamido)methyl)-5,7- dimethylisoquinolin- 1 -yl)carbamate (I- 132);
N-((l-acetamido-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-133);
1-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-N-((5,7-dimethyl-l- (methylamino)isoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-134);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-7-methylimidazo[l,2-a]pyridin-
2-yl)methyl)-lH-pyrazole-4-carboxamide (1-135);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5,6-dimethylimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-136);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-cy cl opropylimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-137);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-5-chloroimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-138); N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromoimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-139);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-ethylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-140);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloro-5-ethylimidazo[l,2-a]pyri din-2- yl)methyl)- lH-pyrazole-4-carboxamide (1-141 );
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl-5-fluoroimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-142);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-cyanoimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-143);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-methoxyimidazo[l,2-a]pyri din-2- yl)methyl)- lH-pyrazole-4-carboxamide (I- 144);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-5-methylimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-145);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl-7-methylirnidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-146);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((7-chloro-6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-147);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-chloro-6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-148);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-7-chloroimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-149); l-((l,5-naphthyridin-2-yl)methyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-150);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(3-chloro-4-(2-(dimethylamino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-151);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)-3- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxamide (1-152);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((7-methylnaphthalen-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-153); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(2-oxo-2-(phenylamino)ethyl)-lH- pyrazole-4-carboxamide (1-154);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(2-(methyl(phenyl)amino)-2-oxoethyl)-lH- pyrazole-4-carboxamide (1-155);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((7-bromoquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-156);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloroquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-157);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-fluoroquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-158);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((8-bromoquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-159);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4-carboxamide (I- 160);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)-5-(methoxymethy 1)- 1 -((2-(pyrrolidin- 1 - yl)pyrimidin-5-yl)methyl)- lH-pyrazole-4-carboxamide (1-161 );
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-3-(methoxymethyl)-l-((2-(pyrrolidin-l- yl)pyrimidin-5-yl)methyl)-lH-pyrazole-4-carboxamide (1-162);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((3-chloroquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-163);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-hydroxyquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-164);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(4-(pyridin-2-ylmethyl)benzyl)-lH- pyrazole-4-carboxamide (1-165);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl )methyl)- l-(4-(thi azol-2-ylmethyl)benzyl)- 1H- pyrazole-4-carboxamide (1-166);
N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(4-(imidazo[l,2-a]pyri din-8- ylmethyl)benzyl)-lH-pyrazole-4-carboxamide (1-167);
N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)- 1 -(4-(pyrimidin-2-ylmethyl)benzy 1)- 1 H- pyrazole-4-carboxamide (1-168); N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(3,5-dimethyl-4-(pyridin-2- ylmethyl)benzyl)-lH-pyrazole-4-carboxamide (1-169);
N-((l-amino-5,7,8-trimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4-carboxamide(I-
170);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4-carboxamide (I-
171);
1 -((8 -(( 1 ,3 ,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[ 1 ,2-a]pyridin-2-yl)methyl)-N-((l - amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-172);
N-((l -amino-7-ethyl-5-methylisoquinolin-6-yl)methyl)-l -benzyl- lH-pyrazole-4-carboxamide (I- 173);
N-((l -amino-7-cy cl opropyl-5-methylisoquinolin-6-yl)methyl)-l -benzyl- lH-pyrazole-4- carboxamide (1-174);
N-(( 1 -amino-5-methyl-7-( 1 -methylcyclopropyl)isoquinolin-6-yl)methyl)- 1 -benzyl- IH-pyrazole- 4-carboxamide (1-175);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(2,2-dimethylcyclopropyl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-176);
(Z)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(prop-l-en-l-yl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-3-carboxamide (1-177);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(2-methylcyclopropyl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-178);
N-(( 1 -amino-5,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-(2-methylprop- 1 -en- 1 -yl)imidazo[ 1 ,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-179); l-(2-amino-l-phenylethyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4- carboxamide (1-180); tert-butyl (2-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2- phenylethyl)carbamate (1-181);
1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide (1-182);
2-(4-(( 1 H-pyrazol- 1 -yl)methyl)benzyl)-N-(( 1 -amino-5 ,7-dimethyli soquinolin-6- yl)methyl)isonicotinamide (1-183); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((4-methyl-lH-pyrazol-l- yl)methyl)benzyl)-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide (1-184); l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3- (trifluoromethyl)- lH-pyrazole-4-carboxamide (1-185);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)-lH-l,2,3-triazole-4-carboxamide (1-186); l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-
(methoxymethyl)-lH-pyrazole-4-carboxamide (1-187); l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-5-
(methoxyrnethyl)-lH-pyrazole-4-carboxamide (1-188);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-(6-cyclopropylimidazo[l,2-a]pyridine-2- carb ony l)i soni coti nami de (I- 189);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-5-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-l,3,4-oxadiazole-2-carboxamide (1-190);
N-((l-amino-5,7,8-trimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)- lH-pyrazole-4-carboxamide (1-191 );
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)- lH-pyrazole-4-carboxamide (I- 192);
N-(( 1 -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-(pyrrolidin- 1 -yl)pyri din-3 -yl)methyl)- 5 -(trifluoromethyl)- 1 H-pyrazol e-4-carboxami de (1-193);
N-(( 1 -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-(pyrrolidin- 1 -yl)pyri din-3 -yl)methyl)- 3 -(trifluoromethyl)- lH-pyrazole-4-carboxamide (I- 194);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-phenylpyrimidin-5-yl)methyl)-lH- pyrazole-4-carboxamide (1-195);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((2-oxo-l -(2,2, 2-trifluoroethyl)- 1,2- dihydropyridin-3-yl)methyl)benzyl)-lH-pyrazole-4-carboxamide (1-196);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)i sonicotinamide (I- 197);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-2-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)thiazole-5-carboxamide (1-198); N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide (1-199);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(l-(3-chloroquinolin-6-yl)ethyl)-lH-l,2,3- triazole-4-carboxamide (1-200);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(trifluoromethyl)imidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-201);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(aminomethyl)-l-benzyl-lH-pyrazole-5- carboxamide (1-202);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-5-(aminomethyl)-l-benzyl-lH-pyrazole-3- carboxamide (1-203);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-
((cyclopropylmethyl)(methyl)amino)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-204);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6r)-6-methyl-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-205);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6s)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-206);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6r)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-207);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6r)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-208);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6s)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-209);
(lR,5S,6s)-3-(2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol- l-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1-210); ethyl (lR,5S,6s)-3-(2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH- pyrazol- 1 -yl)methyl)phenyl)acetyl)-3 -azabicyclo[3.1.0]hexane-6-carboxylate (1-211); ethyl ( 1 R, 5 S,6r)-3 -(2-(4-((4-((( 1 -amino-5 , 7 -dimethyli soquinolin-6-yl)methy l)carbamoy 1)- 1 H- pyrazol-l-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (1-212);
(1R, 5 S,6r)-3-(2-(4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol- l-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1-213); N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-214); l-(4-(2-(3-azabicyclo[3.1.1]heptan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-215);
3-(2-(4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-l-carboxylic acid (1-216); methyl 3-(2-(4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetyl)-3 -azabicyclo[3.1 ,0]hexane- 1 -carboxylate (1-217);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(2,5-dimethylpyrrolidin-l-yl)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-218);
N-(( 1 -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -(4-(2-(azetidin- 1 -yl)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-219);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(benzyl(methyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-220);
N-((l -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -(4-(2-(bicyclo[ 1.1.1 ]pentan- 1 -ylamino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-221); l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-222);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-oxo-2-(piperi din- l-yl)ethyl)benzyl)- lH-pyrazole-4-carboxamide (1-223);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(cy cl opropyl(methyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-224);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-morpholino-2-oxoethyl)benzyl)-lH- pyrazole-4-carboxamide (1-225);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(diethylamino)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-226);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)- l-(4-(2-oxo-2-(phenylamino)ethyl)benzyl)- lH-pyrazole-4-carboxamide (1-227);
N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(methyl(phenyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-228); N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(benzylamino)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-229);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(methylamino)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-230); l-(4-(2-amino-2-oxoethyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-231);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-oxo-2-(pyrrolidin-l-yl)ethyl)benzyl)- lH-pyrazole-4-carboxamide (1-232);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(naphthalen-2-ylmethyl)pyrimidine-4,6- diamine (1-233);
N4-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-5- fluoropyrimidine-4,6-diamine (1-234);
N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5- methylpyridazine-3,5-diamine (1-235); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)amino)methyl)benzyl)pyridin-2(lH)-one (1-236);
1-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)benzyl)pyridin-2(lH)-one (1-237);
6-(aminomethyl)-N-(4-((3-cyclopropylquinolin-6-yl)methoxy)pyridin-2-yl)-5,7- dimethylisoquinolin-1 -amine (1-238);
6-(((4-((3-cyclopropylquinolin-6-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7- dimethyli soquinolin- 1 -amine (1-239);
N2-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N3-((6-cyclopropylimidazo[l,2-a]pyridin-
2-yl)methyl)pyrazine-2, 3 -diamine (1-240);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((5-(pyridin-2-yl)naphthalen-2- yl)methyl)pyrimidine-4,6-diamine (1-241);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-cyclopropylimidazo[l,2-b]pyridazin- 2-yl)methyl)pyrimidine-4,6-diamine (1-242);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((5-cyclopropylthieno[2,3-b]pyri din-2- yl)methyl)pyrimidine-4,6-diamine (1-243); N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((5-cyclopropylpyrazolo[l,5-a]pyridin-2- yl)methyl)pyrimidine-4,6-diamine (1-244);
1-(6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)naphthalen-l-yl)pyridin-2(lH)-one (1-245);
N4-((5-(lH-pyrazol-l-yl)naphthalen-2-yl)methyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-246);
N-(6,8-dimethyl-7-(((6-((4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)amino)pyrimi din-4- yl)amino)methyl)isoquinolin-l-yl)acetamide (1-247); benzyl (6,8-dimethyl-7-(((6-((4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)amino)pyrirnidin-4- yl)amino)methyl)isoquinolin-l-yl)carbamate (1-248); ethyl (5,7-dimethyl-6-(((6-((4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)amino)pyrimidin-4- yl)amino)methyl)isoquinolin-l-yl)carbamate (1-249);
3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6- cy cl opropylimidazo[l,2-a]pyridin-8-yl)ox etan-3 -ol (1-250);
6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-251);
5,7-dimethyl-6-(((5-(naphthalen-2-ylmethoxy)pyridazin-3-yl)amino)methyl)isoquinolin-l-amine
(1-252);
6-(((3-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3H-[l,2,3]triazolo[4,5-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-253);
6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolo[4,5-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-254);
6-(aminomethyl)-N-(6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)-5- methyl-7-(l-methylcyclopropyl)isoquinolin-l -amine (1-255);
3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)oxazolidin-2-one (1-256);
6-(((6-((6-cyclopropyl-8-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)imidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-257);
2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6- cyclopropylimidazo[l,2-a]pyridine-8-carbonitrile (1-258); l-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6- cyclopropylimidazo[l,2-a]pyridin-8-yl)pyrrolidin-2-one (1-259);
6-(((2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-2H-pyrazolo[3,4-c]pyridin-7-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-260);
6-(((6-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-261);
6-(((6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-262);
6-(((2-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-263);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-264);
6-(((2-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-265);
6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazolo[4,3-c]pyri din-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-266);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-267);
6-(((l -((6-cy cl opropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazolo[4,3-c]pyri din-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-268);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-269); ethyl 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)propanoate (1-270);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-271);
6-(((6-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-272);
3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)propanoic acid (1-273); ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (1-274);
6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-275);
(R*)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-276);
(S*)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-277);
(S)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine;
(R)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine;
6-(((5-((4-(2-(lH-pyrazol-l-yl)ethyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-278);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-279);
6-(((5-chloro-4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyri din-2- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-280);
6-(((6-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-281);
6-(((6-((5-cyclopropylbenzo[d]thiazol-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-282);
6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-283);
6-(((4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-284);
6-((( 1 -((6-cy clopropylimidazof 1 ,2-a]pyri din-2 -yl)methyl)-3 -fluoro- lH-pyrrolo[3 ,2-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-285);
6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-3-fluoro-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-286); 6-(((3-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrazin-2-yl)amino)rnethyl)-5,7- dimethylisoquinolin- 1 -amine (1-287);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)pyrimidine-4,5-diamine (1-288);
6-(((3-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-289);
6-(((6-(((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)thio)pyrimidin-4-yl)amino)methyl)-
5.7 -dimethyli soquinolin- 1 -amine (1-290); ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoate (1-291); ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-
[1.2.4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (1-292);
3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-293);
3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-294);
3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-
[1.2.4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-295); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-296);
5.7-dimethyl-6-(((6-((4-((l -methyl- lH-pyrazol-3-yl)methyl)benzyl)oxy)pyrimi din-4- yl)amino)methyl)isoquinolin-l -amine, formic acid salt (1-297);
5.7-dimethyl-6-(((6-((4-((l -methyl- lH-pyrazol-3-yl)methyl)benzyl)oxy)pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine;
5.7-dimethyl-6-(((6-((2-(pyrrolidin-l-yl)pyrimidin-5-yl)methoxy)pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine (1-298);
3-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)-l-methylpyridin-2(lH)-one (1-299);
6-(((6-((6-((lH-pyrazol-l-yl)methyl)pyridin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-300); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-301);
4-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)benzyl)morpholin-3-one, trifluoroacetic acid salt (1-302);
4-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)morpholin-3-one; l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(lH)-one, formic acid salt (1-303); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(lH)-one;
6-(((6-((6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)- 5,7-dimethylisoquinolin-l -amine (1-304);
6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-305);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-2-ylmethyl)pyrimidine-4,6- diamine (1-306);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-methoxyquinolin-2- yl)methyl)pyrimidine-4,6-diamine (1-307);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-methyl-N6-(quinolin-6- ylmethyl)pyrimidine-4,6-diamine (1-308);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-chloroquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-309);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(l-(3-chloroquinolin-6- yl)ethyl)pyrimidine-4,6-diamine (1-310);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-methylquinolin-7- yl)methyl)pyrimidine-4,6-diamine (1-311);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-(trifluoromethyl)quinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-312);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-chloroimidazo[l,2-a]pyri din-2- yl)methyl)pyrimidine-4,6-diamine, formic acid salt (1-313); N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-chloroimidazo[l,2-a]pyridin-2- yl)methyl)pyrimidine-4,6-diamine;
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-cyclopropylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-314);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(isoquinolin-3-ylmethyl)pyrimidine-4,6- diamine (1-315);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-methyl-N6-(quinolin-3- ylmethyl)pyrimidine-4,6-diamine (1-316);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-3-ylmethyl)pyrimidine-4,6- diamine, formic acid salt (1-317);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-3-ylmethyl)pyrimidine-4,6- di amine;
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-methoxynaphthalen-2-yl)methyl)-N6- methylpyrimidine-4,6-diamine (1-318);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(benzo[d]thiazol-2-ylmethyl)pyrimidine- 4,6-diamine (1-319);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(isoquinolin-6-ylmethyl)pyrimidine-4,6- diamine (1-320);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(imidazo[l,2-a]pyridin-2- ylmethyl)pyrimidine-4,6-diamine (1-321);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((7-methylimidazo[l,2-a]pyridin-2- yl)methyl)pyrimidine-4,6-diamine (1-322);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methoxyquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-323);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-324);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6,7-dimethylquinolin-3- yl)methyl)pyrimidine-4,6-diamine (1-325);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)methyl)pyrimidine-4,6-diamine, formic acid salt (1-326); N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)rnethyl)pyrimidine-4,6-diamine;
6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-4- methyl-2H-benzo[b][l,4]oxazin-3(4H)-one, formic acid salt (1-327);
6-(((6-((( 1 -amino-5 , 7 -dimethyli soquinolin-6-yl)methyl)amino)pyrimidin-4-y l)amino)methyl)-4- methyl-2H-benzo[b][l,4]oxazin-3(4H)-one;
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((5-chloroisoquinolin-3- yl)methyl)pyrimidine-4,6-diamine, formic acid salt (1-328);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((5-chloroisoquinolin-3- yl)methyl)pyrimidine-4,6-diamine;
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-(trifluoromethyl)imidazo[ 1,2- a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (1-329);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-chloro-5-methylimidazo[ 1,2- a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (1-330);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methyl)pyrimidine-4,6-diamine (1-331);
2-(((6-((( 1 -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)imidazo[l,2-a]pyridine-6-carbonitrile (1-332) ;
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-methylimidazo[l,2-a]pyri din-2- yl)methyl)pyrimidine-4,6-diamine (1-333);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((3-fluoroquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-334);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((2-methylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-335);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((3-methylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-336);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-6-ylmethyl)pyrimidine-4, 6- diamine (1-337);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyrazin-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-338); N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-cyclopropylbenzyl)pyrimidine-4,6- diamine (1-339);
N4-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-340);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-benzylpyrimidine-4,6-diamine (1-341);
N4-(( 1 -amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(( 1 -methyl- 1 H- 1 ,2,4-triazol-5- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-342);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((5-methyl-l,3,4-thiadiazol-2- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-343);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-l-one, formic acid salt (I- 344);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(3-azabicyclo[3. 1.0]hexan-3-yl)ethan-l-one;
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(pyrrolidin-l-yl)ethan-l-one (1-345);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)- 1 -(piperidin- 1 -yl)ethan- 1 -one (1-346);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(azetidin-l-yl)ethan-l-one, formic acid salt (1-347);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy )- 1 -(azetidin- 1 -yl)ethan- 1 -one;
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)- 2,6-dimethylphenoxy)-N,N-dimethylacetamide (1-348);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyridin-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine, formic acid salt (1-349);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyridin-2- ylmethoxy)benzyl)pyrimidine-4,6-di amine;
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(thiazol-4- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-350); N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(oxazol-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine (1-351);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenoxy)-2,2-difluoro-N,N-dimethylacetamide (1-352);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(3,5-dimethyl-4-(pyri din-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine, formic acid salt (1-353);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(3,5-dimethyl-4-(pyridin-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine;
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N,2-trimethylpropanamide, formic acid salt (1-354);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N,2-trimethylpropanamide;
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(3,5-dimethyl-4-(thiazol-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine (1-355);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(thiazol-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine (1-356); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N-dimethylcyclopropane-l-carboxamide, formic acid salt (1-357)
1-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N-dimethylcyclopropane-l -carboxamide;
N4-(4-((lH-pyrazol-3-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-358);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-
2.6-dimethylphenyl)- 1 -(3 -azabicy clo[3.1.0]hexan-3 -yl)ethan- 1 -one (1-359);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-
2.6-dimethylphenyl)-N,N-dimethylacetamide (1-360);
N4-((l -amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyri din-2 -yloxy )benzyl)pyrimidine-
4.6-diamine (1-361);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(thiazol-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-362); N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyridin-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-363);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((4-methylpyridin-2- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-364);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((3-chloropyridin-2- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-365);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(l-(4-(pyridin-2- ylmethyl)phenyl)ethyl)pyrimidine-4,6-diamine (1-366);
N4-(4-((lH-pyrazol-l-yl)methyl)-3,5-dimethylbenzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-367);
N4-(( 1 -amino-5 , 7-dimethyli soquinolin-6-yl)methyl)-N6-(3 , 5 -dimethyl-4-(pyridin-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-368);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((5-chloropyridin-2- yl)methyl )benzyl )py rimidine-4, 6-diamine (1-369); l-(3-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-370);
5.7-dimethyl-6-(((6-((2-methylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin- 1 -amine (1-371);
5.7-dimethyl-6-(((6-((6-methylquinolin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin- 1-amine (1-372);
6-(((6-((3-chloroquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-
1 -amine (1-373);
5.7-dimethyl-6-(((6-(quinolin-6-ylmethoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-l -amine (1-374);
2-(4-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenyl)-N,N-dimethylacetamide (1-375);
N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)- l,2,4-triazine-3,5-diamine (1-376);
2-(4-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenoxy)-N,N-dimethylacetamide (1-377); 2-(4-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenyl)- 1 -(3 -azabicy clo[3.1.0]hexan-3 -y l)ethan- 1 -one (1-378);
N4-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-N6-((l -amino-5, 7-dimethylisoquinolin-6- yl)methyl)pyrirnidine-4,6-diamine (1-379);
N4-(4-(( IH-pyrazol- 1 -yl)methyl)-2-(trifluoromethyl)benzyl)-N6-(( 1 -amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (1-380) ;
N-(4-((lH-pyrazol-l-yl)methyl)-2-(trifluoromethyl)benzyl)-N-(6-(((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)nitrous amide (1-381);
N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(difluoro(lH-pyrazol- 1- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-382);
N4-(4-((lH-pyrazol- l-yl)methyl)-3-(trifluoromethyl)benzyl)-N6-((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (1-383);
6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-384);
N5-(4-((lH-pyrazol- l-yl)methyl)-2-fluorobenzyl)-N3-((l -amino-5, 7-dimethylisoquinolin-6- yl)methy l)py ridazine-3 , 5 -diamine (1-385);
6-(((6-((3-cyclopropylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-386);
6-(((6-((6-cyclopropylquinolin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-387);
6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-388);
6-(((6-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methoxy)-2-(trifluoromethyl)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-389);
6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5- methyl-7-(l -methylcy cl opropyl)isoquinolin-l -amine (1-390);
6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-b]pyridazin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-391);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-392); 6-(((l-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methyl)-lH-pyrazolo[4,3-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-393);
6-(((6-((6-cyclopropyl-8-(pyrrolidin-l-ylmethyl)imidazo[l,2-b]pyridazin-2- yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-394);
6-(((6-((5-cyclopropylbenzo[b]thiophen-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-395); ethyl 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoate (1-396);
2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxymethyl)-6- cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (1-397);
6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3- chloroquinoline-8-carbonitrile (1-398);
6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-8- butyl-3 -chloroquinoline 1 -oxide (1-399);
6-(((6-((5-cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-400);
6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3- chloroquinoline-8-carboxamide (1-401);
6-(((6-((8-butyl-3-chloroquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-402);
6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-403);
6-(((6-((6-cy cl opropylimidazo[l,2-a]pyri din-2 -yl)difluoromethyl)pyrimidin-4-yl)amino)methyl)-
5.7 -dimethyli soquinolin- 1 -amine (1-404);
6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-
5.7-dimethylisoquinolin-l -amine (1-405);
(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(6- cyclopropylimidazofl ,2-a]pyridin-2-yl)methanol (1-406);
6-(((5-((3-chloroquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine (1-407); 5.7-dimethyl-6-(((5-((6-methylquinolin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-408);
5.7-dimethyl-6-(((5-(quinolin-6-ylmethoxy)pyridazin-3-yl)amino)methyl)isoquinolin-l-amine (I- 409);
6-(((5-(imidazo[l,2-a]pyridin-6-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-410);
6-(((5-(imidazo[l,2-a]pyridin-2-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-411);
5.7-dimethyl-6-(((5-((2-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-412);
5.7-dimethyl-6-(((5-((l -methyl- lH-indazol-5-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin- 1 -amine (1-413);
6-(((5-(imidazo[l,2-a]pyridin-3-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-414);
6-(((5-((6-fluoroquinolin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-
1 -amine (1-415);
5.7-dimethyl-6-(((5-((3-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-416);
6-(((5-((5-chlorobenzo[b]thiophen-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine formic acid salt (1-417);
6-(((5-((5-chlorobenzo[b]thi ophen-2 -yl)methoxy)pyridazin-3-yl)amino)methyl)-5, 7- dimethylisoquinolin-1 -amine
6-(((5-((2,3-dimethylquinoxalin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine formic acid salt (1-418);
6-(((5-((2,3-dimethylquinoxalin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine
5.7-dimethyl-6-(((5-(l-(3-methylquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-419);
6-(((5-(l-(3-chloroquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine formic acid salt (1-420); 6-(((5-(l-(3-chloroquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine;
5,7-dimethyl-6-(((5-((4-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine formic acid salt (1-421);
5.7-dimethyl-6-(((5-((4-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine;
6-(((5-((3-cyclopropylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-422);
5.7-dimethyl-6-(((5-((3-(trifluoromethyl)quinolin-6-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-423);
5.7-dimethyl-6-(((5-((6-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-424);
5.7-dimethyl-6-(((5-((6-methylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-425);
6-(((5-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine formic acid salt (1-426);
6-(((5-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine;
3-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenoxy)-l-methylpyridin-2(lH)-one (1-427);
N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-methyl-N5-(quinolin-6- ylmethyl)pyridazine-3,5-diamine (1-428);
6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-429);
5.7-dimethyl-6-(((5-((2-phenylthiazol-4-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-l- amine (1-430);
6-(((5-((4-((3-cyclopropyl-lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-
5.7-dimethylisoquinolin-l -amine (1-431);
6-(((5 -((4-(( 1 H-pyrazol- 1 -yl)methyl)benzyl)oxy)py ridazin-3 -yl)amino)methyl)-5 , 7 - dimethylisoquinolin- 1 -amine (1-432); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)piperidin-2-one (1-433);
4-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)morpholin-3-one (1-434); l-(3-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-435); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-436); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(lH)-one (1-437); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-438);
5.7-dimethyl-6-(((5-((4-((l -methyl- lH-pyrazol-3-yl)methyl)benzyl)oxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-439);
3-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)-l-methylpyridin-2(lH)-one (1-440);
6-(((5-((4-(lH-imidazol-l-yl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine formate (1-441);
6-(((5-((4-(lH-imidazol-l-yl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine;
5.7 -dimethyl-6-(((5 -(( 1 -phenyl- 1 H-pyrazol-4-yl)methoxy)pyridazin-3 - yl)amino)methyl)isoquinolin- 1 -amine (1-442);
6-(((5-(benzyloxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-443);
6-(((5-((4-(imidazo[l,2-a]pyridin-8-ylmethyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-444);
6-(((5-((6-((lH-pyrazol-l-yl)methyl)pyridin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-445);
6-(((5-((5-((lH-pyrazol-l-yl)methyl)pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-446);
N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyridazine-3,5-diamine (1-447); N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-benzylpyridazine-3,5-diamine (1-448); 6-(((6-(benzyloxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-449); 6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-450);
N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-6- (trifluoromethyl)pyridazine-3,5-diamine (1-451);
6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-4-((quinolin-6- ylmethyl)amino)pyridazine-3 -carboxamide (1-452);
2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridin-4-yl)(6- cy cl opropylimidazo[l,2-a]pyri din-2 -yl)m ethanol (1-453);
6-(((4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-2-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-454);
6-(((2-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-455);
1-(4-(((2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-chloropyridin-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-456);
6-(((5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-457);
6-(((l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-458);
6-(((2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-459);
6-((6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-460);
(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenyl)methanol (1-461);
2-(4-(((5-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-462); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)benzyl)-3,5-dichloropyridin-2(lH)-one (1-463); N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((2,3-dimethylquinoxalin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-464);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-465);
2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-466);
2-(4-(((6-((6-(aminomethyl)-5,7-dimethylisoquinolin-l-yl)amino)pyrimidin-4- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-467);
4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-2-methylisoindolin-l-one (1-468);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((4-bromophenyl)diflu orom ethyl)- 1H- pyrazole-4-carboxamide (1-469);
N-(6-(((5 -((4-(( 1 H-pyrazol- 1 -yl)methyl)benzyl)oxy)py ridazin-3 -yl)amino)methyl)-5 , 7- dimethylisoquinolin- l-yl)acetamide (1-470); l-(4-((4-(l-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)arnino)-2,2,2-trifluoroethyl)-lH- pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one (1-471);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(difluoro(phenyl)methyl)-lH-pyrazole-4- carboxamide (1-472);
6-((6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-473); l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)-3-chlorobenzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-474);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l-methyl-2-oxopyrrolidin-3-yl)benzyl)- lH-pyrazole-4-carboxamide (1-475);
N2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrazine-2,6-diamine (1-476); l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH-pyrazole-4-carboxamide (1-477); l-(4-(((2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-478); l-(4-(2-(3-azabicyclo[3.1 ,0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l -amino -5,7- dimethylisoquinolin-6-yl)rnethyl)-4-fluoro-lH-pyrrole-3-carboxamide (1-479); ethyl (6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(4-((2- oxopyridin- 1 (2H)-yl)methyl)benzyl)carbamate (1-480); ethyl (6-(((l-((ethoxycarbonyl)amino)-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (1-481) ;
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-482);
(Z)-N4-(4-(l-(lH-pyrazol-l-yl)prop-l-en-l-yl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-483);
N4-(4-(l-(lH-pyrazol-l-yl)propyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-484);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboxamide (1-485);
4-(((l -amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[l, 2, 4]tri azolof 1,5- a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (1-486);
4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (1-487);
4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylic acid (1-488); ethyl 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylate (1-489);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-sulfonamide (1-490);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-l,2,3-triazole-4-sulfonamide (1-491);
6-(((4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-492);
6-(((6-(l-(6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)ethoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-493 ); 7-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)-2,7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (1-494);
3-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methoxy)picolinic acid (1-495);
7-((l -amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-(((6-cy cl opropylimidazo[l,2-a]pyri din-2- yl)methyl)amino)-2,7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (1-496);
3-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-(((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)amino)picolinic acid (1-497);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrazin-8- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-498);
6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-499);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3H-imidazo[4,5-c]pyri din-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-500);
6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolo[4,5-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-501);
6-((12-azanyl)methyl)-N-(l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-
[ 1,2, 3]triazolo[4,5-c]pyridin-6-yl)-5,7-dimethylisoquinolin-l -amine (1-502);
6-(((l -((6-cyclopropyl-[l, 2, 4]tri azolof l,5-a]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyri din-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-503);
6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyri din-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-504);
2-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-oxopyrimidin-l(6H)- yl)methyl)-6-cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (1-505);
N2-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N3-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)pyridine-2,3-diamine (1-506); l-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(5-((6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methoxy)pyrimidin-4-yl)urea (1-507);
4-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2-methylbutan-2-ol (1-508); 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanamide (1-509);
3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanenitrile (1-510);
N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-((6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methyl)-l,2,4-thiadiazole-3,5-diamine (1-511);
6-(((6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[l,2-a]pyridin-2- yl)py rrolidin- 1 -yl)pyrimidin-4-yl)amino)methy l)-5 , 7-dimethy li soquinolin- 1 -amine (1-512); (3S,5R)-l-(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)-5-(6- cyclopropylimidazo[l,2-a]pyridin-2-yl)pyrrolidin-3-ol (1-513);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)isonicotinamide (1-514);
5.7-dimethyl-6-(((5-((2-methylquinolin-6-yl)methyl)-5H-pyrrolo[3,2-c]pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-515);
N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-cyclopropylimidazo[l,2-b]pyridazin- 2-yl)methyl)-N6-(2,2,2-trifluoroethyl)pyrimidine-4,6-diamine (1-516);
5.7-dimethyl-6-(((l-(quinolin-6-ylmethyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)isoquinolin-l -amine (1-517);
6-(((l-((3-chloroquinolin-6-yl)methyl)-lH-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-518);
6-(((3-((3-chloroquinolin-6-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-l-amine (1-519);
6-(((3-((3-chloroquinolin-6-yl)methyl)imidazo[l,5-a]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-520);
(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)imidazo[l,2-a]pyri din-3- yl)(naphthalen-2-yl)methanol (1-521);
5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyridin-6-yl)amino)methyl)- isoquinolin-1 -amine (1-522);
5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,5-a]pyrazin-6- yl)amino)methyl)isoquinolin- 1 -amine (1-523); 5.7-dimethyl-6-(((l-methyl-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-c]pyridin-5- yl)amino)methyl)isoquinolin-l -amine (1-524);
5.7-dimethyl-6-(((2-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyrazin-8- yl)amino)methyl)isoquinolin-l -amine (1-525);
5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-c]pyridin-5- yl)amino)methyl)isoquinolin-l -amine (1-526);
5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridin-5- yl)amino)methyl)isoquinolin-l -amine (1-527);
5.7-dimethyl-6-(((l-(quinolin-6-ylmethyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)isoquinolin-l -amine (1-528);
6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-
5.7-dimethylisoquinolin-l -amine (1-529);
6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-530);
6-(((l-((3-chloroquinolin-6-yl)methyl)-lH- pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-531);
6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-532);
6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-5- methylisoquinolin-1 -amine (1-533);
6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-7- methylisoquinolin- 1 -amine. (1-534);
6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-7- (trifluoromethyl)isoquinolin- 1 -amine (1-535); l-(4-(((6-(((l-amino-5-methylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)amino) methyl)benzyl)pyridin-2(lH)-one (1-536); l-(4-(((5-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3-yl)amino) methyl)benzyl)pyridin-2(lH)-one (1-537);
N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)oxazolo[5,4-d]pyrimidin-7-amine (1-538); 6-(((8-((3-chloroquinolin-6-yl)methyl)-9-methyl-9H-purin-6-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-539);
5,7-dimethyl-6-(((6-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine (1-540);
6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-4- fluoroisoquinolin- 1 -amine; or
6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)isoquinolin-l- amine; or a pharmaceutically acceptable salt thereof.
[0246] In some embodiments, a compound is selected from:
Figure imgf000111_0001
1-541 1-542 or a pharmaceutically acceptable salt thereof.
C. Pharmaceutical Compositions
[0247] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formulae (I)-(XVI-c) or a compound of Formulae (I)-(XVI-c) in combination with a pharmaceutically acceptable excipient (e.g., carrier).
[0248] The pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. A compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition may be covalently attached to a carrier moiety, as described above. Alternatively, a compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition is not covalently linked to a carrier moiety.
[0249] A “pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
[0250] The compounds of the invention can be administered alone or can be coadministered to the subject. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
[0251] In some embodiments, a test agent as described herein can be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and described herein for provided compounds.
D. Formulations
[0252] Compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.
[0253] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. [0254] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[0255] The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0256] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
[0257] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
[0258] When parenteral application is needed or desired, particularly suitable admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit dosages. The compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
[0259] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as well-known suspending agents.
Ill [0260] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
[0261] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
[0262] The quantity of active component in a unit dose preparation may be varied or adjusted according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
E. Effective Dosages
[0263] Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat HAE, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g. inhibiting PKa and/or decreasing the amount of bradykinin in a subject).
[0264] The dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to PKa inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention. [0265] For any provided compound or test agent, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing PKa enzymatic activity as measured, for example, using the methods described.
[0266] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring PKa inhibition and adjusting the dosage upwards or downwards, as described above.
[0267] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.
[0268] In one aspect, compounds provided herein display one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, ti/2, AUC, CL, bioavailability, etc.) when compared to a reference compound. In some embodiments, a reference compound is a PKa inhibitor known in the art. In some embodiments, a reference compound is a PKa inhibitor selected from those disclosed in PCT Publication Number WO 2019/178129.
F. Methods of Treatment
[0269] The present disclosure provides compounds for use in medicine. The present disclosure further provides the use of any compounds described herein for inhibiting the activity of PKa, which would be beneficial to treatment of PKa-mediated diseases and conditions.
Exemplary PKa-mediated disorders include edema, which refers to swelling in the whole body of a subject or a part thereof due to inflammation or injury when small blood vessels become leaky and releases fluid into nearby tissues. In some examples, the edema is HAE. In other examples, the edema occurs in eyes, e.g., diabetic macular edema (DME). The present disclosure provides methods of inhibiting the activity of PKa. In certain embodiments, the application provides a method of inhibiting the activity of PKa in vitro via contacting any of the compounds described herein with PKa molecules in a sample, such as a biological sample. In certain embodiments, the application provides a method of inhibiting the activity of PKa in vivo via delivering an effective amount of any of the compounds described herein to a subject in need of the treatment through a suitable route.
[0270] In certain embodiments, the methods comprise administering to a subject in need thereof (e.g., a subject such as a human patient with edema) any of the compounds described herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the methods comprise administering a compound of Formulae (I)-(XVI-c), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a compound of Formulae (I)- (XVI-c), or a pharmaceutically acceptable salt to a subject in need thereof.
[0271] In certain embodiments, the subject to be treated by any of the methods described herein is a human patient having, suspected of having, or at risk for edema, for example, HAE or diabetic macular edema (DME). A subject having an edema can be identified by routine medical examination, e.g., laboratory tests. A subject suspected of having an edema might show one or more symptoms of the disease/disorder. A subject at risk for edema can be a subject having one or more of the risk factors associated with the disease, for example, deficiency in Cl -INH as for HAE.
[0272] In certain embodiments, provided herein are methods of alleviating one or more symptoms of HAE in a human patient who is suffering from an HAE attack. Such a patient can be identified by routine medical procedures. An effective amount of one or more of the provided compounds can be given to the human patient via a suitable route, for example, those described herein. The compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKa inhibitor (e.g., ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).
[0273] In some embodiments, provided herein are methods or reducing the risk of HAE attack in a human HAE patient who is in quiescent stage. Such a patient can be identified based on various factors, including history of HAE attack. An effective amount of one or more of the compounds can be given to the human patient via a suitable route, for example, those described herein. The compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKa inhibitor (e.g, ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).
[0274] In some embodiments, provided herein is prophylactic treatment of HAE in human patients having risk to HAE attacks with one or more of the compounds described herein. In some embodiments, patients suitable for prophylactic treatment of HAE are human subjects suffering from HAE (e.g., having history of HAE attacks). In some embodiments, patients suitable for such prophylactic treatment are human subjects where a physician determines a history of HAE attacks warrants a prophylactic approach (e.g., human subjects experiencing more than a particular average number of attacks over a time period, including by way of nonlimiting example, one, two, or more attacks per month). Alternatively, patients suitable for the prophylactic treatment may be human subjects having no HAE attack history but bearing one or more risk factors for HAE (e.g, family history, genetic defects in Cl -INH gene, etc.) Such prophylactic treatment may involve the compounds described herein as the sole active agent, or involve additional anti-HAE agents, such as those described herein.
[0275] In certain embodiments, provided herein are methods for preventing or reducing edema in an eye of a subject (e.g., a human patient). In some examples, the human patient is a diabetic having, suspected of having, or at risk for diabetic macular edema (DME). DME is the proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leak, and retinal thickening in diabetes mellitus due to leaking of fluid from blood vessels within the macula. To practice this method, an effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, may be delivered into the eye of the subject where treatment is needed. For example, the compound may be delivered topically, by intraocular injection, or intravitreal injection. A subject may be treated with the compound as described herein, either as the sole active agent, or in combination with another treatment for DME. Non-limiting examples of treatment for DME include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and/or anti-PDGF agents.
[0276] In certain embodiments, the methods disclosed herein comprise administering to the subject an effective amount of a compound of Formulae (I)-(VLb), or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.
[0277] In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.
[0278] Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered at the same time as the compound of Formulae (I)- (XVI-c), or at different times than the compound of Formulae (I)-(XVI-c). For example, the compound of Formulae (I)-(XVl-c) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of the compound of Formulae (I)-(XVI-c) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formulae (I)-(XVI-c) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.
[0279] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of an edema, such as HAE or DME. Examples of such agents are provided herein.
Exemplary Enumerated Embodiments
1. A compound of F ormul a (I) :
CyB— L'— CyA— L— Cyc (I) or a pharmaceutically acceptable salt thereof, wherein:
CyA is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyA is substituted with 0-4 -RA groups; each RA is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, - SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur; each R is independently hydrogen or an optionally substituted C1-6 aliphatic group;
L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each Rz is independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group;
Figure imgf000119_0001
wherein: each of RB1 and RB2 is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;
RB3 is hydrogen or C1-6 aliphatic; RB4 is -N(RX)2; each Rx is independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. wherein no more than one of RB1 or RB2 is hydrogen; or
Figure imgf000120_0001
wherein:
RB5 is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of RB6 and RB7 is independently hydrogen or an optionally substituted Ci-6 aliphatic;
L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
Cyc is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups; each Lc is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each Rc is independently selected from oxo, halogen, -CN, -C(O)R,
-C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R,
-OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
2. The compound of embodiment 1, wherein the compound is of Formula (Il-a):
Figure imgf000121_0001
or a pharmaceutically acceptable salt thereof.
3. The compound of any one of embodiments 1-2, wherein the compound is of Formula (Ill-a), (IILb), (III-c), or (IILd):
Figure imgf000121_0002
(III-c) (in-d) or a pharmaceutically acceptable salt thereof.
4. The compound of any one of embodiments 1-2, wherein the compound is of Formula (III-a-1), (III-a-2), or (III-a-3):
Figure imgf000122_0001
or a pharmaceutically acceptable salt thereof.
5. The compound of any one of embodiments 1-3, wherein the compound is of Formula (III-b-1), (III-b-2), or (III-b-3):
Figure imgf000122_0002
(III-b-3) or a pharmaceutically acceptable salt thereof.
6. The compound of any one of embodiments 1-3, wherein the compound is of Formula
Figure imgf000122_0003
Figure imgf000123_0001
or a pharmaceutically acceptable salt thereof
7. The compound of any one of embodiments 1-6, wherein the compound is of Formula (V- a), (V-b), or (V-c):
Figure imgf000123_0002
(V-c) or a pharmaceutically acceptable salt thereof
8. The compound of any one of embodiments 1-6, wherein the compound is of Formula (VLa), (VLb), or (VI-c):
Figure imgf000123_0003
Figure imgf000124_0001
or a pharmaceutically acceptable salt thereof.
9. The compound of any one of embodiments 1-6, wherein the compound is of Formula (VILa), (VILb), or (VII-c):
Figure imgf000124_0002
(VII-c) or a pharmaceutically acceptable salt thereof.
10. The compound of any one of embodiments 1-6, wherein the compound is of Formula
(VIILa), (Vlll-b), or (VIILc):
Figure imgf000124_0003
(Vlll-a) (Vlll-b)
Figure imgf000125_0001
(VIII-c) or a pharmaceutically acceptable salt thereof.
11. The compound of any one of embodiments 1-6, wherein the compound is of Formula
Figure imgf000125_0002
(IX-c) or a pharmaceutically acceptable salt thereof.
12. The compound of any one of embodiments 1-6, wherein the compound is of Formula (X-
Figure imgf000125_0003
or a pharmaceutically acceptable salt thereof. 13. The compound of any one of embodiments 1-6, wherein the compound is of Formula
Figure imgf000126_0001
(XI-c) or a pharmaceutically acceptable salt thereof.
14. The compound of any one of embodiments 1-6, wherein the compound is of Formula
Figure imgf000126_0002
(XII-c) or a pharmaceutically acceptable salt thereof.
15. The compound of any one of embodiments 1-6, wherein the compound is of Formula (Xlll-a), (XIILb), or (XIILc):
Figure imgf000126_0003
(XIILa) (Xlll-b)
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof.
16. The compound of any one of embodiments 1-6, wherein the compound is of Formula
Figure imgf000127_0002
(XIV-c) or a pharmaceutically acceptable salt thereof.
17. The compound of any one of embodiments 1-6, wherein the compound is of Formula
(XV-a), (XV-b), or (XV-c):
Figure imgf000127_0003
(XV-a)
Figure imgf000128_0001
(XV-c) or a pharmaceutically acceptable salt thereof.
18. The compound of any one of embodiments 1-6, wherein the compound is of Formula
(XVI-a), (XVI-b), or (XVI-c):
Figure imgf000128_0002
(XVI-c) or a pharmaceutically acceptable salt thereof.
19. The compound of any one of embodiments 1-3, 5, or 7-18, wherein RB1 is hydrogen or Ci-6 aliphatic.
20. The compound of any one of embodiments 1-3, 5, or 7-19, wherein RB1 is hydrogen. 21. The compound of any one of embodiments 1-3, 5, or 7-19, wherein RB1 is Ci-6 aliphatic.
22. The compound of any one of embodiments 1-3, 5, 7-19, or 21, wherein RB1 is methyl
23. The compound of any one of embodiments 1-4 or 7-22, wherein RB2 is hydrogen or Ci-6 aliphatic.
24. The compound of any one of embodiments 1-4 or 7-23, wherein RB2 is hydrogen.
25. The compound of any one of embodiments 1-4 or 7-23, wherein RB2 is methyl, ethyl, - CF. or
26. The compound of any one of embodiments 1-4, 7-23, or 25, wherein RB2 is methyl.
27. The compound of any one of embodiments 1-3, 6, or 19-26, wherein RB3 is hydrogen.
28. The compound of any one of embodiments 1-3, 6, or 19-26, wherein RB3 is methyl.
29. The compound of any one of embodiments 1-6 or 19-26, wherein each Rx is hydrogen.
30. The compound of any one of embodiments 1-6 or 19-26, wherein each Rx is independently selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.
31. The compound of any one of embodiments 1-6 or 19-26, wherein one Rx is hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.
32. The compound of embodiment 1 or 2, wherein CyB is selected from the group consisting of:
Figure imgf000130_0001
33. The compound of embodiment 1, wherein the compound is of Formula (II-b):
Figure imgf000130_0002
or a pharmaceutically acceptable salt thereof.
34. The compound of embodiment 1 or 33, wherein RB5 is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl.
35. The compound of any one of embodiments 1 or 33-34, wherein RB6 is an optionally substituted Ci-6 aliphatic. 36. The compound of any one of embodiments 1 or 33-35, wherein RB7 is Ci-6 aliphatic.
37. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis phenylene, wherein CyA is substituted with 0-4 -RA groups.
38. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis a 5- to 6- membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups.
39. The compound of any one of embodiments 1-6, 10-36, or 38, wherein CyAis selected from the group consisting of phenylene, thiazolediyl, pyridinediyl, pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadiazolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein CyA is substituted with 0-4 -RA groups.
40. The compound of any one of embodiments 1-6 or 10-36, wherein CyA is an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups.
41. The compound of any one of embodiments 1-6, 10-36, or 40, wherein CyA is an 8- membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups.
42. The compound of any one of embodiments 1-6, 10-36, or 40, wherein CyA is a 9- membered bicyclic heteroarylene having 1-4 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups.
43. The compound of any one of embodiments 1-6, 10-36, or 40, wherein CyA is a 10- membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyA is substituted with 0-4 -RA groups. 44. The compound of any one of embodiments 1-6 or 10-36, wherein CyA is a 7- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 -RA groups.
45. The compound of any one of embodiments 1-6, 10-36, or 44, wherein CyA is a 9- membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyA is substituted with 0-1 -RA groups.
46. The compound of any one of embodiments 1-6, 10-36, or 44, wherein CyA is a 10- membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyA is substituted with 0-1 -RA groups.
47. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis selected from the group consisting of
Figure imgf000132_0001
Figure imgf000133_0001
wherein * represents the point of attachment to L’. 48. The compound of any one of embodiments 1-47, wherein each RAis independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.
49. The compound of any one of embodiments 1-9 or 12-48, wherein L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
50. The compound of any one of embodiments 1-9 or 12-49, wherein L’ is selected from the group consisting of
Figure imgf000134_0001
and O , wherein # represents the point of attachment to CyB.
51. The compound of any one of embodiments 1-9 or 12-50, wherein L’ is selected from the group consisting of:
Figure imgf000134_0002
, wherein # represents the point of attachment to CyB.
52. The compound of any one of embodiments 1-11 or 14-51, wherein L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a 5-membered saturated or partially unsaturated heterocyclene having 1 nitrogen heteroatom, optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein each R° is independently hydrogen of Ci-6 aliphatic. 53. The compound of any one of embodiments 1-11 or 14-52, wherein L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, or -S-.
54. The compound of any one of embodiments 1-11 or 14-52, wherein L is selected from the group consisting of:
Figure imgf000135_0001
wherein % represents the point of attachment to Cyc.
55. The compound of any one of embodiments 1-11, 14-52, or 54, wherein L is selected from the group consisting of:
Figure imgf000136_0001
wherein % represents the point of attachment to Cyc.
56. The compound of any one of embodiments 1-13 or 19-55, wherein Cyc is phenyl, wherein Cyc is substituted with 0-5 -Lc-Rc groups.
57. The compound of any one of embodiments 1-13 or 19-55, wherein Cyc is 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
58. The compound of any one of embodiments 1-13 or 19-55, wherein Cyc is pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein Cyc is substituted with 0-4 - Lc-Rc groups.
58. The compound of any one of embodiments 1-13, 19-55, or 58, wherein Cyc is selected from the group consisting of:
Figure imgf000136_0002
59. The compound of any one of embodiments 1-13 or 19-55, wherein Cyc is an 8- to 10- membered bicyclic aryl, wherein Cyc is substituted with 0-6 -Lc-Rc groups. 60. The compound of any one of embodiments 1-13, 19-55, or 59, wherein Cyc is indazolyl, benzotri azolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro- 2J/-benzo[Z>][l,4]oxazinyl, or dihydro-2/f-benzo[6][l,4]oxazinonyl, substituted with 0-6 -Lc-Rc groups.
61. The compound of any one of embodiments 1-13 or 19-55, wherein Cyc is a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups.
62. The compound of any one of embodiments 1-13, 19-55, or 61, wherein Cyc is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cyc is substituted with 0-6 -Lc- Rc groups.
63. The compound of any one of embodiments 1-13 or 19-55, wherein Cyc is selected from the group consisting of
Figure imgf000137_0001
Figure imgf000138_0001
64. The compound of any one of embodiments 1-13 or 19-55, wherein Cyc is
Figure imgf000138_0002
65. The compound of any one of embodiments 1-64, wherein Lc is selected from the group consisting of: *-NH-, *-NCH3-, *-O-, *-CH2-, *-CH2C(CH3)2-, *-CH2CH2-, *-CH2C(O)N(CH3)-, *-CH2C(O)N(CH3)CH2-, *-CF2-, *-CH(CH3)-, *-OCH2-, *-OCF2-, *-OC(CH3)2-, *-CH2C(O)-, *-OCH2C(O)-, *-CH2C(O)NH-,*-CH2C(O)NHCH2-,*-N(CH3)C(O)-, *-C(CH2CH3)-, *- C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cyc.
66. The compound of any one of embodiments 1-65, wherein each Rc is independently selected from oxo, halogen, -CN, -C(O)2R, -C(0)N(R)2, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3 - to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
67. The compound of any one of the preceding embodiments, wherein the compound is selected from compounds 1-1 through 1-540, or a pharmaceutically acceptable salt thereof.
68. A pharmaceutical composition comprising a compound of any one of the preceding embodiments.
69. The pharmaceutical composition comprising a compound of any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.
70. The composition of embodiment 68 or 69, wherein the composition is suitable for oral administration.
71. A method of treating a plasma kallikrein-mediated disease or disorder using a compound or composition of any one of the preceding embodiments.
72. The method of embodiment 71, wherein the disease or disorder is hereditary angioedema.
73. The method of embodiment 71, wherein the disease or disorder is diabetic macular edema.
74. A method of treating hereditary angioedema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments. 75. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.
76. The method of any one of embodiments 72 or 74, wherein administration of the compound partially or completely inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a hereditary angioedema.
77. The method of embodiment 76, wherein the compound is administered orally.
IV. Examples
[0280] In certain embodiments, the Examples describe compounds comprising one or more stereocenters, where a particular stereocenter is designated “S*” or “R* ” In both cases, the depiction of the generally indicates that the exact configuration is unknown (e.g., for a compound with a single stereocenter, the depiction R*- or S*- indicates that either the R- or S- isomer was isolated, but the configuration at the stereocenter of the particular isomer isolated was not determined).
[0281] It will be appreciated that compounds described within the Examples may comprise more than one stereocenter. As described above, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Within a particular compound name, where more than one “S*” or “R*” appear within a single pair of parentheses (e.g., “(1S*,2S*)”), it is understood that the S* and/or R* configurations are relative to each other. For example, a compound denoted “(1S*,2S*)-” or “(1R*,2R*)-” would be understood to refer specifically to either the “(1S,2S)-” or “(1R,2R)-” isomer, but not the “(1 S,2R)-” or “(1R,2S)-” isomers. Furthermore, a compound denoted “rac-(lS*,2S*)-” or “rac-(lR*,2R*)-” would be understood to include a racemic mixture of the “(1S,2S)-” and “(1R,2R)-” isomers. Similarly, a compound denoted “(1S*,2R*)-” or “(1R*,2S*)-” would be understood to refer specifically to either the “(1R,2S)-” or “(1S,2R)-” isomer, but not the “(1S,2S)-” or “(1R,2R)-” isomers. In addition, a compound denoted “rac-(lR*,2S*)-” or “rac-(lS*,2R*)-” would be understood to include a racemic mixture of the “(1R,2S)-” and “(1S,2R)-” isomers. [0282] In certain embodiments, the Examples include schemes that depict compounds with one or more stereocenters. In some embodiments, the symbol
Figure imgf000141_0001
followed by a number appears adjacent to a stereocenter. In such cases, it is understood to include a mixture of both configurations (e.g., R- and S-) at that position.
[0283] In some embodiments, the term “or” followed by a number appears adjacent to a stereocenter. In such cases, it is understood to denote either an “R-” or “S-” isomer, but the particular isomer was not determined.
[0284] In some embodiments, the numbering following the symbol
Figure imgf000141_0002
or term “or” refers to one stereocenter’s relation to another stereocenter in that compound. For example, where two stereocenters in a compound are each denoted with the same number (e.g., two instances of “&1”), it is understood that the configurations are relative to each other (e.g., if the structure is drawn as (S,S) and both stereocenters are denoted “&1”, it is understood to include a mixture of the (S,S) and (R,R) isomers, but not the (S,R) or (R,S) isomers). However, where each stereocenter is denoted with a different number (e.g., one instance of “&1” and one instance of “&2”), it is understood that that the configurations may be independent to each other (e.g., if the structure is drawn (S,S) and one stereocenter is denoted “&1” and one is denoted “&2,” it is understood to include a mixture of the (S,S), (S,R), (R,S), and (R,R) isomers).
Synthesis of Intermediates
Figure imgf000141_0003
[0285] Synthesis of methyl 4-cyclopropyl-3-methylbenzoate. To a solution of methyl 4- bromo-3 -methylbenzoate (700 mg, 3.1 mmol) in toluene/H2O = 1 : 1(10 mL) was added K3PO4 (1.95 g, 9.2 mmol), Pdi(dba)3 (283 mg, 0.31 mmol) and Xantphos (359 mg, 0.62 mmol). The mixture was stirred at 90 °C for 16 h under N2. After the reaction was cooled to room temperature, the reaction was quenched with NH4Q (sat. aq., 80 mL) and then extracted with DCM (100 mL x3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-70% EtOAc in PE to give methyl 4-cyclopropyl-3- methylbenzoate(390 mg, yield: 66%) as yellow oil . ESI-MS [M +H]+: 191.1.
[0286] Synthesis of (4-cyclopropyl-3-methylphenyl)methanol. To a solution of methyl 4- cy cl opropyl-3 -methylbenzoate (390 mg, 2.1 mmol) in THF (6 m ) was added LiAlIE (IM in THF, 6.3 mL, 6.3 mmol) dropwise slowly at 0 °C. The mixture stirred at 0 °C for 2 h. The reaction mixture was quenched NH4CI (sat. aq., 40 mL) at 0 °C and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-80% EtOAc in PE to give (4-cyclopropyl-3- methylphenyl)methanol(214 mg, yield: 63%) as colorless oil. ESLMS [M +H]+: 163.1.
Figure imgf000143_0001
[0287] Synthesis of ethyl 6-methyliniidazo[l,2-a]pyridine-2-carboxylate. A mixture of 5- methylpyridin-2-amine (500 mg, 4.6 mmol) and ethyl 3-bromo-2-oxopropanoate (1.8 g, 9.2 mmol) in EtOH (20 mL) was stirred at 95 °C for 12 h. After the reaction was cooled to room temperature, NaHCOi (sat. aq., 80 mL) was added, and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel (PE/EtOAc= 5/1) to give ethyl 6-methylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, yield: 32%). ESLMS [M +H]+: 205.2.
[0288] Synthesis of (6-methylimidazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6-methylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, 1.5 mmol) in THF (20 mL) was added LiAULi (1 M in THF, 3.0 mL, 3mmol) slowly at 0 °C under Nr. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was then quenched with water (5 mL), solid precipitate was filtered through the Celite1® and washed with MeOH (20 mL.) The filtrate was concentrated to give the crude product, which was purified by Prep-TLC (eluent: MeOH/DCM = 1/10) to give (6-methylimidazo[l,2-a]pyridin-2-yl)methanol (200 mg, yield: 82%) as a brown solid. ESLMS [M +H]+: 163.2
Figure imgf000143_0002
[0289] Synthesis of 2-imino-5-methylpyridin-l(2H)-amine. To a solution of 5- methylpyridin-2-amine (3.24 g, 30 mmol) in DCM (50 mL) was added O- (mesitylsulfonyl)hydroxylamine (12.9 g, 60 mmol) at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction was concentrated to give 2-imino-5-methylpyridin-l(2H)- amine (16.2 g, crude) as a yellow solid, which was used in the next step directly. ESI-MS [M +H]+: 124.1
[0290] Synthesis of ethyl 6-methyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate. A mixture of 2-imino-5-methylpyridin-l(2H)-amine (16.2 g, crude) and ethyl 2-chloro-2-oxoacetate (8.16 g, 60 mmol) in pyridine (50 mL) was stirred at 100 °C for 14 h. After the reaction was cooled to room temperature, the mixture was concentrated. The residue was diluted with NaHCCh (sat. aq., 100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: EtOAc/PE from 0 to 50%) to give ethyl 6-methyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (2.0 g, yield: 32 % over two steps) as a yellow solid. ESI-MS [M +H]+: 206.2
[0291] Synthesis of ethyl 6-methyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate. To a solution of ethyl 6-methyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (710 mg, 3.46 mmol)) in THF/EtOH (30mL/5 mL) was added LiBH4 (440 mg, 20.0 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h and then quenched with NH4Q (sat. aq., 50 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: EtOAc/PE from 0 to 100%) to give ethyl 6-methyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (450 mg, 80%) as a white solid. ESI-MS [M +H]+: 164.2.
Figure imgf000144_0001
[0292] Synthesis of 2-bromo-4-(hydroxymethyl)benzaldehyde. To a solution of methyl 3- bromo-4-cyanobenzoate (1.0 g, 4.17 mmol) in THF (10 mL) was added dropwise of DIBAL-H (IM in hexane, 12.5 mL, 12.5 mmol) at -65 °C. The mixture was stirred at -65 °C for 0.5 h. The resulting mixture was warmed to room temperature and stirred for another 0.5 h. The reaction mixture was quenched with NaOH (1 M aq., 20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give the residue, which was purified by column chromatography on silica gel, eluting with 0-20% EtOAc in PE to give 2-bromo-4-(hydroxymethyl)benzaldehyde (500 mg, yield: 56%) as a white solid. ESLMS [M +H]+: 215.0.
[0293] Synthesis of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde. To a solution of 2-bromo-4-(hydroxymethyl)benzaldehyde(500 mg, 2.33 mmol) in DCM (10 mL) was added Imidazole (476 mg, 6.99 mmol) and TBSC1 (351 mg, 2.33 mmol). The mixture was stirred at room temperature for 2 h. Water (20 mL) was added and extracted with ethyl acetate (20 mL*3). The organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude, which was purified by silica gel chromatography, eluting with 0-50% EtOAc in PE to give 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde (500 mg, yield: 65 %) as a white solid. ESLMS [M +H]+: 329.1
[0294] Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylquinazoline. To a mixture of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde (500 mg, 1.52 mmol) and acetamidine (265 mg, 4.56 mmol) in DMSO (5 mL) was added Cui (57 mg, 0.3 mmol), L- proline (70 mg, 0.61 mmol), and CS2CO3 (1.49 g, 4.56 mmol) at room temperature under N2 atmosphere. After the mixture was stirred at 70 °C for 1 h, the mixture was cooled to room temperature and filtered. The filter cake was washed with DCM/MeOH (v/v = 3/1, 30 mL). The filtrates were concentrated in vacuo and the residue was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated to give the residue, which was purified by column chromatography on silica gel, eluting with 0-5% MeOH in DCM to give 7-(((tert- butyldimethylsilyl)oxy)methyl)-2-methylquinazoline (100 mg, 23%) as a pale-yellow solid. ESIMS [M +H]+: 289.2
[0295] Synthesis of (2-methylquinazolin-7-yI)methanoi. To a solution of 7-(((tert- butyldimethylsilyl)oxy)methyl)-2-methylquinazoline (80 mg, 0.28 mmol) in MeOH (3 mL) was added HC1 (1 mL, 4M in MeOH) at room temperature, and the mixture was stirred at room temperate for 1 h. The reaction was concentrated to give to give (2-methylquinazolin-7- yl)methanol (50 mg, quant) as a white solid, which was used in the net step without purification.
ESLMS [M +H]+: 175.1
Figure imgf000146_0001
[0296] Synthesis of methyl 4-(l-aminocyclopropyl)benzoate. To a solution of methyl 4- cyanobenzoate (1.0 g, 6.21 mmol) in PhMe (20 mL) was added Ti(OPr-i)4 (1.9 g, 6.82 mmol) at -40 °C, followed by dropwise addition of EtMgBr (4.5 mL, 13.6 mmol, 3 M in ether). The mixture was stirred at -40 °C for 1 h, and boron trifluoride etherate (1.57ml, 12.7 mmol) was added at once. After the reaction mixture was stirred at the same temperature for 2 h, HC1 (2 M aq., 20 mL) was added to quench the reaction. The reaction mixture was filtered. The aqueous phase was separated, and the organic layer was washed with water (30 mL x 3). The combined aqueous layers were basified with NaOH (2 M aq.) to adjust the pH to 8. The mixture was then extracted with EtOAc (100 mL x 3). The combined organic layers were washed dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give methyl 4-(l- aminocyclopropyl)benzoate (290 mg, yield: 24.4%) as a white solid. ESLMS [M +H]+: 192.1.
[0297] Synthesis of methyl 4-(l-acetamidocyclopropyl)benzoate. To a solution of methyl 4- (l-aminocyclopropyl)benzoate (140 mg, 0.73 mmol) in DCM (10 mL) was added F.tiN (148 mg, 1.46 mmol) and AcCl (57 mg, 0.73 mmol). After the mixture was stirred at 0 °C for 1 h, water (10 mL) was added and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give methyl 4-(l-acetamidocyclopropyl)benzoate (140 mg, yield 82.3%) as a white solid. ESIMS [M +H]+: 234.1 [0298] Synthesis ofN-(l-(4-(hydroxymethyl)phenyl)cyclopropyl)acetamide. To a solution of methyl 4-(l-acetamidocyclopropyl)benzoate (140 mg, 0.60 mmol) in THF (10 mL) was added DIBAL-H (1.8 mL, IM in hexane, 1.80 mmol) at -60 °C. After the mixture was stirred at -60 °C for 1 h, the reaction mixture was quenched with H2O (20 mL) at -60 °C and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give N-(l-(4- (hydroxymethyl)phenyl)cyclopropyl)acetamide (25 mg, yield 20.3%) as white solid. ESI-MS [M + H]+: 206.1.
Figure imgf000147_0001
[0299] Synthesis of (4-bromo-3,5-dimethylphenyl)methanol. To a solution of 4-bromo-3,5- dimethylbenzaldehyde (106 mg, 0.5 mmol) in EtOH (2 mL) was added NaBHi(38 mg, 1 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched by H2O (0.5 mL) and concentrated in vacuo to give the crude, which was purified by Prep-
TLC(DCM/MeOH=20/l) to give (4-bromo-3, 5 -dimethylphenyl)m ethanol (80 mg, yield: 75%) as a yellow solid. ESI-MS (M+H)+:214.1.
[0300] Synthesis of 5-((benzyloxy)methyl)-2-bromo-l,3-dimethylbenzene. To a solution of (4-bromo-3,5-dimethylphenyl)methanol (85 mg, 0.4 mmol) in THF(5 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then benzyl chloride (126 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 15 h. The reaction was then quenched by NH4CI (sat.aq., 20 mL) and extracted by EtOAc (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (PE/EtOAc=l/l) to give 5-((benzyloxy)methyl)-2-bromo-l,3-dimethylbenzene (84 mg, yield: 69%) as a yellow oil. ESI-MS (M+H)+: 305.1.
[0301] Synthesis of tert-butyl 2-(4-((benzyloxy)methyl)-2,6-diniethylphenyl)acetate. To a solution of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 mL, 0.4 mmol, 0.4 M in THF) in THF (3 mL) was added 5-((benzyloxy)methyl)-2-bromo-l,3-dimethylbenzene (84 mg, 0.28 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and X-Phos (28 mg, 0.06 mmol) under N2. The mixture was stirred at 70 °C for 4 h. After the mixture was cooled to room temperature, the reaction was filtered by Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated in vacuo to give the residue, which was purified by Prep-TLC (PE/EtOAc=3/l) to afford tert-butyl 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetate (56 mg, yield: 59%) as a yellow oil. ESI-MS (M+H)+:341.2.
[0302] Synthesis of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetic acid. To a solution of tert-butyl 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetate (56 mg, 0.16 mmol) in DCM (3 mL) was added TFA (0.5 mL). After the mixture was stirred at room temperature for 2 h, water (15 mL) was added to dilute the reaction, and the pH of the mixture was adjusted to 5-6 by adding NaHCCh (sat. aq.). The reaction mixture was extracted with DCM (20 mL x 3). The combined organics were concentrated in vacuo to give 2-(4-((benzyloxy)methyl)-2,6- dimethylphenyl)acetic acid (60 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS (M+H)+:285.2.
[0303] Synthesis of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide.
To a solution of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetic acid (60 mg, crude) in DMF (2 mL) was added HOBT (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). The mixture was stirred at room temperature for 30 min. Then dimethylamine (8 mg, 0.17 mmol) and DIPEA (66 mg, 0.51 mmol) was added. The reaction was stirred at room temperature for another 16 h. The reaction was quenched by water (10 mL) and extracted by EtOAc(10 mLx3). The combined organic layers were concentrated in vacuo, and the residue was purified by Prep-TLC (PE/EtOAc=l/l)to give 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide (40 mg, yield: 80% over 2 steps) as a yellow oil. ESI-MS (M+H)+:312.2. [0304] Synthesis of 2-(4-(hydroxymethyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide.
To a solution of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide (40 mg, 0.13 mmol) in MeOH (4 mL) was added Pd/C(10 mg). After the reaction was stirred at room temperature for 1 h under H2, the mixture was filtered through Celite®. The filter cake was washed with MeOH (15 mL), and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (PE/EtOAc=l/2) to give 2-(4-(hydroxymethyl)-2,6-dimethylphenyl)-N,N- dimethylacetamide (24 mg, yield: 84%) as a pale solid. ESLMS (M+H)+:222.3.
Synthesis ofN-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methylpyrrolidine-l- carboxamide
Figure imgf000149_0001
[0305] Synthesis of tert-butyldimethyl((4-nitrobenzyl)oxy)silane. To a solution of (4- nitrophenyl)m ethanol (5.0 g, 32.65 mmol) in DMF (10 mL) was added imidazole (6.7 g, 98.41 mmol) and TBSC1 (4.9 g, 32.51 mmol) at 0 °C. After the mixture was stirred 0 °C for 1 h, the reaction was quenched with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give tert-butyldimethyl((4-nitrobenzyl)oxy)silane (8.0 g, yield: 92%) as a white solid. ESLMS [M +H]+: 268.1
[0306] Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline. To a solution of tert- butyldimethyl((4-nitrobenzyl)oxy)silane (2.0 g, 7.5 mmol) in MeOH (20 mL) was added Pd/C (0.2 g) at room temperature, the mixture was stirred at this temperature under H2 atmosphere for 14 h. Then the mixture was filtered through celite, the filter cake was washed with MeOH (20 mL), and the filtrates was concentrated to give the crude, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give 4-(((tert- butyldimethylsilyl)oxy)methyl)aniline (1.25 g, yield: 70%) as a white solid. ESLMS [M +H]+: 238.1 [0307] Synthesis of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde. To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline (3.8 g, 16 mmol) in MeOH (20 mL) was added formaldehyde (482 mg, 16 mmol) and NaOCHa (1.7 g, 32 mmol). The mixture was stirred at 80 °C for 3 h. After cooling to room temperature, NaBEh (1.2 g, 32 mmol) was added to the solution and the mixture was stirred at rt for another 1 h. Water (50 mL) was added, and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaaSCU, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (1.0 g, yield 24.9%) as white solid. ESI-MS [M +H]+: 252.2
[0308] Synthesis of N-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N- methylpyrrolidine-1 -carboxamide. To a solution of pyrrolidine- 1 -carbonyl chloride (107 mg, 0.80 mmol) in DCM (10 mL) was added 4-(((tert-butyldimethylsilyl)oxy)methyl)-N- methylaniline (200 mg, 0.80 mmol) and pyridine (190 mg, 2.4 mmol). The mixture was stirred at 0 °C for 5 h. Water (50 mL) was added and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give N-(4-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-N-methylpyrrolidine-l-carboxamide (120 mg, yield: 43%) as a white solid. ESI-MS [M +H]+: 349.2
Synthesis of l-(4-(hydroxymethyl)phenyl)-l,3,3-trimethylurea
Figure imgf000150_0001
[0309] Synthesis of tert-butyldimethyl((4-nitrobenzyl)oxy)silane. To a solution of dimethylcarbamoyl chloride (137 mg, 1.27 mmol) in DCM (10 mL) was added 4-(((tert- butyldimethylsilyl)oxy)methyl)-N-methylaniline (320 mg, 1.27 mmol) and pyridine (300 mg, 3.81 mmol). The mixture was stirred at 40 °C for 5 h. Water (20 mL) was added and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give N-(4-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-N-methylpyrrolidine-l-carboxamide (126 mg, yield: 31%) as a white solid. ESLMS [M +H]+: 323.2
[0310] Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline. To a solution of l-(4-
(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-l,3,3-trimethylurea (50 mg, 0.15 mmol) in EtOAc (5.0 mL) was added HC1 (1 mL, 4 M in EtOAc). The resulting mixture was stirred at room temperature for 5 h, then concentrated. The residue was neutralized with NH3 (2 mL, 7 M in MeOH) and stirred for 10 min then concentrated, the residue was purified by Prep-TLC to give l-(4-(hydroxymethyl)phenyl)-l,3,3-trimethylurea (16 mg, yield: 49.6%) as a white solid. ESL MS [M +H]+: 209.1
Synthesis of (2,3-dimethylquinoxalin-6-yl)methanol
Figure imgf000151_0001
[0311] Synthesis of methyl 3-methylquinoxaline-6-carboxylate. To a solution of methyl
3, 4-di aminobenzoate (180 mg, 1.08 mmol) in MeOH (5 mb) was added oxopropanal (117 mg, 1.62 mmol). After the resulting mixture was stirred at 25 °C for 24 h, the reaction was concentrated in vacuo. The residue was diluted with H2O (25 mL) and extracted with DCM (20 mL x 3). The combined organics were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give methyl 3-methylquinoxaline-6-carboxylate (100 mg, yield 45.8%) as a white solid. ESLMS [M +H]+: 203.1
[0312] Synthesis of (2,3-dimethylquinoxalin-6-yl)methanol. To a solution of methyl 3- methylquinoxaline-6-carboxylate (100 mg, 0.46 mmol) in THF (5 mL) was added dropwise of DIBAL-H (IM in THF, 1.38 mL, 1.38 mmol) at -65 °C. The mixture was stirred at -65 °C for 0.5 h. The resulting mixture was warmed to room temperature and stirred for another 0.5 h. The reaction mixture was quenched with NaOH (1 M aq., 5 mL) and water (15 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-20% EtOAc in PE to give (2,3 -dimethylquinoxalin-6-yl)m ethanol (40 mg, yield: 46.2%) as a white solid. ESLMS [M +H]+: 189.1
Figure imgf000152_0001
[0313] To a solution of ethyl chloroformate (173 mg, 1 .59 mmol) in DCM (10 mL) was added 4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (400 mg, 1.59 mmol) and pyridine (377 mg, 4.77 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 h. Water (20 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NazSCh, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give ethyl (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)carbamate (459 mg, yield: 89%) as white solid. ESLMS [M +H]+: 324.2
Figure imgf000152_0002
[0314] Synthesis of (4-bromo-3-methylphenyl)methanol. To a solution of 4-bromo-3- methylbenzaldehyde (100 mg, 0.5 mmol) in EtOH (4 mL) was added NaBHi (38 mg, 1 mmol).
The mixture was stirred at room temperature for 2 h. The reaction was quenched by H2O (1 mL) and concentrated in vacuo to give the crude, which was purified by Prep- TLC(DCM/MeOH=20/l) to give (4-bromo-3-methylphenyl)methanol (80 mg, yield: 80%) as a yellow solid. ESLMS (M+H)+:201.1. [0315] Synthesis of 4-((benzyloxy)methyl)-l-bromo-2-methylbenzene. To a solution of (4- bromo-3-methylphenyl)methanol (80 mg, 0.4 mmol) in THF(4 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then (chloromethyl)benzene (126 mg, 1.0 mmol) was added. The resulting mixture was stirred at room temperature for 15 h. The reaction was quenched by NHtCl (sat.aq., 20 mL) and extracted by EtOAc (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo to give the crude, which was purified by Prep-TLC (PE/EtOAc=l/l) to give 4-((benzyloxy)methyl)-l-bromo-2-methylbenzene (84 mg, yield:72%) as a yellow oil. ESLMS (M+H)+:291.1.
[0316] Synthesis of tert-butyl 2-(4-((benzyloxy)methyl)-2-methylphenyl) acetate. To a solution of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1.1 mL, 0.4 M in THF, 0.44 mmol) in THF (4 mL) was added 4-((benzyloxy)methyl)-l-bromo-2-methylbenzene (84 mg, 0.29 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and X-Phos (28 mg, 0.06 mmol). After the mixture was stirred at 70 °C for 4 h under N2, the mixture was cooled to room temperature and then filtered by Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated in vacuo to give the residue, which was purified by Prep-TLC (PE/EtOAc=3/l) to afford tert-butyl 2-(5-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)acetate (56mg, yield: 59%) as a yellow oil. ESLMS (M+H)+: 327.1.
[0317] Synthesis of 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetic acid. To a solution of tert-butyl 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetate (56 mg, 0.17 mmol) in DCM (3 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 h. Water (15 mL) was added, and the pH of the reaction was adjusted to 5-6 by adding NaHCCh (sat. aq.). The reaction was extracted with DCM (20 mL*3). The combined organics were concentrated in vacuo to give 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetic acid (60 mg, crude) as a yellow solid. ESI-MS (M+H)+:271.2.
[0318] Synthesis of 2-(4-((benzyloxy)niethyl)-2-methylphenyl)-N,N-dimethylacetamide.
To a solution of 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetic acid (60 mg, crude) in DMF (3 mL) was added HOBT(35 mg, 0.26 mmol) and EDCI(50 mg, 0.26 mmol). The mixture was stirred at room temperature for 30 min. Then dimethylamine (12 mg, 0.25 mmol) and DIPEA (66 mg, 0.51 mmol) were added. The resulting reaction mixture was stirred at room temperature for another 16 h. The reaction was quenched by H2O (20 mL) and extracted by EtOAc (20 mL><3). The combined organics were concentrated in vacuo and the residue was purified by Prep-TLC (PE/EtOAc=l/l)to give 2-(4-((benzyloxy)methyl)-2-methylphenyl)-N,N-dimethylacetamide(40 mg, yield: 80%) as a yellow oil. ESI-MS (M+H)+:298.2.
[0319] Synthesis of 2-(4-(hydroxymethyl)-2-methylphenyl)-N,N-dimethylacetamide. To a solution of 2-(4-((benzyloxy)methyl)-2-methylphenyl)-N,N-dimethylacetamide(40 mg, 0.13 mmol) in MeOH (4 mL) was added Pd/C(10 mg). The reaction was stirred at room temperature for 1 h under H2. The mixture was filtered through Celite®. The filter cake was washed with MeOH (10 mL), and the filtrate was concentrated and purified by Prep-TLC (PE/EtOAc=l/2) to give 2-(4-(hydroxymethyl)-2-methylphenyl)-N,N-dimethylacetamide(24 mg, yield: 88%) as a pale solid. ESI-MS (M+H)+:208.3.
Figure imgf000154_0001
[0320] Synthesis of 7-bromo-2-methylquinoline. A mixture of 3 -bromoaniline (500 mg, 2.91 mmol) and 2,4,6-trimethyl-l,3,5-trioxane (3.46 g, 26.19 mmol) in HC1 (cone. 5 mL) was stirred at room temperature for 1 hour, and then heated to reflux for 3 hours. After cooling to 0 °C, a solution of NaOH (sat. aq., 10 mL) was added slowly and the mixture was extracted with DCM (20 mL*3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated to give the crude, which was purified by flash column chromatography on silica gel, eluting with 0-10% EtOAc/PE to afford 7-bromo-2-methylquinoline (100 mg, yield: 15%) as pale-yellow solid. ESI-MS [M +H]+: 222.2.
[0321] Synthesis of 2-methylquinoline-7-carboxylic acid. To a solution of 7-bromo-2- methylquinoline(146 mg, 0.66 mmol) in THF (5 mL) was added n-BuLi (0.66 mL, 2M in hexane, 1.32 mmol) slowly at -78 °C under CO2. After the mixture was stirred at - 78 °C for 3 h, the reaction was quenched by NH4CI (sat.aq., 10 mL) and extracted by EtOAc (20 mL*3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (PE/EtOAc=l/l) to give 2-methylquinoline-7-carboxylic acid (100 mg, yield: 81%) as a yellow oil. ESI-MS (M+H)+: 188.1.
[0322] Synthesis of (2-methylquinolin-7-yl)methanol . To a solution of 2-methylquinoline-
7-carboxylic acid (100 mg, 0.53 mmol) in THF (5 mL) was added BHs-THF (2 mL, 1 M in THF, 2 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched by NEECl (sat. aq., 10 mL) and extracted by EtOAc (20 mL*3). The combined organic layers were dried over NazSCE and concentrated to give the crude, which was purified by Prep- TLC (MeOH/DCM=l :20) to give (2-methylquinolin-7-yl)methanol (30 mg, yield: 33%) as a pale solid. ESLMS (M+H)+: 174.1.
Synthesis of 3-(4-(hydroxymethyl)benzyl)-l-methylpyridin-2(lH)-one
Figure imgf000155_0001
[0323] Synthesis of methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate. To a solution of methyl 4-(bromomethyl)benzoate (1 g, 4.37 mmol) in MeOH(15 mL) was added (2- methoxypyridin-3-yl)boronic acid (802 mg, 5.24 mmol), Pd(PPhs)4(509 mg, 0.44 mmol), and Na2CO3(1.6 g, 13.11 mmol). The mixture was stirred at 115 °C for 2 h under N2. After cooled to the room temperature, the reaction was diluted with H2O (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by column chromatography on silica gel, eluting with 0-100% EtOAc in PE to give methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate(500 mg, yield: 44%) as a yellow solid. ESI-MS (M+H)+: 258.1.
[0324] Synthesis of 4-((2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoic acid. A mixture of methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate (300 mg, 1.17 mmol) in HBr (40% in AcOH, 5 mL) was stirred at 70 °C for 16 h under N2. After cooled to the room temperature, the reaction was concentrated, and the residue was diluted with water (20 mL) and neutralized with NaHCO3(sat. aq.) to adjust to pH to 6, then extracted by EtOAc (40 mL*3). The combined organics were concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0-100% EtOAc in PE to give 4-((2-oxo-l,2-dihydropyridin-3- yl)methyl)benzoic acid (250 mg, yield: 93%) as a yellow solid. ESI-MS (M+H)+:230.1.
[0325] Synthesis of methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoate.
To a solution of 4-((2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoic acid (98 mg, 0.43 mmol) in DMF(3 mL) was added Mel (303 mg, 2.15 mmol) and NaH (60% in mineral oil, 86 mg, 2.15 mmol). The mixture was stirred at room temperature for 6 h. Water (10 mL) was added and the reaction was extracted by EtOAc (10 mL x 3). The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0- 60% EtOAc in PE to give methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoate (80 mg, yield: 72%) as a yellow oil. ESLMS (M+H)+: 258.1.
[0326] Synthesis of 3-(4-(hydroxymethyl)benzyl)-l-methylpyridin-2(lH)-one. To a solution of methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoate (80 mg, 0.31 mmol) in THF (4 mL) was added Li Al FL (24 mg, 0.62 mmol) at 0 °C. After the reaction was stirred at 0 °C for 1 h, the reaction was quenched by NaSO-i-10H2O (500 mg) and stirred at room temperature for lOmin. The mixture was filtered through Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated and purified by Prep-TLC (DCM/MeOH=20/l) to give 3-(4-(hydroxymethyl)benzyl)-l-methylpyridin-2(lH)-one(50 mg, yield: 70%) as a yellow solid. ESI-MS (M+H)+:230.1.
Figure imgf000156_0001
[0327] Synthesis of 3-cyclopropylbenzoic acid. To a solution of l-bromo-3- cyclopropylbenzene (400 mg, 2.05 mmol) in THF (5 mL) was added n-BuLi (2M in THF, 2 mL, 4 mmol) slowly at -78 °C under CO2. After the mixture was stirred at -78 °C for 3 h, the reaction was quenched by NH4Q (sat.aq., 20 mL) and extracted by EtOAc(20 mLx3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (PE/EtOAc=l/l) to give 2-methylquinoline-7-carboxylic acid (200 mg, yield: 60%) as a yellow oil. ESI-MS (M+H)+: 163.2.
[0328] Synthesis of (3-cyclopropylphenyl)methanol. To a solution of 3 -cyclopropylbenzoic acid (200 mg, 1.23 mmol) in THF (5 mL) was added to BH3-THF (3 mL, 1 M in THF, 3 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched by NH4Q (sat.aq., 20 mL), and extracted by EtOAc(20 mL*3). The combined organic layers were dried over Na2SC>4 and concentrated to give the crude, which was purified by Prep-TLC (MeOH/DCM=l :20) to give (3-cyclopropylphenyl)methanol (150 mg, yield: 82%) as a pale solid. ESI-MS (M+H)+: 149.2.
Synthesis of (S)-l-phenylethan-l-ol
Figure imgf000157_0001
[0329] To a solution of acetophenone (1 g, 8.32 mmol) in MeOH (10 mL) was added NaBHi (629 mg, 16.64 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched by NH4Q (sat. aq., 20 mL) and extracted by EtOAc (30 mL*3). The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 0-20% MeOH in DCM to give 1-phenylethan-l-ol (800 mg, yield: 79%) as a pale solid. ESI-MS (M+H)+: 123.2.
Synthesis of 4-(chloromethyl)-l -methyl-2-(trifluoromethyl)benzene
Figure imgf000157_0002
[0330] To a solution of 4-methyl-3-(trifluoromethyl)benzoic acid (500 mg, 2.45 mmol) in THF (10 mL) was added to BH3-THF(10 mL, 1 M in THF, 10 mmol) at 0°C. The mixture was stirred at room temperature for 16 h. The reaction was quenched by HC1 (IM aq., 10 mL), and extracted by EtOAc (20 mL*3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (MeOH/DCM=l :20) to give 4- (chloromethyl)- l-methyl-2-(trifluoromethyl)benzene (400 mg, yield: 86%) as a pale solid. ESIMS (M+H)+: 191.1.
Synthesis of (4-((l,3,4-oxadiazol-2-yl)methyl)phenyl)methanol
Figure imgf000158_0001
[0331] Synthesis of 2-(4-(hydroxymethyl)phenyl)acetohydrazide. A mixture of ethyl 2-(4- (hydroxymethyl)phenyl)acetate (200 mg, 1.03 mmol) and hydrazine solution (0.1 mL, 80% aq.) in MeOH (4 mL) was stirred at 50 °C for 3 h. After the reaction mixture was cooled to room temperature, the mixture was concentrated in vacuo to afford 2-(4- (hydroxymethyl)phenyl)acetohydrazide (180 mg, yield: 97%) as a yellow solid, which was used in the next step without purification. ESI-MS [M +H]+: 181.1
[0332] Synthesis of (4-((l,3,4-oxadiazol-2-yl)niethyl)phenyl)methanol. To a solution of 2- (4-(hydroxymethyl)phenyl)acetohydrazide (100 mg, 0.56 mmol) in xylene (5 mL) was added triethoxymethane (415 mg, 2.80 mmol) and AcOH (1 mL), and the mixture was stirred at 140 °C for 20 h. After the reaction mixture was cooled to room temperature, the reaction was quenched with NaHCOs (sat. aq.,15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were concentrated and purified by Prep-TLC(EtOAc/ PE=2/1) to give (4-((l ,3,4- oxadiazol-2-yl)methyl)phenyl)methanol (80 mg, yield: 75%) as a white solid. ESLMS [M +H]+: 191.2
Figure imgf000158_0002
[0333] Synthesis of ethyl 2-oxo-2H-[l,2'-bipyridine]-5'-carboxylate. To a solution of ethyl
6-chloronicotinate (650 mg, 3.51 mmol) and pyridin-2(lH)-one (500 mg, 5.27 mmol) in DMF (15 mL) was added K2CO3 (1.21 g, 8.78 mmol), and the mixture was stirred at 80 °C for 10 h. After the reaction mixture was cooled to room temperature, the reaction was quenched with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc/PE to give ethyl 2-oxo-2H-[l,2'-bipyridine]-5'-carboxylate (550 mg, yield: 64%) as a yellow solid. ESLMS [M +H]+: 245.2
[0334] Synthesis of 5'-(hydroxymethyl)-2H-[l,2'-bipyridin]-2-one. To a solution of 2-oxo- 2H-[l,2'-bipyridine]-5'-carboxylate (280 mg, 1.15 mmol) in EtOH (5 mL) was added NaBEh (131 mg, 3.45 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc/PE to give 5'-(hydroxymethyl)-2H-[l,2'-bipyridin]-2-one (210 mg, yield: 91%) as a white solid. ESLMS [M +H]+: 203.2
Synthesis of (4-(2-(lH-pyrazol-l-yl)ethyl)phenyl)methanol
Figure imgf000159_0001
[0335] Synthesis of ethyl 4-(2-chloroethyl)benzoate. To a solution of 4-(2- chloroethyl)benzoic acid (5.0 g, 27.17 mmol) in EtOH (80 mL) was added con. H2SO4 (2 mL), and the mixture was reflux for 12 h. After the reaction was cooled to room temperature, the reaction mixture was concentrated, the residue was diluted with water (50 mL) and neutralized with Na2COs (sat. aq., 50 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc/PE to give ethyl 4-(2-chloroethyl)benzoate (5.3 g, yield: 92%) as a yellow solid. ESLMS [M +H]+: 213.2
[0336] Synthesis of ethyl 4-(2-(lH-pyrazol-l-yl)ethyl)benzoate. To a solution of ethyl 4-(2- chloroethyl)benzoate (1.0 g, 4.72 mmol) in DMF (10 mL) was added CS2CO3 ( 4.6 g, 14.16 mmol), Nal (2.1 g, 14.16 mmol), and IH-pyrazole (481 mg, 7.08 mmol), and the mixture was stirred at 90 °C for 12 h. After the reaction mixture was cooled to room temperature, water (50 mL) was added, and the reaction was extracted with EtOAc (80 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc/PE to give ethyl 4-(2-(lH-pyrazol-l-yl)ethyl)benzoate (550 mg, yield: 48%) as a yellow solid. ESI-MS [M +H]+: 245.2
[0337] Synthesis of (4-(2-(lH-pyrazol-l-yl)ethyl)phenyl)methanol. To a solution of ethyl 4- (2-(lH-pyrazol-l-yl)ethyl)benzoate (50 mg, 0.20 mmol) in MeOH (1 mL) and THF (1 mL) was added LiBHi (13 mg, 0.60 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was concentrated and purified by Prep-TLC (PE/EtOAc=l/l) to give (4-(2-(lH-pyrazol- l-yl)ethyl)phenyl)methanol (30 mg, yield: 73%) as a white solid. ESLMS [M +H]+: 203.2
Synthesis of l-(4-(hydroxymethyl)phenethyl)pyridin-2(lH)-one
Figure imgf000160_0001
[0338] Synthesis of ethyl 4-(2-(2-oxopyridin-l(2H)-yl)ethyl)benzoate. To a solution of ethyl 4-(2-chloroethyl)benzoate (106 mg, 0.50 mmol) in DMF (5 mL) was added CS2CO3 ( 489 mg, 1.50 mmol), Nal (225 mg, 1.50 mmol), and pyridin-2-ol (71 mg, 0.75 mmol), and the mixture was stirred at 90 °C for 16 h. After the reaction mixture was cooled to room temperature, the reaction mixture was quenched with H2O (25 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated and purified by Prep-TLC (PE/EtOAc=l/l) to give ethyl 4-(2-(2-oxopyridin-l(2H)-yl)ethyl)benzoate (71 mg, yield: 52%) as a yellow solid. ESLMS [M +H]+: 272.2
[0339] Synthesis of l-(4-(hydroxymethyl)phenethyl)pyridin-2(lH)-one. To a solution of ethyl 4-(2-(2-oxopyridin-l(2H)-yl)ethyl)benzoate (71 mg, 0.26 mmol) in MeOH (1 mL) and THF (1 mL) was added LiBFL (18 mg, 0.78 mmol), and the mixture was stirred at room temperature for 3 h. The reaction was concentrated and purified by Prep-TLC (PE/EtOAc=l/2) to give l-(4-(hydroxymethyl)phenethyl)pyridin-2(lH)-one (31 mg, yield: 52%) as a white solid.
ESI-MS [M +H]+: 230.2
Synthesis of (7-chloroquinolin-3-yl)methanol
Figure imgf000161_0001
[0340] To a solution of 7-chloroquinoline-3-carboxylic acid (500 mg, 2.41 mmol) in THF (10 mL) was added isobutyl chloroformate (658 mg, 4.82 mmol) and EtsN (487 mg, 4.82 mmol) at -20 °C, and the mixture was stirred at -20 °C for 20 min. After the mixture was warmed to 0 °C, NaBH4 (275 mg, 7.23 mmol) was added and the reaction was stirred at room temperature for 18 h. Water (30 mL) was added and the reaction was extracted with EtOAc (40 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc/PE to give (7-chloroquinolin-3-yl)methanol (121 mg, yield: 26%) as a yellow solid. ESI-MS [M +H]+: 194.1
Figure imgf000161_0002
[0341] To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (500 mg, 3.01 mmol) in DMF (10 mL) was added dimethyl amine (180 mg, 4 mmol), EDCI (1.1 g, 6.02 mmol), and HOBT (813 mg, 6.02 mmol) and DIPEA (1.9 g, 15.05 mmol). The mixture was stirred at room temperature for 3 h. Water (100 mL) was added, and the reaction was extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc/PE to give 2-(4- (hydroxymethyl)phenyl)-N,N-dimethylacetamide ( 470 mg, yield: 81%) as a yellow solid. ESIMS [M +H]+: 194.2
Figure imgf000162_0001
[0342] To a solution of (lH-benzo[d]imidazol-2-yl)methanol (148 mg, 1 mmol) in MeCN (10 mL) was added KF (116 mg, 2 mmol) and diethyl (bromodifluoromethyl)phosphonate (266 mg, 1 mmol), the mixture was stirred at room temperature for 12 h under N2. The reaction was quenched with water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc/PE to give 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide (150 mg, yield: 75%) as a yellow solid. ESI-MS [M +H]+: 199.2
Synthesis of (6-bromoquinolin-2-yl) methanol
Figure imgf000162_0002
[0343] Synthesis of 6-bromoquinoline-2-carbaldehyde. SeCh (103 mg, 1.2 mmol, 1.3 eq) in suspension in dioxane (5 mL) was heated at 60°C. 6-bromoquinaldine (200 mg, 0.9 mmol) was added, and the mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered through celite, washed with dioxane, and concentrated under reduced pressure to give 6-bromoquinoline-2-carbaldehyde (330 mg, crude) as a white solid, which was used in the next step without purification. ESI-MS [M +H]+: 236.2
[0344] Synthesis of (6-bromoquinolin-2-y I) methanol. To a solution of 6-bromoquinoline-2- carbaldehyde (330 mg, crude) in EtOH (10 mL) was added sodium borohydride (58 mg, 1.5 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by Prep-TLC (EtOAc/PE=l/l) to give (6-bromoquinolin- 2-yl)methanol (120 mg, yield: 56% over 2 steps) as a white solid. ESI-MS [M +H]+: 238.2 Synthesis of (8-methylquinolin-3-yl)methanol NaBH4, Pd(dppf)CI2 . TMEDA
Figure imgf000163_0001
THF, r.t., 12 h HO^XXCX
[0345] Synthesis of (2-chloro-8-niethylquinolin-3-yl)methanol. To a solution of 2-chloro- 8-methylquinoline-3-carbaldehyde (205 mg, 1.00 mmol) in MeOH (5 mL) was added NaBHi (114 mg, 3.00 mmol), and the mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc/PE to (2-chloro-8-methylquinolin-3-yl)methanol (200 mg, yield: 97%) as a white solid. ESLMS [M +H]+: 208.2
[0346] Synthesis of (8-methylquinolin-3-yl)nethanol. To a solution of (2-chloro-8- methylquinolin-3-yl)m ethanol (200 mg, 0.97 mmol) in THF (5 mL) was added Pd(dppf)Ch (139 mg, 0.19 mmol), TMEDA (337 mg, 2.91 mmol) and NaBHi (110 mg, 2.91 mmol), and the mixture was stirred at room temperature for 12 h under N2. Water (30 mL) was added, and the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc/PE to (8-methylquinolin-3-yl)methanol (105 mg, yield: 62.5%) as a yellow solid. ESIMS [M +H]+: 174.2
Synthesis of quinoxalin-6-ylmethanol
Figure imgf000163_0002
[0347] To a solution of quinoxaline-6-carboxylic acid (200 mg, 1.15 mmol) in THF (5 mL) was added LiAlHi (52 mg, 1.38 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-70% EtOAc/PE to give quinoxalin-6- ylmethanol (134 mg, yield: 73%) as a white solid. ESLMS [M +H]+: 161.1 Synthesis of (3-chloroquinolin-6-yl)methanol
Figure imgf000164_0001
[0348] Synthesis of methyl 3-chloroquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (6 g, 32 mmol) and NCS (4.7 g, 35 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCCh (sat. aq., 150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over NarSCL, and concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3-chloroquinoline-6-carboxylate (5 g, 71%) as a yellow solid. ESI-MS [M +H]+: 222.2
[0349] Synthesis of (3-chloroquinolin-6-yl) methanol. To a solution of methyl 3- chloroquinoline-6-carboxylate (500 mg, 2.3 mmol) in THF/MeOH (20 mL / 4 mL) was added LiBFL (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was quenched with NHrCl (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SOr, and concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give (3-chloroquinolin-6- yl)methanol (350 mg, 79%) as a yellow solid. ESI-MS [M +H]+: 194.2
Synthesis of (7-chloroquinolin-3-yl)methanol
Figure imgf000164_0002
[0350] To a solution of 7-chloroquinoline-3-carboxylic acid (500 mg, 2.41 mmol) in THF (10 mL) was added isobutyl chloroformate (658 mg, 4.82 mmol) and EtsN (487 mg, 4.82 mmol) at -20 °C, and the mixture was stirred at -20 °C for 20 min. After the mixture was warmed to 0 °C, NaBJL (275 mg, 7.23 mmol) was added and the reaction was stirred at room temperature for 18 h. Water (30 mL) was added, and the reaction was extracted with EtOAc (40 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc/PE to give (7-chloroquinolin-3-yl)methanol (121 mg, yield: 26%) as a yellow solid. ESLMS [M +H]+: 194.1
Figure imgf000165_0001
[0351] To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (500 mg, 3.01 mmol) in DMF (10 mL) was added dimethyl amine (180 mg, 4 mmol), EDCI (1.1 g, 6.02 mmol), HOBT (813 mg, 6.02 mmol), and DIPEA (1.9 g, 15.05 mmol). The mixture was stirred at room temperature for 3 h. Water (100 mL) was added, and the reaction was extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc/PE to give 2-(4- (hydroxymethyl)phenyl)-N,N-dimethylacetamide ( 470 mg, yield: 81%) as a yellow solid. ESIMS [M +H]+: 194.2
Figure imgf000165_0002
[0352] To a solution of (lH-benzo[d]imidazol-2-yl)methanol (148 mg, 1 mmol) in MeCN (10 mL) was added KF (116 mg, 2 mmol) and diethyl (bromodifluoromethyl)phosphonate (266 mg, 1 mmol), the mixture was stirred at room temperature for 12 h under N2. The reaction was quenched with water (50 mL), extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc/PE to give 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide (150 mg, yield: 75%) as a yellow solid. ESLMS [M +H]+: 199.2. Synthesis of (6-bromoquinolin-2-y I) methanol
Figure imgf000166_0001
[0353] Synthesis of 6-bromoquinoline-2-carbaldehyde. SeCh (103 mg, 1.2 mmol, 1.3 eq) in suspension in dioxane (5 mL) was heated at 60 °C. 6-bromoquinaldine (200 mg, 0.9 mmol) was added and the mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered through celite, washed with dioxane and concentrated under reduced pressure to give 6-bromoquinoline-2-carbaldehyde (330 mg, crude) as a white solid, which was used in the next step without purification. ESI-MS [M +H]+: 236.2.
[0354] Synthesis of (6-bromoquinolin-2-yl)methanol. To a solution of 6-bromoquinoline-2- carbaldehyde (330 mg, crude) in EtOH (10 mL) was added Sodium borohydride (58 mg, 1.5 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by Prep-TLC (EtOAc/PE=l/l) to give (6-bromoquinolin-2- yl)methanol (120 mg, yield: 56% over 2 steps) as a white solid. ESI-MS [M +H]+: 238.2.
Synthesis of (8-methylquinolin-3-yl)methanol
Figure imgf000166_0002
[0355] Synthesis of (2-chloro-8-methylquinolin-3-yl)methanol. To a solution of 2-chloro- 8-methylquinoline-3-carbaldehyde (205 mg, 1.00 mmol) in MeOH (5 mL) was added NaBHt (114 mg, 3.00 mmol), the mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc/PE to (2-chloro-8-methylquinolin-3-yl)methanol (200 mg, yield: 97%) as a white solid. ESI-MS [M +H]+: 208.2.
[0356] Synthesis of (8-methylquinolin-3-y I) methanol. To a solution of (2-chloro-8- methylquinolin-3-yl)m ethanol (200 mg, 0.97 mmol) in THF (5 mL) was added Pd(dppf)C12 (139 mg, 0.19 mmol), TMEDA (337 mg, 2.91 mmol) and NaBH4 (110 mg, 2.91 mmol), the mixture was stirred at room temperature for 12 h under N2. Water (30 mL) was added and the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc/PE to (8-methylquinolin-3-yl)methanol (105 mg, yield: 62.5%) as a yellow solid. ESIMS [M +H]+: 174.2.
Synthesis of quinoxalin-6-ylmethanol
Figure imgf000167_0001
[0357] To a solution of quinoxaline-6-carboxylic acid (200 mg, 1.15 mmol) in THF (5 mL) was added LiAlHi (52 mg, 1.38 mmol) at 0 °C, the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-70% EtOAc/PE to give quinoxalin-6- ylmethanol (134 mg, yield: 73%) as a white solid. ESI-MS [M +H]+: 161.1.
Synthesis of (3-chloroquinolin-6-yl)methanol
Figure imgf000167_0002
[0358] Synthesis of methyl 3-chloroquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (6 g, 32 mmol) and NCS (4.7 g, 35 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCCh (sat. aq., 150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3-chloroquinoline-6-carboxylate (5 g, 71%) as a yellow solid. ESLMS [M +H]+: 222.2.
[0359] Synthesis of (3-chloroquinolin-6-yl)methanol. To a solution of methyl 3- chloroquinoline-6-carboxylate (500 mg, 2.3 mmol) in THF/MeOH (20 mL / 4 mL) was added LiBHi (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was quenched with NH-iCI (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give (3-chloroquinolin-6- yl)methanol (350 mg, 79%) as a yellow solid. ESI-MS [M +H]+: 194.2.
Synthesis of methyl 3-chloroquinoline-6-carboxylate
Figure imgf000168_0001
[0360] A mixture of methyl quinoline-6-carboxylate (6 g, 32 mmol) and NCS (4.7 g, 35 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCOs (sat. aq., 150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3- chloroquinoline-6-carboxylate (5 g, 71%) as a yellow solid. ESLMS [M +H]+: 222.2.
Synthesis of (3-chloroquinolin-6-yl)methanol
Figure imgf000168_0002
[0361] To a solution of methyl 3-chloroquinoline-6-carboxylate (500 mg, 2.3 mmol) in THF/MeOH (20 mL / 4 mL) was added LiBHi (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was quenched with NH-iCl (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give (3-chloroquinolin-6-yl)methanol (350 mg, 79%) as a yellow solid. ESLMS [M +H]+: 194.2. Synthesis of (6-chloroimidazo l, 2-a]pyridin-2-yl) methanol
Figure imgf000169_0001
[0362] To a solution of ethyl 6-chloroimidazo[l,2-a]pyridine-2-carboxylate (200 mg, 0.9 mmol) in THF (10 mL) was added DIBAL-H (1 M in THF, 2.7 mL, 2.7 mmol) slowly at -20 °C under N2. After the reaction mixture was at stirred at -20 °C for 1 h, Na2SO4*10H2O (2 g) was added and the mixture was stirred at room temperature for 10 min. Then the reaction was filtered through celite, filter cake was washed with THF (20 mL), the filtrate was concentrated to give the crude product, which was purified by column chromatography (eluent: MeOH/DCM = 1/10) to give (6-chloroimidazo[l,2-a]pyridin-2-yl)methanol (50 mg, yield: 30%) as a yellow solid. ESLMS [M +H]+: 183.2.
Synthesis of (6, 7-dimethylimidazo[l ,2-a]pyridin-2-yl) methanol
Figure imgf000169_0002
[0363] Synthesis of ethyl 6, 7-dimethylimidazofL,2-a]pyridine-2-carboxylate. To a solution of 4,5-dimethylpyridin-2-amine (500 mg, 4.1 mmol) in EtOH (10 mL) was added ethyl 3-bromo- 2-oxopropanoate (1.58 g, 8.2 mmol), the mixture was stirred at 95 °C for 12 h. After the reaction was cooled to room temperature, NaHCOs (30 mL, 10%) was added, the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated in vacuo to give the crude, which was purified with combi flash chromatography with (PE/EtOAc= 5/1) to give ethyl 6,7-dimethylimidazo[l,2-a]pyridine-2- carboxylate (300 mg, 33%) as a yellow solid. ESLMS [M +H]+: 219.2.
[0364] Synthesis of (6, 7-dimethylimidazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6,7-dimethylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, 1.38 mmol) in THF (10 mL) was added LiAlHi (1 M in THF, 2.8 mL, 2.8 mmol) slowly at 0 °C under N2. The reaction mixture was raised to room temperature and stirred for 1 h. The reaction was quenched with Na2SO4*10H2O (3 g) and stirred at room temperature for 10 min. Then filtered, the filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: MeOH/DCM = 1/10) to give (6,7- dimethylimidazo[l,2-a]pyridin-2-yl)methanol (200 mg, yield:82%) as a brown solid. ESI-MS [M +H]+: 177.2.
Synthesis of (7-methylimidazo[l,2-a]pyridin-2-yl)methanol
Figure imgf000170_0001
[0365] Synthesis of ethyl 7-methylimidazo[l,2-a]pyridine-2-carboxylate. To a solution of 4-methylpyridin-2-amine (500 mg, 4.6 mmol) in EtOH (10 mL) was added ethyl 3-bromo-2- oxopropanoate (1.77 g, 9.2 mmol). The mixture was stirred at 95 °C for 12 h. After the reaction was cooled to room temperature, NaHCOi (80 mL, 10% aq.) was added and the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated in vacuo to give the crude, which was purified with combi flash chromatography with (PE/EtOAc= 5/1) to give ethyl ethyl 7-methylimidazo[l,2-a]pyridine-2- carboxylate (300 mg, yield: 32%). ESI-MS [M +H]+: 205.2.
[0366] Synthesis of (7-niethylimidazo[l,2-a]pyridin-2-yl)methanoL To a solution of ethyl 7-methylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, 1.5 mmol) in THF (10 mL) was added LiAlH4 (1 M in THF, 3.0 mL, 3 mmol) slowly at 0 °C under N2. The reaction mixture was then slowly raised to room temperature and stirred for 1 h. The reaction was quenched with Na2SO4*10H2O (3 g) and stirred at room temperature for 10 min. Then filtered, the filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude product, which was purified by column chromatography (eluent: MeOH/DCM = 1/10) to give (7- methylimidazo[l,2-a]pyridin-2-yl)methanol (220 mg, yield: 82%) as a brown solid. ESI-MS [M +H]+: 163.2.
Figure imgf000170_0002
[0367] Synthesis of methyl 4-cyclopropylbenzoate. A mixture of methyl 4-bromobenzoate (500 mg, 2.3 mmol), cyclopropylboronic acid (300 mg, 3.5 mmol), Pd(OAc)2 (52 mg, 0.23 mmol), PPhs (61 mg, 0.23 mmol) and K3PO4 (1.5 g, 6.9 mmol) in dioxane/BLO (25 mL / 2.5 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was cooled to room temperature and concentrated. Water (40 mL) was added and extracted by EtOAc (50 mL x 3). The combined organic layers were concentrated to give the crude, which was purified with silica gel chromatography (PE/EtOAc = 10/1) to give methyl 4-cyclopropylbenzoate (400 mg, yield: 98%) as a yellow solid, ESI-MS [M +H]+: 177.2.
[0368] Synthesis of (4-cyclopropylphenyl) methanol To a solution of methyl 4- cyclopropylbenzoate (400 mg, 2.3 mmol) in THF (10 mL) was added LiAlHi (1 M in THF, 4.6 mL, 4.6 mol) slowly at 0 °C under N2. The reaction mixture was then slowly raised to room temperature and stirred for 1 h. The reaction was quenched with Na2SO4* I OH2O (5 g) and filtered. The filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude product, which was purified by column chromatography (eluent: MeOH/DCM = 1/10) to give (4-cyclopropylphenyl)methanol (200 mg, yield: 59%) as a yellow solid. ESI-MS [M +H]+: 149.2.
Figure imgf000171_0001
[0369] Synthesis of ethyl 6-cyclopropyl-5-methylimidazo[l,2-a]pyridine-2-carboxylate. A mixture of 5-cyclopropyl-6-methylpyridin-2-amine (300 mg, 2.0 mmol) and ethyl 3-bromo-2- oxopropanoate (776 mg, 4.0 mmol) in EtOH (10 mL) was stirred at 90 °C for 16 h. After the reaction was cooled to room temperature, NaHCO3 (50 mL, 10% aq.) was added and the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: PE/EtOAc = 5/1) to give ethyl 6-cyclopropyl-5-methylimidazo[l,2- a]pyridine-2-carboxylate (150 mg, yield: 31%) as a yellow solid. ESI-MS [M +H]+: 245.2. [0370] Synthesis of (6-cyclopropyl-5-methylinndazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6-cyclopropyl-5-methylimidazo[l,2-a]pyridine-2-carboxylate (100 mg, 0.41 mmol) in THF (5 mL) was added LiAlH4 (IM solution in THF, 1.2 mL, 1.2 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with NH4CI (sat. aq., 20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give (6-cyclopropyl-5- methylimidazo[l,2-a]pyridin-2-yl)methanol (50 mg, yield: 60%) as a colorless oil. ESI-MS [M +H]+: 203.2.
Figure imgf000172_0001
[0371] Synthesis of ethyl 6-chloro-5-methylimidazo[l,2-a]pyridine-2-carboxylate. A mixture of 5-chloro-6-methylpyridin-2-amine (600 mg, 4.2 mmol) and ethyl 3-bromo-2- oxopropanoate (1.6 g, 8.4 mmol) in EtOH (20 mL) was stirred at 90 °C for 16 h. After the reaction was cooled to room temperature, NaHCCh (50 mL, 10% aq.) was added and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried with Na SCL, concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: PE/EtOAc = 5/1) to give ethyl 6-chloro-5-methylimidazo[l,2- a]pyridine-2-carboxylate (500 mg, yield: 50%) as a yellow solid. ESLMS [M +H]+: 239.2.
[0372] Synthesis of (5-methylimidazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6-chloro-5-methylimidazo[l,2-a]pyridine-2-carboxylate (500 mg, 2.1 mmol) in THF (10 mL) was added LiAULi (IM solution in THF, 6.3 mL, 6.3 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with Na2SO4*10H2O (5 g) and filtered. The filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give (5- methylimidazo[l,2-a]pyridin-2-yl)methanol (150 mg, yield: 44%) as a colorless oil. ESI-MS [M +H]+: 163.2.
Synthesis of (6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methanol
Figure imgf000173_0001
[0373] To a solution of ethyl 6-chloro-5-methylimidazo[l,2-a]pyridine-2-carboxylate (150 mg, 0.63 mmol) in THF (5 mL) was added DIBAL-H (IM solution in THF, 1.9 mL, 1.9 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with Na2SO4*10H2O (2 g) and filtered. The filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give (6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methanol (50 mg, yield: 40%) as a colorless oil. ESI-MS [M +H]+: 197.2.
Synthesis of (2-chloro-7-methoxyquinolin-3-yl)methanol and (7-niethoxyquinolin-3- yl) methanol
Figure imgf000173_0002
[0374] Synthesis of N-(3-methoxyphenyl)acetamide. To a solution of 3 -methoxy aniline (2 g, 16.3 mmol) and TEA (4.9 g, 48.6 mmol) in DCM (50 mL) was added AC2O (3.3 g, 32.6 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 8 h. Water (70 mL) was added and the reaction was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over NaiSCh, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give N-(3-methoxyphenyl)acetamide (2.1 g, 78%) as a yellow solid. ESI-MS [M +H]+: 166.1.
[0375] Synthesis of 2-chloro-7-niethoxyquinoline-3-carbaldehyde. To a solution ofN-(3- methoxyphenyl)acetamide (2.1 g, 12.7 mmol) in DMF (20 mL) was added POCh (7.7 g, 50.8 mmol) at 0 °C. The resulting reaction was stirred at 100 °C for 14 h. After cooled to room temperature, the reaction was quenched with H2O (70 mL), extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-4% EtOAc in PE to give 2-chloro-7-methoxyquinoline-3-carbaldehyde (1.6 g, 57%) as a yellow solid. ESI-MS [M +H]+: 222.1.
[0376] Synthesis of (2-chloro-7-methoxyquinolin-3-yl)methanol and (7-methoxyquinolin- 3-yl) methanol. To a solution of 2-chloro-7-methoxyquinoline-3-carbaldehyde (222 mg, 1 mmol) in THF (10 mL) was added LiAlLh (5 mL, 5 mmol, 1 M solution in THF) at -40 °C. The reaction was stirred at room temperature for 12 h. After completed, the reaction was quenched with NH4CI (sat. aq., 30 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give (2-chloro-7-methoxyquinolin- 3-yl)methanol (45 mg, 20%), and (7-methoxyquinolin-3-yl)m ethanol (35 mg, 19%) as yellow oil. (2-chloro-7-methoxyquinolin-3-yl)methanol, ESLMS [M +H]+: 224.1 and (7- m ethoxy quinolin-3-yl)m ethanol, ESI-MS [M +H]+: 190.1.
Synthesis of (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanol
Figure imgf000174_0001
[0377] Synthesis of 5-(lH-pyrazol-l-yl)-2-naphthoic acid. A mixture of methyl 5-bromo-2- naphthoate (1 g, 3.8 mmol), IH-pyrazole (775 mg, 11.4 mmol), t-BuONa (730 mg, 7.6 mmol) and CU2O (107 mg, 0.76 mmol) in NMP (10 mL) was degassed with N2 for 10 min, then heated to 120 °C under microwave for 12 h. After cooled to room temperature, the reaction was diluted with H2O (70 mL), extracted with EtOAc (70 mL x 4). The combined organic layers were washed with brine (80 mL), dried over NaiSCh, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-10% MeOH in DCM 5 to give (lH-pyrazol-l-yl)-2-naphthoic acid (530 mg, 58%) as a yellow solid. ESI-MS [M +H]+: 239.2.
[0378] Synthesis of methyl 5-(lH-pyrazol-l-yl)-2-naphthoate. A mixture of 5-(lH-pyrazol- l-yl)-2-naphthoic acid (530 mg, 2.2 mmol) and SOCh (772 mg, 6.6 mmol) in MeOH (25 mL) was stirred at 50 °C for 6 h. After cooled to room temperature, the reaction was concentrated in vacuo. NaHCOs (sat. aq., 40 mL) was added to the residue and extracted with extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to give methyl 5-(lH-pyrazol-l- yl)-2-naphthoate (410 mg, 74%) as a yellow solid. ESI-MS [M +H]+: 253.3.
[0379] Synthesis of (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanol. A mixture of methyl 5- (lH-pyrazol-l-yl)-2-naphthoate (410 mg, 1.62 mmol) and LiBHi (107 mg, 4.86 mmol) in MeOH/THF (2 mL/10 mL) was stirred at 70 °C for 14 h. After cooled to room temperature, the reaction was quenched with NH4CI (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-70% EtOAc in PE to give (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanol (305 mg, 84%) as a yellow solid. ESI-MS [M +H]+: 225.3.
Synthesis of (5-bromonaphthalen-2-yl)methanol
Figure imgf000175_0001
[0380] To a mixture of methyl 5-bromo-2-naphthoate (100 mg, 0.38 mmol) in THF (2 mL) and MeOH (0.5 mL) was added LiBHi (25 mg, 1.13 mmol), the reaction mixture was stirred at room temperature for 16 h. NH4CI (sat. aq., 10 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give (5-bromonaphthalen-2-yl)methanol (80 mg, yield: 89%) as a yellow solid. ESI-MS [M +H]+: 237.1. Synthesis of (5-(pyridin-2-yl)naphthalen-2-yl)methanol
Figure imgf000176_0001
[0381] Synthesis of methyl 5-bromo-2-naphthoate. To a mixture of 5-bromo-2-naphthoic acid (2.5 g, 10 mmol) in MeOH (100 mL) was added SOCh (2.6 g, 22 mmol) dropwise at 0 °C, the mixture was stirred at 70 °C for 16 h. Then cooled to room temperature and concentrated to give methyl 5-bromo-2-naphthoate (2.5 g, crude) as a white solid, which was used in the next step without purification. ESI-MS [M +H]+: 265.1.
[0382] Synthesis of methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-naphthoate.
To a mixture of methyl 5-bromo-2-naphthoate (2.5 g, crude), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (4.4 g, 17.5 mmol), AcOK (2.3 g, 24 mmol) in dioxane (50 mL) was added Pd(dppf)C12 (585 mg, 0.8 mmol), the mixture was stirred at 90 °C for 16 h under N2. After cooled to room temperature, the reaction mixture was filtered through celite and the filter cake was washed with DCM/MeOH (10/1, 200 mL). The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: PE/EtOAc=30/l) to give methyl 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-naphthoate (2.4 g, yield: 77% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 313.2.
[0383] Synthesis of methyl 5-(pyridin-2-yl)-2-naphthoate. To a mixture of methyl 5-
(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-2-naphthoate (1.56 g, 5 mmol), 2-bromopyridine (785 mg, 5 mmol), K2CO3 (2.07 g, 15 mmol) in Dioxane (20 mL) and H2O (5 mL) was added Pd(dppf)Ch (366 mg, 0.5 mmol). The mixture was stirred at 70 °C for 16 h under N2, After cooled to room temperature, the reaction mixture was filtered through celite and the filter cake was washed with DCM/MeOH (10/1, 200 mL). The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: PE/EtOAc=10/l to 6/1) to give methyl 5-(pyridin-2-yl)-2-naphthoate (740 mg, yield: 56%) as a yellow solid. ESI-MS [M +H]+: 264.2. [0384] Synthesis of (5-(pyridin-2-yl)naphthalen-2-yl)methanol. To a mixture of methyl 5- (pyridin-2-yl)-2-naphthoate (430 mg, 1.63 mmol) in THF (10 mL) and MeOH (2 mL) was added LiBHr (216 mg, 9.81 mmol), the reaction mixture was stirred at room temperature for 16 h. NH4CI (sat. aq., 50 mL) was added and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (5s0 mL), dried over anhydrous Na2SOr, and concentrated to give the crude, which was purified by column chromatography (eluent: PE/EtOAc=l/l) to give (5-(pyridin-2-yl)naphthalen-2-yl)methanol (300 mg, yield: 78%) as a yellow solid. ESI-MS [M +H]+: 236.2.
Synthesis of (3-methylquinolin-6-yl)methanol
Figure imgf000177_0001
[0385] Synthesis of 3-methylquinoline-6-carbaldehyde. n-BuLi (1.6 M in hexanes, 0.84 mL, 1.4 mmol) was added dropwise to a solution of 6-bromo-3 -methylquinoline (300 mg, 1.35 mmol) in THF (8.0 mL). The solution was stirred at -78°C for 1 h. DMF (0.15 mL) was added and the mixture was warmed to room temperature and stirred for 1 h. NH4CI (sat. aq. 30 mL) was added to quench the reaction and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 20-50% EtOAc in PE to give the 3-methylquinoline-6-carbaldehyde (82 mg, 35%) as a yellow oil. ESLMS (M+H)+: 172.2.
[0386] Synthesis of (3-methylquinolin-6-yl)methanol. To a solution of 3 -methyl quinoline-
6-carbaldehyde (80 mg, 0.47 mmol) in MeOH (5 mL) was added NaBHi (19 mg, 0.50 mmol), the mixture was stirred at room temperature for 1 h then concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 20-100% EtOAc in PE to give the compound (36 mg, 44%) as a yellow solid. ESI-MS (M+H)+: 174.1. Synthesis of (4-(3-fluoro-2-methoxybenzyl)phenyl)methanol
Figure imgf000178_0001
100 °C, 2 h
[0387] Synthesis of methyl 4-(3-fluoro-2-methoxybenzyl)benzoate. A mixture of (3-fluoro- 2-methoxyphenyl)boronic acid (510 mg, 3 mmol), methyl 4-(bromomethyl)benzoate (684 mg, 3 mmol), Pd(PPh3)4 (347 mg, 0.3 mmol), Na2COs (636 g, 6 mmol) in DMF (10 mL) and H2O(3 mL) was stirred at 120 °C for 2 h under N2. Water (50 mL) was added and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (sat. aq.), dried over MgSOi and concentrated in vacuo to give the residue, which was purified by Prep-TLC (PE/EtOAc=2/l) to give the product methyl 4-(3-fluoro-2- methoxybenzyl)benzoate(100 mg, yield: 12%) as a yellow solid. ESLMS (M+H)+: 275.2.
[0388] Synthesis of (4-(3-fluoro-2-methoxybenzyl)phenyl)methanol. A mixture of methyl 4-(3-fluoro-2-methoxybenzyl)benzoate (100 mg, 0.36 mmol) and LiBEk (80 mg, 3.6 mmol) in THF (5 mL) and CH3OH (1 mL) was stirred at 50 °C for 16 h. After the reaction was cooled to room temperature, Water (30 mL) was added and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (sat. aq.), dried over M SO4 and concentrated in vacuo to give the residue, which was purified by Prep-TLC (DCM/MeOH=20/l) to give the product (4-(3-fluoro-2-methoxybenzyl)phenyl)methanol (80 mg, yield: 90%) as a yellow solid. ESLMS (M+H)+: 247.2.
Figure imgf000178_0002
[0389] Synthesis of 2-(4-(hydroxymethyl)phenyl)acetohydrazide. To a solution of ethyl 2-
(4-(hydroxymethyl)phenyl)acetatem ethanamine (220 mg, 1.13 mmol) in MeOH(5 mL) was added hydrazine hydrate (0.3 mL, 80% aq ). The mixture was stirred at reflux for 10 h. The reaction mixture was cooled to room temperature and concentrated to give 2-(4- (hydroxymethyl)phenyl)acetohydrazide (230 mg, crude) as a yellow oil, which was used in the next step without purification. ESI-MS [M +H]+: 181.1.
[0390] Synthesis of (4-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)phenyl)methanol. A mixture of 2-(4-(hydroxymethyl)phenyl)acetohydrazide (230 mg, crude) and 1,1 -di ethoxy -N,N- dimethylmethanamine (368 mg, 2.5 mol) in HOAc (3 mL) was refluxed for 16 h. The mixture was cooled to room temperature, MeNEL (2M in THF, 5 ml) was added and the mixture was stirred at 70 °C for another 16 h. The mixture was cooled to room temperature and concentrated in vacuo. Water (30 mL) was added, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (sat. aq.), dried over MgSOi and concentrated in vacuo to give the residue, which was purified by Prep-TLC (DCM/MeOH=20/l) to give (4-((4-methyl-4H- 1,2,4- triazol-3-yl)methyl)phenyl)methanol (50 mg, yield: 21.8 % over 2 steps) as a yellow solid. ESI- MS [M +H]+: 204.1.
Synthesis of (2-cyclopropylphenyl)methanol
Figure imgf000179_0001
[0391] Synthesis of ethyl 2-cyclopropylbenzoate. To a solution of ethyl 2-bromobenzoate (500 mg, 2.2 mmol) in DME/H2O (11 mL, v : 10/1) was added cyclopropylboronic acid (301 mg, 3.5 mmol), Pd(PPh3)4 (254 mg, 0.22 mmol) and NarCCh (742 mg, 7.0 mmol) at room temperature under N2 atmosphere. The mixture was stirred at 95 °C for 16 h. The mixture was cooled to room temperature and fdtered. The filter cake was washed with DCM (30 mL) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0~4% MeOH in DCM to give ethyl 2-cyclopropylbenzoate (300 mg, yield: 72%) as a white solid. ESI-MS [M +H]+: 191.0.
[0392] Synthesis of (2-cyclopropylphenyl)methanol. To a solution of ethyl 2- cyclopropylbenzoate (170 mg, 0.89 mmol) in THF (20 mL) was added dropwise LiAlH4 (1 M in THF, 2.7 mL, 2.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with Na2SO410H2O (2 g), filtered and the filtrate was concentrated in vacuo to give the residue, which was purified by Prep-TLC (PE/EtOAc=l/l) to give (2- cyclopropylphenyl)methanol (76 mg, yield: 57%) as white solid. ESI-MS [M + H]+: 149.1.
Synthesis ofN,N-dimethyl-2-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyI)phenyl)propanamide
Figure imgf000180_0001
[0393] Synthesis ofN,N-dimethyl-2-(4-(((tetrahydro-2H-pyran-2- yl) oxy) methyl)pheny I) acetamide. A solution of 2-(4-(hydroxymethyl)phenyl)-N,N- dimethylacetamide (148 mg, 0.77 mmol), DHP (129 mg, 1.54 mmol) and TsOH*H2O(15 mg, 0.08 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by column chromatography (EtOAc/PE from 0 to 20%) to give N,N- dimethyl-2-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)acetamide (150 mg, yield: 70 %) as a white solid. ESI-MS [M +H] +: 278.2.
[0394] Synthesis of N,N-dimethyl-2-(4-(((tetrahydro-2H-pyran-2- yl) oxy) methyl)phenyl) acrylamide. A solution of N,N-dimethyl-2-(4-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)phenyl)acetamide (140 mg, 0.51 mmol), paraformaldehyde (155 mg, 5.1 mmol), B NI (188 mg, 0.51 mmol) and CS2CO3 (334 mg, 10.2 mmol) in DMF(5 mL) was stirred at 90 °C for 20 h. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep-TLC (eluent: EtOAc / PE = 1/5) to give N,N-dimethyl-2-(4-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)phenyl)acrylamide (25 mg, yield: 17%) as a white solid. ESI-MS [M +H] +: 290.2. ropanamide
Figure imgf000181_0002
[0395] A mixture of N,N-dimethyl-2-(4-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)phenyl)acrylamide (25 mg, 0.09 mmol) and Pd/C(10 mg) in MeOH (5 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered through celite® and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated to give N,N-dimethyl- 2-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)propanamide (25 mg, crude) as a brown oil, which was used in the next step without purification. ESLMS [M +H] +: 292.2.
Figure imgf000181_0001
[0396] Synthesis of 3-chloroquinoline-6-carbaldehyde. To a mixture of (3-chloroquinolin- 6-yl)methanol (100 mg, 0.52 mmol) in DCM (5 mL) was added MnOi (671 mg, 7.8 mmol), the mixture was stirred at room temperature for 16 h, then fdtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 30 mL). The filtrate was concentrated to give 3- chloroquinoline-6-carbaldehyde (80 mg, crude) as a white solid, which was used in the next step without purification. ES MS [M +H]+: 192.1.
[0397] Synthesis of l-(3-chloroquinolin-6-yl)ethan-l-ol. To a solution of 3- chloroquinoline-6-carbaldehyde (80 mg, crude) in THF (2 mL) was added CHaMgBr (3M in hexane, 0.42 mL, 1.26 mmol) at -30 °C, the reaction mixture was stirred at room temperature for 16 h under N2. NH4CI (sat. aq., 10 mL) was added and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO-i, and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH=20/l) to give l-(3-chloroquinolin-6-yl)ethan-l-ol (50 mg, yield: 46% over 2 steps) as a colorless oil. ESIMS [M +H]+: 208.1.
Figure imgf000182_0001
[0398] Synthesis of 4-cyclopropylpyridine. To a mixture of 4-bromopyridine (4 g, 25.7 mmol), cyclopropylboronic acid (2.42 g, 28.2 mmol) and K2CO3 (10.6 g, 77.13 mmol) in dioxane (80 mL) and H2O (16 mL) was added Pd(dppf)Ch (1.88 g, 2.57 mmol), then the resulting mixture was stirred at 100 °C under N2 for 16 hours. After cooled to room temperature, the reaction mixture was fdtered through celite and concentrated, the residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried (MgSCU), fdtered, and concentrated to give the crude, which was purified column chromatography with (PE/EtOAc= 5/1) to give 4-cyclopropylpyridine (2.7 g, yield: 88%) as a yellow oil. ESLMS [M +H]+: 120.1.
[0399] Synthesis of l-amino-4-cyclopropylpyridin-l-ium 2, 4, 6-trimethylbenzenesulfonate. To a solution of 4-cyclopropylpyridine (750 mg, 6.3 mmol) in DCM (20 mL) was added O- (mesitylsulfonyl)hydroxylamine (1.35 g, 6.3 mmol) at 0 °C and stirred for 30 min, then the reaction was warmed to room temperature and stirred another 2 hours. The reaction mixture was concentrated in vacuo to give l-amino-4-cyclopropylpyridin-l-ium 2, 4, 6- trimethylbenzenesulfonate (2.1 g, crude) was obtained as yellow oil, which was used in the next step without purification. ESLMS [M +H]+: 135.1.
[0400] Synthesis of dimethyl 5-cyclopropylpyrazolo [1, 5-a] pyridine-2, 3-dicarboxylate. To a solution of l-amino-4-cyclopropylpyridin-l-ium 2, 4, 6-dimethylbenzenesulfonate (2.1 g, crude) and dimethyl but-2-ynedioate (3.6 g, 25.22 mmol) in CI LCN (60 mL) was added DBU (3.8 g, 25.22 mmol) at 0 °C for 30 min. Then the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by combi flash chromatography (PE/EtOAc = 2: 1) to give dimethyl 5- cyclopropylpyrazolo [1, 5-a] pyridine-2, 3 -dicarboxylate (1.4 g, yield: 81%) as a yellow oil. ESIMS [M +H]+: 275.2.
[0401] Synthesis of 5-cyclopropylpyrazolo [1, 5-a pyridine-2-carboxylic acid. A solution of dimethyl 5-cyclopropylpyrazolo [1, 5-a] pyridine-2, 3 -dicarboxylate (1.4 g, 5.1 mmol) in dioxane (20 mL) and H2SO4 (1 mL, 50% aq.) was stirred at 85 °C for 5 hours. After cooled to room temperature, Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried bteSCh), filtered and concentrated to give the crude, which was purified by silica column (PE/EtOAc = 1 : 1) to give 5-cyclopropylpyrazolo [1, 5-a] pyridine-2-carboxylic acid (600 mg, yield: 58%) as a white solid. ESI-MS [M +H]+: 203.2.
[0402] Synthesis of (5-cyclopropylpyrazolo [1, 5-a] pyridin-2-yl) methanol. To a solution of 5-cyclopropylpyrazolo [1, 5-a] pyridine-2-carboxylic acid (202 mg, 1.0 mmol) in THF (10 mL) was added LiAlELi (IM in THF, 1.5 mL, 1.5 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min and then warmed to room temperature for 4 hours. The reaction was quenched by Na2SO4*10H2O (2 g), filtered and filter cake was washed by DCM/MeOH = 10/1(50 mL), the filtrate was concentrated to give (5-cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methanol (140 mg, yield: 74.5%) as a yellow oil. ESI-MS [M +H]+: 189.2.
Figure imgf000183_0001
[0403] Synthesis of (l-(4-bromophenyl)cyclopropyl)(pyrrolidin-l-yl)methanone. A mixure of l-(4-bromophenyl)cyclopropane-l -carboxylic acid (200 mg, 0.84 mmol), pyrrolidine (135 mg, 1.9 mmol), HATU (722 mg, 1.9 mmol) and DIPEA (542 mg, 4.2 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. H2O (40 mL) was added and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (EtOAc/PE=l/2) to give (l-(4-bromophenyl)cyclopropyl)(pyrrolidin-l-yl)methanone (220 mg, 89%) as a yellow solid. ESI-MS [M +H]+: 294.1.
[0404] Synthesis of ethyl 4-(l-(pyrrolidine-l-carbonyl)cyclopropyl)benzoate. A mixture of (l-(4-bromophenyl)cyclopropyl)(pyrrolidin-l-yl)methanone (220 mg, 0.75 mmol), Pd(dppf)Ch- DCM (82 mg, 0.1 mmol) and DIPEA (387 mg, 3 mmol) in EtOH (15 mL) was stirred at 80 °C under CO atmosphere for 12 h. After cooled to room temperature, the reaction was diluted with H2O (35 mL), extracted with EtOAc (35 mL x 3). The combined organic layers were washed with brine (45 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 15/1) to give ethyl 4-(l-(pyrrolidine-l- carbonyl)cyclopropyl)benzoate (180 mg, 83%) as a yellow solid. ESLMS [M +H]+: 288.2.
[0405] Synthesis of (l-(4-(hydroxymethyl)phenyl)cyclopropyl)(pyrrolidin-l-yl)methanone. A mixture of ethyl 4-(l -(pyrrolidine- l-carbonyl)cy cl opropyl)benzoate (180 mg, 0.63 mmol) and LiBH4 (58 mg, 2.6 mmol) in THF/MeOH (10 mL/2 mL) was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was quenched with NH4CI (sat. aq., 30 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give (l-(4-(hydroxymethyl)phenyl)cyclopropyl)(pyrrolidin-l- yl)methanone (110 mg, 71%) as a yellow solid. ESLMS [M +H]+: 246.2.
Synthesis of 6-(((tert-butyl(limethylsil l)oxy)methyl)-3-vinylquinoline
Figure imgf000184_0001
[0406] Synthesis of methyl 3-bromoquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (600 mg, 3.2 mmol) and NBS (623 mg, 3.5 mmol) in DMF (20 mL) was stirred at 100 °C for 12 h. After cooled to room temperature, the reaction was quenched with
NaHCCh (sat. aq., 60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3-bromoquinoline-6-carboxylate (500 mg, 59%) as a yellow solid. ESI-MS [M +H]+: 266.2.
[0407] Synthesis of (3-bromoquinolin-6-yl)methanol. To a solution methyl 3- bromoquinoline-6-carboxylate (500 mg, 1.9 mmol) in THF (25 mL) was added LiAlELi (3.8 mL, 3.8 mmol, 1 M solution in THF) slowly at 0 °C. The resulting reaction was stirred at 0 °C for 4 h. The reaction was quenched with NHiCl (sat. aq., 40 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to (3-bromoquinolin-6-yl)methanol (250 mg, 55%) as a yellow solid. ESI-MS [M +H]+: 238.2.
[0408] Synthesis of 3-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)cuinolone. A mixture of (3-bromoquinolin-6-yl)methanol (250 mg, 1.1 mmol), TBSC1 (248 mg, 1.6 mmol) and imidazole (150 mg, 2.2 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. The reaction was diluted with H2O (30 mL), extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: PE/EtOAc = 2/1) to 3-bromo-6- (((tert-butyldimethylsilyl)oxy)methyl)quinoline (275 mg, 71%) as a yellow solid. ESI-MS [M +H]+: 352.2.
[0409] Synthesis of 6-(((tert-butyldimethylsilyl)oxy)methyl)-3-vinylquinoline. A mixture of 3-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)quinoline (275 mg, 0.78 mmol), 4, 4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (240 mg, 1.56 mmol), Pd(dppf)Ch-DCM (64 mg, 0.078) and Na2COi (246 mg, 2.34 mmol) in l,4-dioxane/H2O (15 mL/2 mL) was stirred at 95 °C for 3 h under N2 atmosphere. After cooled to room temperature, the reaction was diluted with H2O (35 mL), extracted with EtOAc (35 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: PE/EtOAc = 2/1) to give 6-(((tert- butyldimethylsilyl)oxy)methyl)-3-vinylquinoline (210 mg, 89%) as a yellow solid. ESI-MS [M +H]+: 300.2. Synthesis of 6-(((tert-butyldimethylsilyl)oxy)methyl)-3-ethylquinoline
Figure imgf000186_0001
[0410] To a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-3-vinylquinoline (250 mg, 0.84 mmol) and CuCI (16 mg, 0.17 mmol) in MeOH (10 mL) was added NaBHi (64 mg, 1.68 mmol) slowly at 0 °C. The resulting reaction mixture was stirred at room temperature for 13 h. After completed, the reaction was quenched with NH4CI (sat. aq., 30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: PE/EtOAc = 3/1) to give 6-(((tert-butyldimethylsilyl)oxy)methyl)-3-ethylquinoline (180 mg, 71%) as a yellow solid. ESI-MS [M +H]+: 302.2.
Synthesis of 6-cyclopropylpyridin-2-amine
Figure imgf000186_0002
[0411] To a mixture of 6-bromopyridin-2-amine (1 g, 5.78 mmol) and cyclopropylboronic acid (0.59 g, 6.94 mmol) in toluene (20 mL) and H2O (2 mL) was added Pd(OAc)2 (0.13 g, 0.58 mmol), S-Phos (0.47 g, 1.16 mmol) and K3PO4 (3.68 g, 17.34 mmol). The solution was degassed with N2 for 3 min, and then stirred at 90 °C for 18 h under N2. The mixture was cooled to room temperature and then filtered by Celite®. The filter cake was washed with EtOAc (20 mL), the filtrate was diluted with H2O (50 mL), and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated to give the residue, which was purified by silica gel chromatography, eluting with 0-30% EtOAc/PE to afford 6-cyclopropylpyridin-2-amine (450 mg, yield: 58%) as a brown solid. ESI-MS [M +H]+: 135.1.
Synthesis of 5-chloro-6-ethylpyridin-2-amine
Figure imgf000186_0003
[0412] To a solution of 6-ethylpyridin-2-amine (500 mg, 4.09 mmol) in DMF (5 mL) was added NCS (601 mg, 4.50 mmol) at -10 °C. The mixture was stirred at -10 °C for 3 h. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by silica gel chromatography, eluting with 0-40% EtOAc/PE to afford 5-chloro-6- ethylpyridin-2-amine (350 mg, yield 55%) as a pale-yellow solid. ESI-MS [M +H]+: 157.1.
Synthesis of 5-cyclopropyl-6-fluoropyridin-2-anune
Figure imgf000187_0001
[0413] Synthesis of 5-bromo-6-fluoropyridin-2-amine. To a solution of 6-fluoropyridin-2- amine (4.0 g, 35.68 mmol) in CH3CN (100 mL) was added NBS (6.3 g, 35.68 mmol), the mixture was stirred at 0 °C for 2 h. The mixture was then concentrated and purified by silica gel chromatography (EtOAc/PE = 1/2) to give 5-bromo-6-fluoropyridin-2-amine (3.0 g, yield: 44%) as a yellow solid. ESI-MS [M +H] +: 191.1.
[0414] Synthesis of 5-cyclopropyl-6-fluoropyridin-2-amine. A mixture of 5-bromo-6- fhioropyridin-2-amine (2.98 g, 15.7 mmol), Cyclopropylboronic acid (1.6 g, 18.84 mmol), Pd(OAc)2 (0.35 mg, 1.57 mmol), PCy3 (0.44 mg, 1.57 mmol) and K3PO4 (10.0 g, 47.10 mmol) in dioxane/LEO (50 mL/5 mL) was stirred at 100 °C for 16 h. After cooled to room temperature, the reaction was filtered through celite, the filtrate was concentrated and diluted with Water (50 mL), then extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4. concentrated and purified by silica gel chromatography (DCM/MeOH = 10/1) to give 5-cyclopropyl-6-fluoropyridin-2-amine (1.2 g, yield: 50%) as a yellow solid. ESIMS [M +H] +: 153.1.
Synthesis of 5-cyclopropyl-4-methylpyridin-2-anune
Figure imgf000187_0002
[0415] A mixture of 5-bromo-4-methylpyridin-2-amine (1.0 g, 5.4 mmol), cyclopropylboronic acid (697 mg, 8.1 mmol), Pd(OAc)2 (121 mg, 0.54 mmol), PCys (142 mg, 0.54 mmol) and K3PO4 (3.4 g, 16.2 mmol) in dioxane/EbO (25 mL / 2.5 mL) was stirred at 100 °C for 12 h. The reaction mixture was fdtered, filter cake was washed with MeOH ( 20 mL), the filtrate was concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH = 30/1) to give the 5-cyclopropyl-4-methylpyridin-2-amine (700 mg, yield: 88%) as a yellow solid. ESLMS [M +H]+: 149.2.
Synthesis of 4-chloro-5-cyclopropylpyridin-2-anune
Figure imgf000188_0001
Toluene, H2O, 80 °C, 16 h
[0416] A mixture of 5-bromo-4-chloropyridin-2-amine (3.2 g, 15.6 mmol), Cyclopropylboronic acid (2.01 g, 23.4 mmol), Pd(OAc)2 (350 mg, 1.56 mmol), PCy (875 mg, 3.12 mmol) and K3PO4 (6.62 g, 31.2 mmol) in toluene (40 mb) and H2O (5 mL) was stirred at 80 °C for 16 h. The mixture was cooled to room temperature and diluted with H2O (100 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4. concentrated and purified by silica gel chromatography, eluting with 40-100% EtOAc/PE to afford 4-chloro-5-cyclopropylpyridin-2-amine (1.89 g, yield: 72%) as a yellow solid. ESLMS [M +H]+: 169.1.
Synthesis of 6-chloro-5-cyclopropylpyridin-2-anune
Figure imgf000188_0002
[0417] A mixture of 5-bromo-6-chloropyridin-2-amine (3.19 g, 15.50 mmol), cyclopropylboronic acid (1.6 g, 18.84 mmol), Pd (OAc)2 (0.35 mg, 1.57 mmol), PCy3 (0.44 mg, 1.57 mmol) and K3PO4 (10.0 g, 47.10 mmol) in dioxane/EbO (50/5 mL) was stirred at 100 °C for 16 h. After cooled to room temperature, Water (100 mL) was added and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (DCM/MeOH = 10/1) to give 6-chloro-5- cyclopropylpyridin-2-amine (1.2 g, yield: 46%) as a yellow solid. ESI-MS [M +H] +: 169.1.
Figure imgf000189_0001
[0418] Synthesis of tert-butyl 2-(2-chloro-4-methylphenyl)acetate. To a solution of added
2-chloro-l-iodo-4-methylbenzene (404 mg, 1.6 mmol) in THF (5 mL) was added (2-(tert- butoxy)-2-oxoethyl)zinc(II) bromide (0.4 M in THF, 6 mL, 2.4 mmol), Pd2(dba)j (146 mg, 0.16 mmol) and X-Phos (114 mg, 0.24 mmol). The mixture was stirred at 70 °C for 5 h under N2. The mixture was cooled to room temperature, and then filtered by Celite®. The filter cake was washed with THF (20 mL), the filtrate was concentrated in vacuo to give the residue, which was purified by silica gel chromatography, eluting with 0-40% EtOAc/PE to afford tert-butyl 2-(5- (((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)acetate (300 mg, yield: 78%) as pale-yellow solid. ESI-MS [M +H]+: 241.1.
[0419] Synthesis of 2-(2-chloro-4-methylphenyl)acetic acid. To a solution of tert-butyl 2-
(2-chloro-4-methylphenyl)acetate (300 mg, 1 .25 mmol) in DCM (4 mL) was added HCl/1,4- di oxane (4 M in 1,4-dioxane, 4 mL). After the mixture was stirred at room temperature for 2 h, the mixture was concentrated in vacuo to afford 2-(2-chloro-4-methylphenyl)acetic acid (300 mg, crude) as a white solid, which was used in next step without purification. ESI-MS [M +H]+: 185.1.
[0420] Synthesis of 2-(2-chloro-4-methylphenyl)-N,N-dimethylacetamide. To a mixture of
2-(2-chloro-4-methylphenyl)acetic acid (300 mg, crude) and Me2NH (364 mg, 8.1 mmol) in DMF (10 mL) was added DIPEA (627 mg, 4.86 mmol) and HATU (924 mg, 2.43 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction diluted with H2O (50 mL), and then extracted with EtOAc (50 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by silica gel chromatography, eluting with 0-50% EtOAc/PE to afford 2-(2-chloro-4-methylphenyl)-N,N-dimethylacetamide (200 mg, yield 76% over 2 steps) as a pale-yellow solid. ESI-MS [M +H]+: 212.1.
Synthesis ofN,N-dimethyl-2-(4-methyl-2-(trifluoroniethyl)phenyl)acetamide
Figure imgf000190_0001
DMF, r.t , 0.5 h
[0421] Synthesis of tert-butyl 2-(4-methyl-2-(trifluoromethyl)phenyl)acetate. To a solution of 2-chl oro-1 -iodo-4-m ethylbenzene (381 mg, 1.6 mmol) in THF (10 mL) was added (2-(tert- butoxy)-2-oxoethyl)zinc(II) bromide (0.4M in THF, 6 mL, 2.4 mmol), Pd2(dba)3 (146 mg, 0.16 mmol) and X-Phos (114 mg, 0.24 mmol). The mixture was stirred at 70 °C for 4 h under N2. The mixture was cooled to room temperature, and then filtered by Celite®. The filter cake was washed with THF (20 mL) and the filtrate was concentrated in vacuo to give the residue, which was purified by silica gel chromatography, eluting with 0-30% EtOAc/PE to afford tert-butyl 2- (5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)acetate (400 mg, yield: 91%) as paleyellow solid. ESI-MS [M +H]+: 275.1.
[0422] Synthesis of 2-(4-methyl-2-(trifluoroniethyl)phenyl)acetic acid. To a solution of tert-butyl 2-(4-methyl-2-(trifluoromethyl)phenyl)acetate (400 mg, 1.46 mmol) in DCM (5 mL) was added HCl/l,4-di oxane (4 M in 1,4-dioxane, 5 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to afford 2-(4-methyl-2- (trifluoromethyl)phenyl)acetic acid (400 mg, crude) as a white solid, which was used in next step without purification.
[0423] Synthesis ofN,N-diniethyl-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide. To a mixture of 2-(4-methyl-2-(trifluoromethyl)phenyl)acetic acid (400 mg, crude) and Me2NH (412 mg, 9.17 mmol) in DMF (10 mL) was added DIPEA (708 mg, 5.49 mmol) and HATU (1.04 g, 2.75 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction diluted with H2O (40 mL), and then extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over NarSO-i, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 0-50% EtOAc/PE to afford N,N-dimethyl-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide (300 mg, yield 84% over 2 steps) as pale-yellow solid. ESLMS [M +H]+: 246.1.
Synthesis of 6-(aminomethy!)-5, 7,8-trimethylisoquinolin-l-amine
Figure imgf000191_0001
84%
NH3, MeOH LiAIH4, THF,
120 °C, 40.5 h 85 °C, 3.5 h
Step 3 Step 4 27% over 2 steps
Figure imgf000191_0002
68%
Figure imgf000191_0003
[0424] Synthesis of 2,3,5,6-tetramethylterephthalonitrile. A mixture of 3,6-dibromodurene
(9.96 g, 34.1 mmol), zinc cyanide (7.98 g, 68.2 mmol) and te/ra£zs(triphenylphosphine)palladium (0) (2.76 g, 2.39 mmol) in anhydrous N,N- dimethylformamide (120 mL) was degassed and heated at 130 °C under nitrogen for 3 h. After being cooled the mixture was concentrated under reduced pressure and the residue was treated with water (100 mL) and ethyl acetate (300 mL). The mixture was filtered through Dicalite, washing the filter cake with ethyl acetate (2 x 100 mL). The filtrate layers were separated, and the organic phase was washed with dilute aqueous sodium hydroxide (0.1 M, 100 mL) and brine (3 x 100 mL). The organic solution was dried (MgSCL) and concentrated under reduced pressure to give a purple solid. Purification by trituration with boiling heptane (100 mL) was partially successful and gave, after filtration 6.117 g of a pale purple solid. Further purification by flash chromatography, eluting with heptane: methyl t-butyl ether = 10:1 and then a gradient of heptane:dichloromethane = 5:1 to 1 : 1 gave 2,3,5,6-tetramethylterephthalonitrile (5.246 g, 84%) as a fluffy colourless solid.
Figure imgf000191_0004
NMR (400 MHz, CDCh, ppm) 5 2.50 (s, 12H).
[0425] Synthesis of (E)-2-(2-(dimethylamino)vinyl)-3,5,6-trimethylterephthalonitrile. A mixture of 2,3,5, 6-tetramethylterephthalonitrile (5.12 g, 27.8 mmol) and tert-buty\-bis- (dimethylamino)methane (9.67 g, 55.6 mmol) in anhydrous N, A-dimethylformamide (40 mL) was heated at 75 °C under nitrogen for 5 h. After being cooled the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (100 mL) and evaporated (twice) and then dissolved in heptane (50 mL) and evaporated (twice). The residue was a deep red- orange solid (7.174 g). Analysis by XH NMR showed this material to consist of a mixture of unreacted 2,3,5,6-tetramethylterephthalonitrile : (E)-2-(2-(dimethylamino)vinyl)-3,5,6- trimethylterephthalonitrile : two Z>A-enamines (A and B, depicted below) in the ratio 34:53:5:8, giving a calculated yield of 60% for the desired product. This material was taken onto step 3 without purification. XH NMR (400 MHz, CDCh, ppm) 5 6.83 (d, J 14 Hz, 1H), 4.96 (d, J 14 Hz, 1H), 2.88 (s, 6H), 2.44-2.49 (signals for Ar-CHi, no assignment possible). ESLMS [M + H]+ 240.
Figure imgf000192_0001
A B
[0426] Synthesis of l-amino-5, 7,8-trimethylisoquinoline-6-carbonitrile. A mixture of crude (E)-2-(2-(dimethylamino)vinyl)-3,5,6-trimethylterephthalonitrile (7.089 g, as prepared above) and methanolic ammonia (7 M, 400 mL) was heated in a stainless steel autoclave at 120 °C for 23 h. The mixture was cooled and concentrated under reduced pressure. The residue was taken up in methanolic ammonia (7 M, 400 mL) and heated in heated in a stainless-steel autoclave at 120 °C for 17.5 h. The mixture was cooled and the residue adsorbed onto silica gel under reduced pressure. The mixture was purified by column chromatography, eluting with 1-2% methanol in dichloromethane, to give l-amino-5, 7, 8-trimethylisoquinoline-6-carbonitrile as a pale orange solid (1.560 g, 27% over steps 2 and 3). XH NMR (400 MHz, CD3SOCD3, ppm) 5 7.87 (d, J 6 Hz, 1H), 7.04 (d, J 6 Hz, 1H), 6.44 (s, 2H), 2.72 (s, 3H), 2.69 (s, 3H), 2.53 (s, 3H). ESLMS [M + H]+ 212.
[0427] Synthesis of 6-(anunomethyl)-5,7,8-trimethylisoquinolin-l-amine. A solution of 1- amino-5,7,8-trimethylisoquinoline-6-carbonitrile (1.349 g, 6.39 mmol) in anhydrous tetrahydrofuran (60 mL) was added dropwise over 20 min to a solution of lithium aluminium hydride (2 M in tetrahydrofuran, 20 mL, 40 mmol) in tetrahydrofuran (75 mL) at 85 °C. The combined mixture was stirred at 85 °C for 3.5 h. The reaction was cooled to room temperature, sodium sulfate decahydrate was added portionwise until effervescence ceased, and the mixture was stirred for 1 h. The mixture was filtered through Dicalite and the filtrate concentrated under reduced pressure to give a pale orange solid. The crude product was combined with another batch of 6-(aminomethyl)-5,7,8-trimethylisoquinolin-l-amine (0.120 g) and purified by column chromatography, eluting with 1-5% 7 M methanolic ammonia in di chloromethane, to give 6- (aminomethyl)-5,7,8-trimethylisoquinolin-l-amine as a pale orange solid (1.054 g, 68%, accounting for added material). XH NMR (400 MHz, CDCh, ppm) 5 7.84 (d, J 6 Hz, 1H), 7.13 (d, J 6 Hz, 1H), 5.09 (br. s, 2H), 4.06 (s, 2H), 2.78 (s, 3H), 2.58 (s, 3H), 2.47 (s, 3H). ESI-MS [M + H]+ 216.
Figure imgf000193_0001
[0428] K2CO3 (1.78 mmol, 129 mg) and 2-(4-(chloromethyl)benzyl)pyridine (0.60 mmol, 129 mg) were added to a solution of methyl lH-pyrazole-4-carboxylate (0.60 mmol, 75 mg) in acetone (5.0 mL). The mixture was heated at 50°C for 32 hours then cooled to room temperature and poured into water. The mixture was extracted with EtOAc then the organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient of iso-hexane — > EtOAc, to give the title compound as a clear oil (64 mg, 35%). ESI-MS (M+H):+ 308.2.
Synthesis of methyl l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxylate
Figure imgf000193_0002
[0429] Synthesis of (3-chloroquinolin-6-yl)methyl methanesulfonate. Methanesulfonyl chloride (0.50 mmol, 0.039 mL) was added to a mixture of (3 -chi oroquinolin-6-yl)m ethanol (0.5 mmol, 97 mg) and TEA (0.50 mmol, 0.070 mL) in DCM (4 mL) at room temperature. The mixture was stirred for 1.5 h then a further aliquot of methanesulfonyl chloride (0.25 mmol, 0.020 mL) was added. Stirring was continued for a further 1.5 h then the mixture was diluted with water (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were passed through a phase separator column then concentrated in vacuo to give the crude mesylate which was used without further purification.
[0430] Synthesis of methyl l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxylate.
A mixture of methyl lH-pyrazole-4-carboxylate (0.4 mmol, 50 mg), (3-chloroquinolin-6- yl)methyl methanesulfonate (0.4 mmol) and K2CO3 (2.0 mmol, 276 mg) in acetone (3 mL) was heated to 50 °C for 20 h. The mixture was cooled to room temperature, diluted with water (20 mL) and extracted with DCM (20 mL). The organics were passed through a phase separator cartridge then concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient of DCM >50% EtOAc in DCM to give the title compound as a white solid (105 mg, 87%). ESLMS (M+H):+ 301.9.
[0431] The intermediate compounds in Table 2 were made by a similar procedure to that used for the synthesis of methyl l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxylate from methyl lH-pyrazole-4-carboxylate and the indicated coupling partner.
Table 2
Figure imgf000194_0001
Figure imgf000195_0002
Synthesis of l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxylic acid
Figure imgf000195_0001
[0432] A mixture of methyl l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxylate (0.34 mmol, 102 mg) and LiOH (0.37 mmol, 16 mg) in THF (5 mb) and water (1 mL) was stirred at room temperature for 3 hours. Further LiOH (0.37 mmol, 16 mg) and water (0.5 mL) were added and stirring was continued for a further 5 hours at room temperature then overnight at 90 °C. The mixture was cooled to room temperature then concentrated in vacuo. The residue was suspended in 1,4-di oxane (2 mL) then HC1 (4M in 1,4-dioxane, 1 mL) was added. The suspension was stirred for 5 min then concentrated in vacuo to give the title compound as a hydrochloric acid salt which was used without further purification (quant.). ESI-MS (M+H):+ 287.9.
[0433] The intermediate compounds in Table 3 were prepared in a similar manner to l-((3- chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxylic acid from the indicated ester coupling partner. Table 3
Figure imgf000196_0001
Synthesis of methyl l-((8-((l,3, 4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[l,2-a]pyridin-2-
Figure imgf000197_0001
[0434] Synthesis of methyl l-((8-bronw-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-4-carboxylate. A mixture of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[ 1 ,2- a]pyridine (1.0 g, 3.5 mmol), methyl lH-pyrazole-4-carboxylate (440 mg, 3.5 mmol) and CS2CO3 (2.3 g, 7.1 mmol) in DMF (15 m ) was stirred at 50 °C for 3 h. The reaction mixture was cooled to room temperature and poured into water (60 mL) and extracted with EtOAc (50 mb x 3). The combined organic layers were washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous Na2SO4, concentrated to give the crude product, which was purified by column chromatography on silica gel, eluting with 10 ~ 30% EtOAc in PE to give methyl 1- ((8-bromo-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxylate (1.3 g, yield: quant.) as a yellow solid. ESLMS [M + H]+: 375.1.
[0435] Synthesis of methyl l-((8-(2-(tert-butoxy)-2-oxoethyl)-6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazoIe-4-c(irboxyIate. A mixture of methyl l-((8-bromo-6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxylate (1.3 g, 3.5 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.5 M in THF, 8.4 mL, 4.2 mmol), Pd2(dba)3 (0.32 g, 0.35 mmol) and Q-phos (0.50 g, 0.70 mmol) in THF (20 mL) was stirred at 65 °C for 8 h under N2. The reaction was cooled to room temperature and diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaiSO-i, concentrated to give the crude product, which was purified by column chromatography on silica gel, eluting with 10 ~ 30% EtOAc in PE to give methyl 1- ((8-(2-(tert-butoxy)-2-oxoethyl)-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole- 4-carboxylate (1.1 g, yield: 76%) as a yellow solid. ESI-MS [M + H]+: 411.1.
[0436] Synthesis of 2-(6-cyclopropyl-2-((4-(methoxycarbonyl)-lH-pyrazol-l- yl)methyl)imidazo[l,2-a]pyridin-8-yl)acetic acid. To a stirred solution of methyl l-((8-(2-(tert- butoxy)-2-oxoethyl)-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxylate (985 mg, 2.4 mmol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and dried in vacuo to give 2- (6-cy cl opropyl-2-((4-(methoxy carbonyl)- IH-pyrazol- 1 -yl)methyl)imidazo[ 1 ,2-a]pyridin-8- yl)acetic acid (700 mg, crude) as a yellow oil, which was sued into next step without further purification. ESI-MS [M + H]+: 355.2.
[0437] Synthesis of methyl l-((8-(2-(2-(tert-butoxycarbonyl)hydrazinyl)-2-oxoethyl)-6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxylate. To a stirred solution of 2-(6-cyclopropyl-2-((4-(methoxycarbonyl)- IH-pyrazol- 1 -yl)methyl)imidazo[ 1,2- a]pyridin-8-yl)acetic acid (700 mg, crude) in DMF (10 mL) was added DIPEA (1.3 g, 10 mmol) and HATU (0.84 g, 2.2 mmol). The mixture was stirred at room temperature for 10 min and tertbutyl hydrazinecarboxylate (0.32 g, 2.4 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organics were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, concentrated to give the crude product, which was purified by column chromatography on silica gel, eluting with 20 ~ 50% EtOAc in PE to give methyl l-((8-(2-(2- (tert-butoxycarbonyl)hydrazinyl)-2-oxoethyl)-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-4-carboxylate (550 mg, yield: 49% over 2 steps) as a yellow solid. ESI-MS [M + H]+: 469.1.
[0438] Synthesis of methyl l-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxyIate. To a stirred solution of methyl l-((8-(2-(2- (tert-butoxycarbonyl)hydrazinyl)-2-oxoethyl)-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-4-carboxylate (550 mg, 1.17 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and dried in vacuo to give methyl l-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxylate (430 mg, crude) as a yellow solid. ESI-MS [M + H]+: 369.1.
[0439] Synthesis of methyl l-((8-((l,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxylate. The mixture of methyl l-((6-cyclopropyl-8- (2-hydrazinyl-2-oxoethyl)imidazo[l,2-a]pyri din-2 -yl)methyl)-lH-pyrazole-4-carboxylate (430 mg, crude) and ethyl orthoformate (0.36 g, 2.4 mmol)) in toluene (10 mb) and AcOH (2 mL) was stirred at 100 °C for 10 h. The reaction mixture was concentrated, the residue was washed with NaHCOs (sat. aq., 50 mL), extracted with EtOAc (50 ml x 3). The combined organics was washed with brine (50 mL), dried over anhydrous Na2SCh, concentrated and purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give methyl 1 -((8-((l ,3,4- oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxylate (300 mg, yield: 68% over 2 steps) as a yellow solid. ESI-MS [M + H]~: 379.2.
Figure imgf000199_0001
[0440] A mixture of ethyl lH-pyrazole-4-carboxylate (575 mg, 4.1 mmol), (bromomethyl)benzene (700 mg, 4.1 mmol) and CS2CO3 (2.67 g, 8.2 mmol) in DMF (10 mL) was stirred for at room temperature for 16 h. The reaction was diluted with water (40 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc/PE = 1/4) to give ethyl 1 -benzyl- lH-pyrazole-4-carboxylate (850 mg, yield: 90%) as a yellow solid. ESI-MS [M +H]+: 231.0. Synthesis of ethyl (Z)~ l-((6- (prop- 1 -en- 1 -yl)imidazo[ 1, 2-a]pyridin-2-yl) methyl)- 1 H-pyrazole-3- carboxylate.
Figure imgf000200_0001
[0441] Synthesis of 6-bromo-2-(chloromethyl)imidazo[l,2-a]pyridine. To a solution of 5- bromopyridin-2-amine (5.0 g, 28.9 mmol) in DMF (100 mL) was added l,3-dichloropropan-2- one (11.0 g, 86.7 mmol). The mixture was stirred at 90 °C for 2 h. After cooled to room temperature, the reaction was neutralized with NaHCCh (sat. aq., 150 mL), extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to give the crude, which was purified by silica gel chromatography (eluent: EtOAc/PE = 0 ~ 50%) to give 6-bromo-2-(chloromethyl)imidazo[l,2- a]pyridine (2.5 g, yield: 35%) as yellow oil. ESLMS [M+H]+: 246.9.
[0442] Synthesis of ethyl l-((6-bromoimidazo[l ,2-a]pyridin-2-yl)methyl)-lH-pyrazole-3- carboxylate. To a solution of 6-bromo-2-(chloromethyl)imidazo[l,2-a]pyridine (2.5 g, 10.2 mmol) and ethyl lH-pyrazole-4-carboxylate (1.7 g, 12.2 mmol) in DMF (30 mL) was added CS2CO3 (6.65 g, 20.4 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was diluted with H2O (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated to give the crude, which was purified by silica gel chromatography (eluent: EtOAc / PE = 0 ~ 80%) to give ethyl l-((6-bromoimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-3-carboxylate (2.8 g, yield: 79%) as a yellow oil. ESLMS [M+H]+: 349.1.
[0443] Synthesis of ethyl l-((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-3-carboxylate. To a mixture of ethyl l-((6- bromoimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-3-carboxylate (1.3 g, 3.7 mmol), 4,4,4',4',5,5,5',5'-octamethyL2,2'-bi(l,3,2-dioxaborolane) (1.4 g, 5.6 mmol) and KO Ac (1.1 g, 11.1 mmol) in 1,4-dioxane (30 mL) was added Pd(dppf)Ch (293 mg, 0.4 mmol). The mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was used in the next step without further purification. ESI-MS [M +H]+: 397.2.
[0444] Synthesis of ethyl (Z)-l-((6-(prop-l-en-l-yl)imidazo[l,2-a]pyridin-2-yl)methyl)-lH- pyrazole-3-carboxylate. To the reaction mixture above was added (Z)-l-bromoprop-l-ene (1.3 g, 11.1 mmol), CS2CO3 (2.4 g, 7.4 mmol) and Pd(PPhi)4 (231 mg, 0.2 mmol). The mixture was stirred 100 °C for another 16 h. under N2. After cooled to room temperature, the reaction was diluted with water (100 mb) was added and the mixture was extracted with EtOAc (100 mb x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated to give the crude, which was purified by silica gel chromatography (eluent: EtOAc / PE = 0 ~ 50%) to give tert-butyl (Z)-(5-(prop-l-en-l-yl)pyridin-2-yl)carbamate (1.0 g, yield: 87%) as a yellow solid. ESI-MS [M+H]+: 311.1.
Synthesis of ethyl l-(2-((tert-butoxycarbonyl)amino)-l-phenylethyl)-lH-pyrazole-4-
Figure imgf000201_0001
[0445] Synthesis of methyl 2-bromo-2-phenylacetate. To a mixture of 2-bromo-2- phenylacetic acid (2 g, 9.3 mmol) in MeOH (20 mL) was added SOCh (2 mL) and the reaction mixture was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was concentrated to give methyl 2-bromo-2-phenylacetate (2 g, crude) as a yellow solid. ESI-MS [M +H]+: 229.0. [0446] Synthesis of ethyl l-(2-methoxy-2-oxo-l -phenylethyl)-] H-pyrazole-4-carboxylate.
To a mixture of methyl 2-bromo-2-phenylacetate (2 g, crude) and ethyl lH-pyrazole-4- carboxylate (1.23 g, 8.8 mmol) in DMF (20 mL) was added CS2CO3 (5.7 g, 17.6 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. Water (100 mL) was added and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc=10/l to 5/1) to give ethyl 1 -(2-methoxy-2-oxo- 1 - phenylethyl)-lH-pyrazole-4-carboxylate (2 g, yield over 2 steps: 74%) as a yellow solid. ESLMS [M +H]+: 289.1.
[0447] Synthesis of ethyl l-(2-hydroxy-l-phenylethyl)-lH-pyrazole-4-carboxylate. To a mixture of ethyl l-(2-methoxy-2-oxo-l -phenylethyl)- lH-pyrazole-4-carboxylate (2 g, 6.9 mmol) in MeOH (20 mL) was added NaBH-i (524 mg, 13.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h under N2. The reaction was quenched with NH4CI (sat. aq., 60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc=2/l) to give ethyl l-(2-hydroxy-l- phenylethyl)-lH-pyrazole-4-carboxylate (1.5 g, yield: 84%) as a yellow solid. ESLMS [M +H]+: 261.1.
[0448] Synthesis of ethyl l-(2-((methylsulfonyl)oxy)-l-phenylethyl)-lH-pyrazole-4- carboxylate. To a mixture of ethyl l-(2-hydroxy-l-phenylethyl)-lH-pyrazole-4-carboxylate (1.5 g, 5.75 mmol) in DCM (30 mL) was added TEA (2.1 g, 20.7 mmol), followed by MsCl (1.18 g, 10.4 mmol) 0 °C. The reaction mixture was stirred at room temperature for 2 h under N2. The reaction was diluted with DCM (50 mL), washed with H2O (40 mL), brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give ethyl l-(2-((methylsulfonyl)oxy)-l-phenylethyl)- lH-pyrazole-4-carboxylate (1.7 g, crude) as a yellow solid. ESLMS [M +H]+: 339.1.
[0449] Synthesis of ethyl l-(2-azido-l-phenylethyl)-!H-pyrazole-4-carboxylate. To the mixture of ethyl L(2-((methylsulfonyl)oxy)-l-phenylethyl)-lH-pyrazole-4-carboxylate (1.7 g, crude) in DMSO (20 mL) was added NaNs (462 mg, 7.1 mmol). The resulting mixture was stirred at 80 °C for 16 h. After cooled to room temperature, the reaction was diluted with water (100 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4, and concentrated to give ethyl L(2-azido-L phenylethyl)- lH-pyrazole-4-carboxylate (1.6 g, crude) as a yellow solid, which was used into the next step without further purification. ESI-MS [M +H]+: 286.1.
[0450] Synthesis of ethyl l-(2-amino-l-phenylethyl)-lH-pyrazole-4-carboxylate. A mixture of ethyl l-(2-azido-l-phenylethyl)-lH-pyrazole-4-carboxylate (1.6 g, crude) and Pd/C (200 mg) in MeOH (20mL) was stirred at room temperature for 2 h under H2. The reaction mixture was filtered, filter cake washed with MeOH (50 mL). The filtrate was concentrated to give ethyl l-(2-amino-l -phenylethyl)- lH-pyrazole-4-carboxylate (1.5 g, crude) as a yellow solid. ESI-MS [M +H]+: 260.1.
[0451] Synthesis of ethyl l-(2-((tert-butoxycarbonyl)amino)-l-phenylethyl)-lH-pyrazole-4- carboxylate. To a mixture of ethyl l-(2-amino-l-phenylethyl)-lH-pyrazole-4-carboxylate (1.5 g, crude) in DCM (20 mL) was added BOC2O (2.53 g, 11.6 mmol), TEA (1.76 g, 17.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with H2O (60 mL), extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc=l/l) to give ethyl l-(2-((tert- butoxycarbonyl)amino)-l -phenylethyl)- lH-pyrazole-4-carboxylate (1.2 g, yield: 58% over 4 steps) as a yellow solid. ESI-MS [M +H]+: 360.1.
Synthesis of ethyl l-(4-(2-(3-aziibicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-3-
Figure imgf000203_0001
[0452] Synthesis of l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(hydroxyniethyl)phenyl)ethan-
1-one. To a mixture of 2-(4-(hydroxymethyl)phenyl)acetic acid (1 g, 6 mmol) and 3- azabicyclo[3.1.0]hexane (498 mg, 6 mmol) in DMF (20 mL) was added DIPEA (2.3 g, 18 mmol) and HATU (3.4 g, 9 mmol). After the reaction mixture was stirred at room temperature for 2 h, the reaction was quenched with water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 10/1 to 5/1) to give l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4- (hydroxymethyl)phenyl)ethan-l-one (900 mg, yield: 65%) as a yellow solid. ESI-MS [M +H]+: 232.1.
[0453] Synthesis of l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(chloromethyl)phenyl)ethan-l- one. To a mixture of l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(hydroxymethyl)phenyl)ethan-l- one (150 mg, 0.65 mmol) in DCM (5 mL) was added SOCI2 (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h under N2. The reaction was concentrated to give l-(3- azabicyclo[3.1.0]hexan-3-yl)-2-(4-(chloromethyl)phenyl)ethan-l-one (150 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS [M +H]+: 250.1.
[0454] Synthesis of ethyl l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-3- (trifluoromethyl)-lH-pyrazole-4-carboxylate. To a mixture of l-(3-azabicyclo[3.1.0]hexan-3- yl)-2-(4-(chloromethyl)phenyl)ethan-l-one (150 mg, crude) and ethyl 3-(trifluoromethyl)-lH- pyrazole-4-carboxylate (135 mg, 0.65 mmol) in DMF (5 mL) was added K2CO3 (270 mg, 1.95 mmol). The reaction mixture was stirred at room temperature for 16 h. Water (30 mL) was added and the reaction was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SCh, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc= 2/1) to give ethyl l-(4-(2-(3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-3-(tri fluoromethyl)- lH-pyrazole-4-carboxylate (120 mg, yield: 44% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 422.1.
Figure imgf000204_0001
[0455] Synthesis of methyl 2-(trimethylstannyl)isonicotinate. To a mixture of methyl 2- chloroisonicotinate (500 mg, 2.9 mmol) and hexamethylditin (1.4 g, 4.4 mmol) in dioxane (10 mL) was added Pd(PPh3)4 (346 mg, 0.3 mmol) and the reaction mixture was stirred at 90 °C for 3 h under N2. After cooled to room temperature, the reaction was diluted with water (40 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaiSC , and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc = 3/1) to give methyl 2-(trimethylstannyl)isonicotinate (750 mg, yield: 86%) as a yellow solid. ESI-MS [M +H]+: 302.1.
[0456] Synthesis of methyl 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)isonicotinate. To a mixture of methyl 2-(trimethylstannyl)isonicotinate (600 mg, 2 mmol) and l-(4- (chloromethyl)benzyl)-lH-pyrazole (412 mg, 2 mmol) in 1,4-dioxane (10 mL) was added PdCh(PPh3)2 (140 mg, 0.2 mmol). The reaction mixture was stirred at 90 °C for 6 h under N2. After cooled to room temperature, the reaction was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by Prep- TLC (eluent: PE/EtOAc=2/l) to give methyl 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)isoni cotinate (80 mg, yield: 13%) as a yellow solid. ESI-MS [M +H]+: 308.1.
Synthesis of ethyl l-(4-((4-methyl-lH-pyrazol-l-yl)methyl)benzyl)-3-(trifluoromethyl)-lH-
Figure imgf000205_0001
[0457] Synthesis of methyl 4-((4-methyl-lH-pyrazol-l-yl)methyl)benzoate. A mixture of methyl 4-(bromomethyl)benzoate (2.5 g, 10.9 mmol), 4-methyl-lH-pyrazole (984 mg, 12 mmol) and CS2CO3 (8.8 g, 27 mmol) in DMF (30 mL) was stirred at room temperature for 5 h. The reaction was poured into H2O (100 mL), extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to give methyl 4-((4-methyl-lH-pyrazol-l-yl)methyl)benzoate (2.3 g, 92%) as a yellow solid. ESI-MS : 231.1. [0458] Synthesis of (4-((4-methyl-lH-pyrazol-l-yl)methyl)phenyl)methanol. To a solution of methyl 4-((4-methyl-lH-pyrazol-l-yl)methyl)benzoate (1.2 g, 5.2 mmol) in THF (40 mL) was added LiAlH4 (15.6 mL, 15.6 mmol, 1 M solution in THF) slowly at 0 °C. After the resulting reaction was stirred at room temperature for Ih, the reaction was cooled to 0 °C and quenched with NH4Q (sat. aq., 80 mL), extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-10% MeOH in DCM to give (4-((4-methyl-lH-pyrazol-l-yl)methyl)phenyl)methanol (730 mg, 70%) as a yellow solid. ESLMS[M+1]+: 203.2.
[0459] Synthesis of ethyl l-(4-((4-methyl-lH-pyrazol-l-yl)methyl)benzyl)-3-
(trifluoromethyl)-lH-pyrazole-4-carboxylate. To a solution of (4-((4-methyl-lH-pyrazol-l- yl)methyl)phenyl)methanol (326 mg, 1.6 mmol), ethyl 3-(trifluoromethyl)-lH-pyrazole-4- carboxylate (333 mg, 1.6 mmol) and PPh; (632 mg, 2.4 mmol) in dry THF (20 mL) was added DEAD (418 mg, 2.4 mmol) dropwise. The resulting reaction was stirred at room temperature for 12 h. H2O (50 mL) was added and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0- 7% MeOH in DCM to give ethyl l-(4-((4-methyl-lH-pyrazol-l-yl)methyl)benzyl)-3- (trifluoromethyl)-lH-pyrazole-4-carboxylate (420 mg, 67%) as a yellow solid. ESI-MS[M+1]+: 393.2.
[0460] Synthesis of ethyl l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-3-(trifluoromethyl)-lH- pyrazole-4-carboxylate. To a solution of (4-((lH-pyrazol-l-yl)methyl)phenyl)methanol (320 mg, 1.6 mmol), ethyl 3-(trifluoromethyl)-lH-pyrazole-4-carboxylate (333 mg, 1.6 mmol) and PPI13 (632 mg, 2.4 mmol) in dry THF (20 mL) was added DEAD (418 mg, 2.4 mmol) dropwise. The resulting reaction was stirred at room temperature for 12 h. After completed, the reaction was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-7% MeOH in DCM to give (4-((lH-pyrazol-l-yl)methyl)phenyl)methanol (480 mg, 79%) as a yellow solid. ESI-MS[M+1]+: 379.2. Synthesis of ethyl l-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)-lH-l,2,3-triazole-4- carboxylate.
Figure imgf000207_0001
[0461] Synthesis of l-(4-(azidomethyl)benzyl)pyridin-2(lH)-one. A mixture of l-(4- (chloromethyl)benzyl)pyridin-2(lH)-one (500 mg, 2.1 mmol) and NaN3 (208 mg, 3.2 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. The reaction was diluted with H2O (30 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-40% EtOAc in PE to give l-(4- (azidomethyl)benzyl)pyridin-2(lH)-one (400 mg, 79%) as a yellow solid. ESI-MS[M+1]+: 241.2.
[0462] Synthesis of ethyl l-(4-((2-oxopyridin-l (2H)-yl)methyl)benzyl)-lH-l,2,3-triazole-4- carboxylate. To a solution of l-(4-(azidomethyl)benzyl)pyridin-2(lH)-one (400 mg, 1.7 mmol) and ethyl propiolate (176 mg, 1.8 mmol) in tBuOH (15 mL) was added CuSO4 (142 mg, 0.9 mmol, solution in 4 mL H2O) and sodium ascorbate (178 mg, 0.9 mmol, solution in 4 mL H2O). The resulting reaction was stirred at room temperature for Ih. The reaction was diluted with H2O (30 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give ethyl l-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)-lH-l,2,3-triazole-4-carboxylate (120 mg, 20%) as a yellow solid. ESLES[M+1]+: 339.2.
Synthesis of methyl l-(4-((l H-pyrazol- 1 -yl) methyl) benzyl)-5-(methoxymethyl)-l H-pyraz.ole-4- carhoxylate and methyl l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-5-(methoxymethyl)-lH- pyrazole-4-carboxylate.
Figure imgf000208_0001
[0463] A mixture of l-(4-(chloromethyl)benzyl)-lH-pyrazole (247 mg, 1.2 mmol), methyl 3- (methoxymethyl)-lH-pyrazole-4-carboxylate (200 mg, 1.2 mmol) and K2CO3 (497 mg, 3.6 mmol) in DMF (8 mb) was stirred at room temperature for 5 h. The reaction was diluted with H2O (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give methyl l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-3-(methoxymethyl)-lH-pyrazole-4- carboxylate (180 mg, 44%) and methyl l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-5- (methoxymethyl)-lH-pyrazole-4-carboxylate (80 mg, 20%) as a yellow solid. ESI-ES[M+1]+: 341.2.
Synthesis of ethyl 5-((6-cyclopropyliniidazo[l,2-a]pyridin-2-yl)methyl)-l,3,4-oxadiazole-2-
Figure imgf000208_0002
[0464] Synthesis of ethyl 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetate. To a solution
5-cyclopropyl-4-rnethylpyridin-2-amine (30 g, 224 mmol) in EtOH (400 mL) was added ethyl 4- chloro-3-oxobutanoate (110 g, 671 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 16 h. After cooled to room temperature, the reaction was concentrated in vacuo. The residue was washed with NaHCCh (aq. sat., 200 mL), extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (250 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography (DCM/MeOH = 10/1) to give ethyl 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetate (40 g, impure) as a black solid. ESI-MS [M +H]+: 245.2.
[0465] Synthesis of 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetohydrazide. A mixture of ethyl 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetate (40 g, impure) and JShH LLO (50 mL, 80% aq.) in EtOH (300 mL) was stirred at 85 °C for 12 h. The mixture was then concentrated and purified by silica gel chromatography (DCM/MeOH = 10/1) to give 2-(6- cyclopropylimidazo[l,2-a]pyridin-2-yl)acetohydrazide (17.1 g, yield: 32% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 231.1.
[0466] Synthesis of ethyl 2-(2-(2-(6-cyclopropylimidazo[l,2-a]pyridin-2- yl)acetyl)hydrazinyl)-2-oxoacetate. To a solution of 2-(6-cyclopropylimidazo[l,2-a]pyri din-2 - yl)acetohydrazide (17 g, 73.9 mmol) and DIPEA (28 g, 222 mmol) in DCM (300 mL) was added ethyl 2-chloro-2-oxoacetate (15 g, 111 mmol) slowly at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Water (200 ml), and the mixture was extracted with DCM (200 mL x 2). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (DCM/MeOH = 10/1) to give (ethyl 2-(2-(2-(6- cyclopropylimidazo[l,2-a] pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate (17g, yield: 70%) as a yellow solid. ESI-MS [M +H]+: 331.1.
[0467] Synthesis of ethyl 5-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-l,3,4- oxadiazole-2-carboxylate. To a solution of ethyl 2-(2-(2-(6-cyclopropylimidazo[l,2-a]pyridin- 2-yl)acetyl)hydrazinyl)-2-oxoacetate (17 g, 51.5 mmol) and EtsN (20 g, 200 mmol) in DCM (300 mL) was added a solution of TsCl (11.8 g, 61.8 mmol) in DCM (50 mL) at room temperature.
The reaction mixture was stirred at this temperature for 16 h. The reaction was diluted with water (200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (DCM/MeOH = 10/1) to give 2- (chi oromethyl)-5-methylimidazo[l,2-a]pyri dine ( 8.2 g, yield: 51%) as a yellow oil. ESI-MS [M +H]+: 313.2.
Synthesis of ethyl l-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)-lH-pyrazole-4-carboxylate
Figure imgf000210_0001
[0468] Synthesis of l-(4-(hydroxymethyl)benzyl)pyridin-2(lH)-one. A mixture of (4- (chloromethyl)phenyl)m ethanol (2.46 g, 15.8 mmol), 2-pyridone (1.0 g, 10.5 mmol) and anhydrous potassium carbonate (2.90 g, 21 mmol) in CH3CN (60 mL) was stirred for 3 h at 50 °C. After cooled to room temperature, the mixture was concentrated, and the residue was diluted with water (60 mL) and extracted by EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4 to give the residue, which was purified by silica gel chromatography (eluent: PE: EtOAc = 10 : 1) to give l-(4- (hydroxymethyl)benzyl)pyridin-2(lEI)-one (1.47 g, 65%) as white solid. ESLMS [M +H]+: 216.1.
[0469] Synthesis of l-(4-(bromomethyl)benzyl)pyridin-2(lH)-one. To a solution of l-(4- (hydroxymethyl)benzyl)pyridin-2(lH)-one (1.47 g, 6.8 mmol) in dry DCM (30 mL) was added PBn (3.67 g, 13.6 mmol) slowly at 0 °C. The reaction mixture was stirred at room temperature for 18 h. Water (50 mL) was added and the reaction was extracted by DCM (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SOr and concentrated to give the residue, which was purified by silica gel chromatography (eluent: PE: EtOAc = 5 : 1) to give l-(4-(bromomethyl)benzyl)pyridin-2(lH)-one as brown solid (1.2 g, 63%). ESI-MS [M +H]+: 278.1.
[0470] Synthesis of ethyl l-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)-lH-pyrazole-4- carboxylate. A mixture of l-(4-(bromomethyl)benzyl)pyridin-2(lH)-one (706 mg, 2.55 mmol), ethyl lH-pyrazole-4-carboxylate (357 mg, 2.55 mmol) and caesium carbonate (1.66 g, 5.1 mmol) in DMF (15 mL) was stirred for 18 h at 50 °C. After cooled to room temperature, the reaction was diluted with water (50 mL) and extracted by EtOAc (50mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO-i and concentrated to give the residue, which was purified by silica gel chromatography (eluent: PE: EtOAc = 5 : 1) to give ethyl l-(4- ((2-oxopyridin-l(2H)-yl)methyl)benzyl)-lH-pyrazole-4-carboxylate (650 mg, 76%) as a white solid. ESI-MS [M +H]+: 338.1.
Synthesis of ethyl l-((6-(pyrrolidin-l-yl)pyridin-3-yl)methyl)-5-(trifluoromethyl)-lH-pyrazole- 4-carboxylate and ethyl l-((6-(pyrrolidin-l-yl)pyridin-3-yl)methyl)-3-(trifluoromethyl)-lH-
Figure imgf000211_0001
[0471] Synthesis of ethyl 6-(pyrrolidin-l-yl)nicotinate. To a solution of ethyl 6- chloronicotinate (1 g, 5.4 mmol) in DMF (10 mL) was added Pyrrolidine (422 mg, 5.93 mmol) and K2CO3 (1.49 g, 10.8 mmol). The resulting reaction mixture was stirred at 60 °C for 4 h. After cooled to room temperature, the mixture was quenched with H2O (40 mL), extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give the residue, which was purified by silica gel chromatography (eluent: PE: EtOAc = 5 : 1) to give ethyl 6-(pyrrolidin-l-yl)nicotinate (1.01 g, 85%) as a white solid. ESI-MS [M +H]+: 221.2.
[0472] Synthesis of (6-(pyrrolidin-l-yl)pyridin-3-yl)methanol. To a solution of ethyl 6- (pyrrolidin-l-yl)nicotinate (818 mg, 3.7 mmol) in THF (20 mL) was added LiAlH (2.5 M in THF, 3.7 mL, 9.25 mmol) at 0 °C. After the reaction solution was stirred at room temperature for 2h, the mixture was quenched with Na2SO4»10H2O (3 g) at 0 °C, filtered and filter cake was washed with DCM/MeOH (10/1, 40 mL). The filtrate was concentrated to give the residue, which was purified by silica gel chromatography (eluent: PE: EtOAc = 2 : 1) to give (6- (pyrrolidin-l-yl)pyridin-3-yl)methanol (530 mg, 80%) as a white solid. ESLMS [M +H]+: 179.2.
Synthesis of methyl l-((2-phenylpyrimidin-5-yl)methyl)-lH-pyrazole-4-carboxylate
Figure imgf000212_0001
[0473] Synthesis of 5-methyl-2-phenylpyrimidine. A mixture of phenylboronic acid (610 mg, 5 mmol), 2-chloro-5-methylpyrimidine (645 mg, 5 mmol), Pd(dppf)Ch (365 mg, 0.5 mmol), CS2CO3 (4.9 g, 15 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred at 100 °C for 16 h under N2. After cooled to room temperature, the reaction mixture was filtered through celite® and washed with DCM / MeOH (10/1, 50 mL). The filtrate was concentrated and purified by silica gel chromatography (PE/EtOAc = 3/1) to give the product 5-methyl-2-phenylpyrimidine (600 mg, yield: 70%) as yellow oil. ESLMS [M +H]+: 171.2.
[0474] Synthesis of 5-(bromomethyl)-2-phenylpyrimidine. A mixture of 5-methyl-2- phenylpyrimidine (600 mg, 3.53 mmol), NBS (755 mg, 4.24 mmol), BPO (97 mg, 0.4 mmol) in CCI4 (10 mL) was stirred at 100 °C for 16 h. After cooled to room temperature, the reaction mixture was quenched with H2O (30 mL), extracted with DCM (30 mL x 3), and the combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated to give the residue, which was purified by silica gel chromatography (eluent: PE: EtOAc = 4 :1) to give the product 5-(bromomethyl)-2-phenylpyrimidine (350 mg, yield: 40%) as a yellow oil. ESLMS [M +H]+: 249.2.
[0475] Synthesis of methyl l-((2-phenylpyrimidin-5-yl)methyl)-lH-pyrazole-4-carboxylate.
A mixture of methyl lH-pyrazole-4-carboxylate (302 mg, 2.4 mmol), 5-(bromomethyl)-2- phenylpyrimidine (600 mg, 2.4 mmol) and K2CO3 (994 mg, 7.2 mmol) in dry DMF (10 mL) was stirred at 0 °C for 2 h. The mixture was quenched with H2O (30 mL), extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4 and concentrated to give the residue, which was purified by silica gel chromatography (eluent: DCM/MeOH = 100/1) to give methyl l-((2-phenylpyrimidin-5-yl)methyl)-lH-pyrazole-4- carboxylate (300 mg, yield: 42%) as a white solid. ESLMS [M +H]+: 295.1.
Synthesis of methyl l-(4-((2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridin-3-
Figure imgf000213_0001
[0476] Synthesis of methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate. A mixture of (2- m ethoxy pyri di n-3-yl)b or onic acid (2.7 g, 17.6 mmol), methyl 4-(bromomethyl)benzoate (4.0 g, 17.6 mmol), Pd(PPhs)4 (2.03 g, 1.76 mmol) and NazCCh (5.54 g, 52.8 mmol) in dry MeOH (30 mb) was stirred at 120 °C by microwave for 1 h under N2. The reaction mixture was cooled to room temperature then diluted with H2O (100 mb), extracted with ethyl acetate (80 mb x 3). The combined organic layers were washed with brine (50 mb), dried over Na2SO4 and concentrated to give the residue, which was purified by silica gel chromatography (eluent: EtOAc/PE = 1/10) to give methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate (1.8 g, yield: 40%) as a white solid. ESI-MS [M +H]+: 258.1.
[0477] Synthesis of methyl 4-((2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoate. A mixture of 4-((2-methoxypyridin-3-yl)methyl)benzoate (1.2 g, 5.1 mmol) and 48% HBr (850 mg, 5.1 mmol) in HOAc (15 mL) in a sealed tube was heated at 70 °C for 16 h. After cooled to room temperature, the reaction was poured into NaHCCh (sat. aq.,100 mL) slowly, and then extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, and concentrated to afford l-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-l-ol (980 mg, yield: 79%) as a yellow oil, which was used into the next step without further purification. ESI-MS [M +H]+: 244.1.
[0478] Synthesis of methyl 4-((2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridin-3-yl) methyl) benzoate. A mixture of l-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-l-ol (500 mg, 2 mmol), 2,2,2-trifluoroethyl trichloromethanesulfonate (560 mg, 2 mmol) and CS2CO3 (652 mg, 2 mmol) in DCM (20 mL) was stirred at room temperature for 16 h. Water (50 mL) was added and the reaction was extracted by DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give the residue, which was purified by Prep-TLC (eluent: EtOAc/PE = 5/1) to give methyl 4-((2-oxo-l -(2,2,2-trifluoroethyl)- 1,2 - dihydropyridin-3-yl)methyl)benzoate (300 mg, 46%) as yellow oil. ESLMS [M +H]+: 326.1.
[0479] Synthesis of 3-(4-(hydroxymethyl)benzyl)-l-(2,2,2-trifluoroethyl)pyridin-2(lH)-one.
To a solution of 4-((2 -oxo- 1 -(2,2,2-trifluoroethyl)- 1,2 -dihydropyridin-3-yl)methyl)benzoate (300 mg, 0.9 mmol) in THF (10 mL) and MeOH (5 mL) was added LiBELi (200 mg, 9 mmol) at 0 °C. After the reaction mixture was stirred at room temperature for 1 h, the reaction was quenched with water (30 mL) was added and extracted by EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the residue, which was purified by silica gel chromatography (eluent: EtOAc/PE = 2/1) to give 3-(4-(hydroxymethyl)benzyl)-l- (2,2,2-trifluoroethyl)pyridin-2(lH)-one (200 mg, yield: 75%) as a colorless oil. ESI-MS [M +H]+: 298.1.
[0480] Synthesis of 3-(4-(chloromethyl)benzyl)-l-(2,2,2-trifluoroethyl)pyridin-2(lH)-one. A mixture of 3-(4-(hydroxymethyl)benzyl)-l-(2,2,2-trifluoroethyl)pyridin-2(lH)-one (200 mg, 0.67 mmol) and SOCI2 (1 mL) in DCE (5 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to get 3-(4-(chloromethyl)benzyl)-l -(2,2,2- trifluoroethyl)pyridin-2(lH)-one (250 mg, crude), which was used directly into the next step without purification. ESI-MS [M +H]+: 316.1.
[0481] Synthesis of methyl l-(4-((2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridin-3- yl)methyl) benzyl)-lH-pyrazole-4-carboxylate. A mixture of 3-(4-(chloromethyl)benzyl)-l- (2,2,2-trifluoroethyl)pyridin-2(lH)-one (250 mg, crude), methyl lH-pyrazole-4-carboxylate (125 mg, 1 mmol) and K2CO3 (280 mg, 2 mmol) in MeCN (10 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was diluted with water (30 mL) and extracted by EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the residue, which was purified by Prep-TLC (EtOAc/PE = 1/1) to give methyl l-(4-((2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridin-3-yl)methyl)benzyl)-lH- pyrazole-4-carboxylate (200 mg, 74% over 2 steps) as a white solid. ESI-MS [M +H]+: 406.1.
Synthesis of ethyl 2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylate
Figure imgf000215_0001
[0482] Synthesis of 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetannde. A solution of ethyl 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetate (3.6 g, 14.7 mmol) in NEE (7M solution in MeOH, 50 m ) in a sealed tube was stirred at 60 °C for 12 h. The reaction was concentrated to give the 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetamide (3.4 g, crude) as a yellow oil, which was used into next step without further purification. ESI-MS [M +H]+: 216.2. [0483] Synthesis of 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)ethanethioamide. To a solution of 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetamide (3.4 g, crude) in 1,4-di oxane (50 mL) was added Lawesson's reagent (6.38 g, 15.8 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched with H2O (70 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the 2-(6-cyclopropylimidazo[l,2-a]pyridin-2- yl)ethanethioamide (3 g, crude) as a yellow oil, which was used into next step without further purification. ESI-MS [M +H]+: 232.2.
[0484] Synthesis of ethyl 2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)thiazole-5- carboxylate. A mixture of 2-(6-cy cl opropylimidazo[l,2-a]pyri din-2 -yl)ethanethioamide (750 mg, crude), pyridine (480 mg, 6.2 mmol) and ethyl 2-chl oro-3 -ox opropanoate (698 mg, 4.65 mmol) in EtOH (25 mL) was stirred at 65°C for 14h. The reaction was cooled to room temperature and concentrated to give the crude, which was purified with silica gel chromatography (EtOAc/PE = 1/1) to give the ethyl 2-((6-cyclopropylimidazo[l ,2-a]pyridin-2- yl)methyl)thiazole-5-carboxylate (105 mg, yield: 10% over 3 steps) as a yellow solid. ESI-MS [M +H]+: 328.1.
Synthesis of ethyl lf(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-lH-
Figure imgf000216_0001
[0485] Synthesis of ethyl l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate. A mixture of ethyl lH-pyrazole-4-carboxylate (2.8 g, 20 mmol), l-(chloromethyl)-4-methoxybenzene (4.7 g, 30 mmol) and CS2CO3 (13.1 g, 40 mmol) in DMF (20 mL) was stirred at room temperature for 2 h. The reaction was quenched with water (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography (EtOAc/PE from 0 to 30%) to give ethyl l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate (4.5 g, yield: 86%) as colorless oil. ESLMS [M +H] +: 261.1.
[0486] Synthesis of ethyl 5-formyl-l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate. To a solution of ethyl l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate (2.6 g, 10.0 mmol) in THF (30 mL) was added n-BuLi (5.0 ml, 12.0 mmol, 2.4 M solution in hexane) at -60 °C and the mixture was stirred at -60 °C for 10 min. Then dry DMF (1.5 g, 20 mmol) was added at -60 °C and the mixture was stirred at -60 °C for another 1 h. The reaction was quenched with NH4CI (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified column chromatography (eluent: EtOAc / PE = 0 - 30%) to give ethyl 5-formyl-l -(4-methoxybenzyl)- lH-pyrazole-4-carboxylate (1.15 g, yield: 40%) as a white solid. ESLMS [M +H] +: 289.1. [0487] Synthesis of ethyl 5-(difluoromethyl)-l-(4-methoxybenzyl)-lH-pyrazole-4- carboxylate. To a solution of ethyl 5-formyl-l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate (400 mg, 1.39 mmol) in DCM (10 mL) was added DAST (483 mg, 3 mmol) at 0 °C and the mixture was stirred at room temperature for 5 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified by column chromatography (eluent: EtOAc / PE = 0 - 30%) to give ethyl 5 -(difluoromethyl)- 1 -(4- methoxybenzyl)-lH-pyrazole-4-carboxylate (316 mg, yield: 73%) as colorless oil. ESLMS [M +H] +: 311.1
[0488] Synthesis of ethyl 5-(difluoromethyl)-lH-pyrazole-4-carboxylate. A solution of ethyl 5-formyl-l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate (310 mg, 1.0 mmol) in TFA (3 mL) was stirred at 60 °C for 3 h. The reaction was concentrated to remove TFA, and the residue was washed with NaHCO (sat. aq., 30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: MeOH / DCM = 0 - 5%) to give ethyl 5-(difluoromethyl)-lH-pyrazole-4-carboxylate (150 mg, yield: 79%) as a brown solid. ESLMS [M +H] +: 191.1.
[0489] Synthesis of ethyl l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3- (difluoromethyl)-lH-pyrazole-4-carboxyl(ite. A mixture of ethyl 5-(difluoromethyl)-lH- pyrazole-4-carboxylate (150 mg, 0.79 mmol), l-(chloromethyl)-4-methoxybenzene (245 mg, 1.19 mmol) and CS2CO3 (517 g, 1.58 mmol) in DMF (5 mL) was stirred at room temperature for Ih. Water (30 mL) was added and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: MeOH / DCM = 0 - 5%)) to give ethyl l-((6-cy cl opropylimidazo[l,2-a]pyridin-2-yl)methyl)-3-(difluorom ethyl)- lH-pyrazole-4- carboxylate (200 mg, yield: 70%) as a yellow solid. ESLMS [M +H] +: 361.1 Synthesis of methyl l-(l-(3-chloroquinolin-6-yl)ethyl)-lH-l,2,3-triazole-4-carboxylate
Figure imgf000218_0001
[0490] Synthesis of methyl 3-chloroquinoline-6-carboxylate. To a solution methyl quinoline-6-carboxylate (10 g, 53.4 mmol) and NCS (14.266 g, 107 mmol) in DMF (150 mL). The mixture was stirred for 16 h at 120 °C. Then the reaction was cooled to room temperature, poured into water (500 mL) and extracted with EtOAc (300 ml x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SC>4, and concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc = 5/1) to give methyl 3- chloroquinoline-6-carboxylate (2.85 g, yield: 24%) as a white solid. ESLMS [M +H]+: 221.9.
[0491] Synthesis of 3-chloroquinoline-6-carboxylic acid. A solution of methyl 3- chloroquinoline-6-carboxylate (1.4 g, 6.3 mmol) and LiOFHLO (530 mg, 12.6 mmol) in MeOH/ water (10 mL/10 mL) was stirred at room temperature for 16 h. The pH of the reaction was adjusted to 5 with HC1 (aq. IN) and concentrated in vacuo to give 3-chloroquinoline-6- carboxylic acid (2 g, crude) as a yellow solid. This material was used directly in the next step without further purification. ESLMS [M +H]+: 208.0.
[0492] Synthesis of 3-chloro-N-methoxy-N-methylquinoline-6-carboxamide. A solution of 3-chloroquinoline-6-carboxylic acid (2 g, crude), N,O-dimethylhydroxylamine hydrochloride (705 mg, 7.23 mmol), HATU (4.58 g, 12 mmol) and DIPEA (3.89 g, 30 mmol) in DMF (20 mL) was stirred for 3 h at room temperature. Then the reaction was poured into water (80 mL) and extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc = 8/1) to give 3-chloro-N-methoxy-N-methylquinoline-6- carboxamide (1.24 g, yield: 79% over 2 steps) as yellow solid. ESI-MS [M +H]+: 251.0. [0493] Synthesis of l-(3-chloroquinolin-6-yl)ethan-l-one. To a solution of 3-chloro-N- methoxy-N-methylquinoline-6-carboxamide (1.24 g, 4.96 mmol) in anhydrous THF (10 mL) was added CHsMgBr (2.5 ml, 7.5 mmol, 3 M solution in ether) at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 3 h. Then the reaction was quenched with NH4CI (sat. aq., 40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc = 5/1) to give l-(3-chloroquinolin-6-yl)ethan-l-one (800 mg, yield: 79%) as a yellow solid. ESLMS [M +H]+: 206.2.
[0494] Synthesis of l-(3-chloroquinolin-6-yl)ethan-l-ol. To a solution of l-(3- chloroquinolin-6-yl)ethan-l-one (800 mg, 3.9 mmol) in MeOH (15 mL) was added NaBEh (304 mg, 8 mmol). After the reaction mixture was stirred at room temperature for 1 h, the reaction was quenched with NH4CI (sat. aq., 30 mL) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (60 mL), dried over NazSO4 and concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc = 2/1) to give l-(3- chloroquinolin-6-yl)ethan-l-ol (778 mg, yield: 96%) as a yellow oil. ESLMS [M +H]+: 208.1.
[0495] Synthesis of 3-chloro-6-(l-chloroethyl)quinolone. A solution of (5- cyclopropylthieno[2,3-b]pyridin-2-yl)methanol (778 mg, 3.74 mmol) in DCM (5 mL) and SOCI2 (2 mL) was stirred at room temperature for 2 h. Then the reaction mixture was concentrated in vacuo. The residue was washed with NaHCO- (sat. aq., 30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give 2-(chloromethyl)-5-cyclopropylthieno[2,3-b]pyridine (800 mg, crude) as a yellow oil. ESLMS [M +H]+: 226.1.
[0496] Synthesis of 6-(l-azidoethyl)-3-chloroquinoline. To a solution of 3-chloro-6-(L chloroethyl)quinoline (100 mg, crude) in DMF (5 mL) was added NaNs (62 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 16 h. Water (20 mL) was added and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), concentrated in vacuo to give 6-(l-azidoethyl)-3 -chloroquinoline (101 mg, crude) as a yellow solid, which was used directly in the next step without further purification. ESLMS [M +H]+: 233.1.
[0497] Synthesis of methyl l-(l-(3-chloroquinolin-6-yl)ethyl)-lH-l,2,3-triazole-4- carboxylate. To a solution 6-(l-azidoethyl)-3-chloroquinoline (101 mg, crude), methyl propiolate (73 mg, 0.87 mmol) in tBuOH (4 mL)/H20 (2 mL) was added Q12SO4 (15 mg, 0.09 mmol) and sodium ascorbate (26 mg, 0.13 mmol). The reaction mixture was stirred for 2 h at room temperature. After completed, the reaction was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by Prep -TLC (eluent: PE/EtOAc = 1/1) to give methyl l-(l-(3-chloroquinolin-6-yl)ethyl)-lH-l,2,3-triazole-4- carboxylate (100 mg, yield: 67% over 3 steps) as a yellow solid. ESLMS [M +H]+: 317.1.
Synthesis of ethyl l-((6-(trifhioromethyl)inuilazo[ 1 ,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxylate
Figure imgf000220_0001
[0498] Synthesis of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[l,2-a]pyridine. A solution of 5-(trifluoromethyl)pyridin-2-amine (500 mg, 3.1 mmol) and l,3-dichloropropan-2- one (780 mg, 6.2 mmol) in DMF (15 mL) was stirred at 95 °C for 13 h. After cooled to room temperature, the reaction was quenched with NaHCCh (sat. aq., 50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-5% MeOH in DCM to give 2-(chloromethyl)-6- (trifluoromethyl)imidazo[l,2-a]pyridine (350 mg, 48%) as a yellow solid. ESLMS [M +H]+: 235.1.
[0499] Synthesis of ethyl l-((6-(trifhioromethyl)inudazo[l,2-a]pyridin-2-yl)methyl)-lH- pyrazole-4-carboxylate. A mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[l,2- a]pyridine (200 mg, 0.85 mmol), ethyl lH-pyrazole-4-carboxylate (182 mg, 1.3 mmol) and CS2CO3 (831 mg, 2.55 mmol) in DMF (10 mL) was stirred at 55 °C for 2 h. After cooled to room temperature, the reaction was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO-i, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 15 /I) to give ethyl l-((6-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxylate (175 mg, 61%) as a yellow solid. ESLMS [M +H]+: 339.2.
Synthesis of methyl l-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-3- carboxylate and methyl l-benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-5- carboxylate
Figure imgf000221_0001
[0500] Synthesis of methyl l-acetyl-5-niethyl-lH-pyrazole-3-carboxylate. To a solution of methyl 5-methyl-lH-pyrazole-3-carboxylate (1 g, 7.1 mmol) in pyridine (25 mL) was added AC2O (1.8 g, 18 mmol). The reaction was stirred at 65 °C for 2 h. After cooled to room temperature, the reaction was concentrated in vacuo to give the residue, which was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-25% of EtOAc in PE to give methyl l-acetyl-5-methyl-lH-pyrazole-3-carboxylate (930 mg, 72%) as a yellow solid. ESI-MS [M +H]+: 183.2.
[0501] Synthesis of methyl l-acetyl-5-(bromomethyl)-lH-pyrazole-3-carboxylate. A solution of methyl l -acetyl-5-methyl-lH-pyrazole-3-carboxylate (930 mg, 5.1 mmol), NBS (1.0 g, 5.6 mmol) and AIBN (84 mg, 0.51 mmol) in CCh (30 mL) was stirred at 95 °C for 12 h. After cooled to room temperature, the reaction was quenched with NaHCOi (sat. aq., 50 mL), extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-25% EtOAc in PE to give methyl 1-acetyl- 5-(bromomethyl)-lH-pyrazole-3-carboxylate (730 mg, 55%) as a yellow solid. ESI-MS [M +H]+: 261.3.
[0502] Synthesis of methyl 5-(aminomethyl)-lH-pyrazole-3-carboxylate. A solution of methyl l-acetyl-5-(bromomethyl)-lEI-pyrazole-3-carboxylate (730 mg, 2.8 mmol) in NEE (20 mL, 7M solution in MeOH) was stirred at room temperature for 14 h. The reaction was concentrated in vacuo to give methyl 5-(aminomethyl)-lH-pyrazole-3-carboxylate (500 mg crude) as a yellow solid, which was used into the next step without further purification. ESI-MS [M +H]+: 156.2.
[0503] Synthesis of l-(tert-butyl) 3-methyl 5-(((tert-butoxycarbonyl)amino)methyl)-lH- pyrazole-l,3-dicarboxylate. To a solution of methyl 5 -(aminomethyl)- lH-pyrazole-3- carboxylate (500 mg crude) and TEA (848 mg, 8.4 mmol) in THF (25 mL) was added BOC2O (1.3 g, 6 mmol). The reaction was stirred at room temperature for 4 h. The reaction was concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to 1 -(tert-butyl) 3-methyl 5- (((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-l,3-dicarboxylate (520 mg, 52% over 2 step) as a yellow solid. ESI-MS [M +H]+: 356.2.
[0504] Synthesis of methyl 5-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-3- carboxylate. A mixture of 3-methyl 5-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-l,3- dicarboxylate (520 mg, 1.46 mmol) and LiOEEEEO (150 mg, 3.56 mmol) in THF/MeOH/HiO (5 mL / 5 mL / 2 mL) was stirred at room temperature for 1 h. The reaction was diluted with H2O (30 mL), extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (35 mL), dried over Na2SOi, concentrated in vacuo to give methyl 5-(((tert- butoxy carbonyl)amino)m ethyl)- lH-pyrazole-3 -carboxylate (400 mg crude) as a yellow solid, which was used into next step without further purification. ESI-MS [M +H]+: 256.3.
[0505] Synthesis of methyl l-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-
3-carboxylate. A mixture of methyl 5-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-3- carboxylate (400 mg crude), (chloromethyl)benzene (277 mg, 2.2 mmol) and CS2CO3 (1.43 g, 4.4 mmol) in DMF (10 mL) was stirred at room temperature for 3 h. FEO (40 mL) was added and the reaction was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-30% EtOAc in PE to give methyl l-benzyl-5-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-3-carboxylate (210 mg, 42%) and methyl l-benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazole-5- carboxylate (195 mg, 39% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 346.1.
Figure imgf000223_0001
[0506] Synthesis of 2-anuno-5-cyclopropyl-l-(prop-2-yn-l-yl)pyridin-l-ium bromide.
[0507] A mixture of 2-amino-5-cyclopropylpyridine (6.70 g, 50.0 mmol) and propargyl bromide (80% w/v in toluene, 11.1 mL, 100 mmol) in 2-propanol (120 m ) was heated at 80°C for 2 h, then allowed to cool to room temperature. The resulting red-brown slurry was cooled in an ice bath and ethyl acetate (50 mL) was added. The mixture was stirred for 1 h and then the solid was collected by filtration to give 2-amino-5-cyclopropyl-l-(prop-2-yn-l-yl)pyridin-l-ium bromide (6.150 g, 49%), as a buff solid. LCMS [System 2, 4.5 min buffered method] RT = 1.58 min; [M]“ 173. XH NMR (400 MHz, CD3SOCD3, ppm) 5 8.46 (br s, 2H), 8.00 (s, 1H), 7.68 (dd, J 1.6, 9 Hz, 1H), 7.01 (d, J 9 Hz, 1H), 5.02 (d, J3 Hz, 2H), 3.79 (t, J3 Hz, 1H), 1.91-1.85 (m, 1H), 0.96-0.92 (m, 2H), 0.69-0.65 (m, 2H).
[0508] Synthesis of ethyl 2-(6-cyclopropylimidazo[l,2-a]pyridine-2-carbonyl)isonicotinate and ethyl 2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinate. A mixture of ethyl 2-iodoisonicotinate (5.611 g, 20.3 mmol), £>/ (triphenylphosphine) palladium chloride (852 mg, 1.22 mmol) and copper (I) iodide (577 mg, 3.04 mmol) in anhydrous N,N-dimethylformamide (100 mL) at 20 °C was degassed thoroughly (vacuum/nitrogen backfill) three times.
Triethylamine (11.3 mL, 81.0 mmol) and 2-amino-5-cyclopropyl-l-(prop-2-yn-l-yl)pyridin-l- ium bromide (6.150 g, 24.3 mmol) were added and the mixture was degassed again (three times). The resulting red solution was stirred at 20 °C for 19 h. The solution was poured into methyl /c'/7-butyl ether (600 mL) and saturated aqueous sodium bicarbonate (200 mL) and filtered through Dicalite. The filtrate layers were separated and the aqueous phase was extracted with methyl /c/'Z-butyl ether (2 x 200 mL). The combined organic solutions were washed with water (200 mL) and brine (3 x 200 mL), dried (Na2SCU) and concentrated under reduced pressure. The crude product was dissolved in di chloromethane and adsorbed onto silica gel (30 g), which was applied to a chromatography column (silica gel 300 g), which was eluted with ethyl acetate : triethylamine = 100: 1. The product containing fractions were combined and concentrated under reduced pressure to give a dark brown oil (3.2 g). This material was dissolved in ethyl acetate and purified by flash chromatography (200g silica gel) eluting with a gradient of ethyl acetate : methanol : acetic acid = 100:0:1 - 100: 10:1. Fractions containing the higher running spot by thin layer chromatography were concentrated to give a brown solid, which was triturated with a little acetonitrile to give ethyl 2-(6-cyclopropylimidazo[l,2-a]pyridine-2-carbonyl)isoni cotinate (279 mg, 4%), as a buff solid. TLC ethyl acetate : methanol : acetic acid = 100:5: 1 Rf 0.55. LCMS [System 2, 4.5 min buffered method] RT = 2.74 min [M + H]+ 336. XH NMR (400 MHz, CDCh, ppm) 5 8.93 (d, J 5 Hz, 1H), 8.86 (s, 1H), 8.81 (s, 1H), 8.07 (dd, J 6, 1 Hz, 1H), 7.94 (s, 1H), 7.62 (d, J 9 Hz, 1H), 7.01 (dd, J9, 2 Hz, 1H), 4.47 (q, JI.6 Hz, 2H), 1.95-1.88 (m, 1H), 1.44 (t, J 7.6 Hz, 3H), 1.04-0.99 (m, 2H), 0.74-0.70 (m, 2H).
[0509] Fractions containing the lower running spot by thin layer chromatography were concentrated to give ethyl 2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinate (2.501 g, 39%), as a brown oil. TLC ethyl acetate : methanol : acetic acid = 100:5: 1 Rr 0.19. LCMS [System 2, 4.5 min buffered method] RT = 2.48 min [M + H]+ 322. XH NMR (400 MHz, CDCh, ppm) 8 8.69 (d, J 6 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.68 (d, J 6 Hz, 1H), 7.41 (d, J 9 Hz, 1H), 7.33 (s, 1H), 6.88 (dd, J9, 2 Hz, 1H), 4.37 (q, J 7.6 Hz, 2H), 4.36 (s, 2H), 1.88-1.81 (m, 1H), 1.37 (t, J 1.6 Hz, 3H), 0.95-0.90 (m, 2H), 0.65-0.61 (m, 2H). Synthesis of (lR,5S,6r)-6-methyl-3-azabicyclo[3. l.OJhexane
Figure imgf000225_0001
[0510] Synthesis of 3-benzyl 6-ethyl (lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6- dicarboxylate and3-benzyl 6-ethyl (lR,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate. To a mixture of benzyl 2,5-dihydro-lH-pyrrole-l-carboxylate (8 g, 39.4 mmol) and Rh(OAc)2 (LI g mg, 3.94 mmol) in DCM (100 mL) was added ethyl 2-diazoacetate (13.5 g, 118.2 mmol) and the reaction mixture was stirred at room temperature for 36 h under N2. Then the reaction mixture was concentrated to give the crude, which was purified by column chromatography (eluent: EtOAc/PE= 0 ~ 10%) to give 3-benzyl 6-ethyl (lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6- dicarboxylate (1.5 g, yield: 13%) and 3-benzyl 6-ethyl (lR,5S,6r)-3-azabicyclo[3.1.0]hexane- 3,6-dicarboxylate (2.5 g, yield: 22%) as yellow oil. ESI-MS [M +H]+: 290.1.
[0511] Synthesis of benzyl (lR,5S,6s)-6-(hydroxymethyl)-3-az(tbicyclo[3.1.0]hexane-3- carboxylate. To a solution of 3-benzyl 6-ethyl (lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6- dicarboxylate (800 mg, 2.8 mmol) in THF (10 mL) was added DIBAL-H (IM in THF, 5.6 mL, 5.6 mmol) at -60 °C and the mixture was stirred at room temperature for 2 h. The reaction was quenched with NH-iCl (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NazSCU, concentrated to give the crude, which was purified by column chromatography (eluent: EtOAc/PE= 0 ~ 30%) to give benzyl (lR,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, yield: 43%) as a yellow oil. ESI-MS [M +H] +: 248.1.
[0512] Synthesis of benzyl (lR,5S,6s)-6-(chloromethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate. To a mixture of benzyl (lR,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate (200 mg, 0.81 mmol) in DCM (5 mL) was added SOCh (0.5 mL) and the reaction mixture was stirred at room temperature for 1 h under N2. Then the reaction mixture was concentrated to give the crude, which was purified by column chromatography (eluent: EtOAc/PE= 0 ~ 10%) to give benzyl (lR,5S,6s)-6-(chloromethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (120 mg, yield: 56%) as a yellow oil. ESLMS [M +H]+: 266.1.
[0513] Synthesis of benzyl (lR,5S,6r)-6-niethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate.
To a solution of benzyl (lR,5S,6s)-6-(chloromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 0.45 mmol) in MeOH (5 mL) was added NaBEh (34 mg, 0.9 mmol) at 0 °C and the mixture was stirred at room temperature for 2 h. The reaction was quenched with NH4CI (sat. aq., 20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude, which was purified by column chromatography (eluent: EtOAc/PE= 0 ~ 10%) to give benzyl (lR,5S,6r)-6-methyl-3- azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, yield: 77%) as a white sold. ESLMS [M +H] +: 232.1.
[0514] Synthesis of (lR,5S,6r)-6-niethyl-3-azabicyclo[3.1. OJhexane. A mixture of benzyl (lR,5S,6r)-6-methyL3-azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 0.35 mmol) and Pd/C (20 mg) in MeOH (5 mL) was stirred at room temperature for 2 h under H2. The reaction was filtered through celite, the filter cake was washed with MeOH (10 mL) and filtrate was concentrated in vacuo to give (lR,5S,6r)-6-methyL3-azabicyclo[3.1.0]hexane (40 mg, yield: quant) as a brown oil, which was used in the next step without purification. ESLMS [M +H]+: 98.1.
Synthesis of (1R, 5S, 6s)-6-(fluoromethyl)-3-azabicyclo[3.1. OJhexane
Figure imgf000226_0001
[0515] Synthesis of benzyl (lR,5S,6s)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate. To a solution of benzyl (lR,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate (120 mg, 0.49 mmol) in THF (5 mL) was added DAST(158 mg, 0.98 mmol) at 0 °C and the mixture was stirred at room temperature for 2 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep- TLC (eluent: EtOAc/PE = 0 ~ 15%) to give benzyl (lR,5S,6s)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, yield: 0.66%) as a yellow oil. ESI-MS [M +H] +: 250.1.
[0516] Synthesis of (1 R,5S,6s)-6-(fluoromethyl)-3-azabicyclo[3.1.0Jhexane. A mixture of benzyl (lR,5S,6s)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 0.32 mmol) and Pd/C (20 mg) in MeOH (5 mL) was stirred at room temperature for 2 h under H2. The reaction was filtered through celite, the filter cake was washed with MeOH (10 mL) and filtrate was concentrated in vacuo to give (lR,5S,6s)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane (40 mg, yield: quant) as a brown oil. ESI-MS [M +H]+: 116.1.
Synthesis of (1R, 5S, 6r)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane
Figure imgf000227_0001
[0517] Synthesis of benzyl (lR,5S,6r)-6-(fhioromethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate. To solution of benzyl (lR,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (120 mg, 0.49 mmol) in THF (5 mL) was added DAST (158 mg, 0.98 mmol) at 0 °C and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep- TLC (eluent: EtOAc/PE= 0 ~ 15%) to give benzyl (lR,5S,6r)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, yield: 0.66%) as a yellow oil. ESI-MS [M +H] +: 250.1.
[0518] Synthesis of (lR,5S,6r)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexane. A mixture of benzyl (lR,5S,6r)-6-(fhroromethyl)-3-azabicyclo[3. 1.0]hexane-3-carboxylate (80 mg, 0.32 mmol) and Pd/C (20 mg) in MeOH (5 mL) was stirred at room temperature for 2 h under H2. The reaction was filtered through celite, the filter cake was washed with MeOH (10 mL) and filtrate was concentrated in vacuo to give (lR,5S,6r)-6-(fluoromethyl)-3-azabicyclo[3. L0]hexane (40 mg, yield: quant) as a brown oil, which was used in the next step without purification. ESI-MS [M +H]+: 116.1. Synthesis of ((lR,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methanol
Figure imgf000228_0001
[0519] A mixture of benzyl (lR,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (100 mg, 0.4 mmol) and Pd/C (20 mg) in MeOH (5 mL) was stirred at room temperature for 2 h under H2. The reaction was filtered through celite, the filter cake was washed with MeOH (10 mL) and filtrate was concentrated in vacuo to give ((lR,5S,6r)-3- azabicyclo[3.1.0]hexan-6-yl)methanol (40 mg, crude) as a brown oil, which was used in the next step without purification. ESLMS [M +H]+: 114.1.
Synthesis of (1R, 5S, 6s)-3-azabicyclo[3.1.0]hexan-6-yl) methanol
Figure imgf000228_0002
[0520] A mixture of benzyl (lR,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (50 mg, 0.2 mmol) and Pd/C (10 mg) in MeOH (3 mL) was stirred at room temperature for 2 h under H2. The reaction was filtered through celite, the filter cake was washed with MeOH (10 mL) and filtrate was concentrated in vacuo to give ((lR,5S,6s)-3- azabicyclo[3.1.0]hexan-6-yl)methanol (20 mg, crude) as a brown oil, which was used in the next step without purification. ESLMS [M +H]+: 114.1.
Synthesis of ethyl (lR,5S,6s)-3-azabicyclo[3.1.0]hexane-6-carboxylate
Figure imgf000228_0003
[0521] A mixture of 3-benzyl 6-ethyl (lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6- dicarboxylate (100 mg, 0.35 mmol) and Pd/C (20 mg) in MeOH (5 mL) was stirred at room temperature for 2 h under H2. The reaction was filtered through celite, the filter cake was washed with MeOH (10 mL) and filtrate was concentrated in vacuo to give ethyl (lR,5S,6s)-3- azabicyclo[3.1.0]hexane-6-carboxylate (50 mg, yield: quant) as a brown oil, which was used in the next step without purification. ESLMS [M +H]+: 156.1. Synthesis of ethyl (lR,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate
Figure imgf000229_0001
[0522] A mixture of 3-benzyl 6-ethyl (lR,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6- dicarboxylate (100 mg, 0.35 mmol) and Pd/C (20 mg) in MeOH (5 mL) was stirred at room temperature for 2 h under H2. The reaction was filtered through celite, the filter cake was washed with MeOH (10 mL) and filtrate was concentrated in vacuo to give ethyl (lR,5S,6r)-3- azabicyclo[3.1.0]hexane-6-carboxylate (50 mg, yield: quant) as a brown oil, which was used in the next step without purification. ESI-MS [M +H]+: 156.1.
Synthesis of (4-((lH-pyrazol-l-yl)methyl)phenyl)methanamine
Figure imgf000229_0002
[0523] Synthesis of methyl 4-((lH-pyrazol-l-yl)methyl)benzoate. A mixture of methyl 4- (bromomethyl)benzoate(22.8 g, 100 mmol), IH-pyrazole (7.5 g, 110 mmol) and CS2CO3 (48.9 g, 150 mmol) in DMF (100 mL) was stirred at room temperature for 16 h under N2. The reaction was quenched with water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 5/1) to give methyl 4-((lH-pyrazol-l-yl)methyl)benzoate (18 g, yield: 83%) as a yellow solid. ESI-MS [M +H]+: 217.2.
[0524] Synthesis of (4-((lH-pyrazol-l-yl)methyl)phenyl)methanol. To a solution of methyl 4-((lH-pyrazol-l-yl)methyl)benzoate (1.8 g, 8.3 mmol) in THF (50 mL) was added LiAlEh (380 mg, 10 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with NH4CI (sat. aq., 100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give (4-((lH-pyrazol-l-yl)methyl)phenyl)methanol (1.3 g, yield: 83%) as a white solid. ESI-MS [M +H]+: 189.2.
[0525] Synthesis of l-(4-(chloromethyl)benzyl)-lH-pyrazole. To a solution of (4-((lH- pyrazol-l-yl)methyl)phenyl)methanol (600 mg, 3.2 mmol) in DCM (10 mL) was added SOCh (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the crude product l-(4-(chloromethyl)benzyl)-lH-pyrazole (600 mg, crude) as a yellow oil, which was used in the next step without purification. ESI-MS [M +H]+: 207.2.
[0526] Synthesis of (4-((lH-pyrazol-l-yl)methyl)phenyl)methanamine. To a solution of 1- (4-(chloromethyl)benzyl)-lH-pyrazole (600 mg, crude) in MeOH (5 mL) was added NH3-H2O (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give (4-((lH-pyrazol-l-yl)methyl)phenyl)methanamine (300 mg, yield: 50% over 2 steps) as a yellow oil. ESI-MS [M +H]+: 188.2.
[0527] Synthesis of l-(4-(aminomethyl)benzyl)pyridin-2(lH)-one. To a solution of l-(4- (chloromethyl)benzyl)pyridin-2(lH)-one (233 mg, 1 mmol) in MeOH (5 mL) was added NH3.H2O (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give l-(4-(aminomethyl)benzyl)pyridin-2(lH)-one (160 mg, yield: 75%) as a yellow oil. ESI-MS [M +H]+: 215.2.
Figure imgf000230_0001
[0528] Synthesis of methyl 5-bromo-2-naphthoate. To a mixture of 5-bromo-2-naphthoic acid (5 g, 20 mmol) in MeOH (100 mL) was added SOCh (3 mL) dropwise at 0 °C, the mixture was stirred at 70 °C for 16 h, then cooled to room temperature and concentrated to give methyl 5- bromo-2-naphthoate (4.6 g, crude) as a white solid, which was used in the next step without purification. ESI-MS [M +H]+: 265.1.
[0529] Synthesis of methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-naphthoate.
To a mixture of methyl 5-bromo-2-naphthoate (2.3 g, crude), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (4.4 g, 17.5 mmol), AcOK (2.3 g, 24 mmol) in Dioxane (50 mL) was added Pd(dppf)C12 (732 mg, 1 mmol), the mixture was stirred at 90 °C for 16 h under N2, then cooled to room temperature. The reaction mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 200 mL). The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: PE/EtOAc=30/l) to give methyl 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-naphthoate (2.0 g, yield: 64% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 313.2.
[0530] Synthesis of methyl 5-(pyridin-2-yl)-2-naphthoate. To a mixture of methyl 5-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-naphthoate (1.56 g, 5 mmol), 2-bromopyridine (785 mg, 5 mmol), K2CO3 (2.07 g, 15 mmol) in Dioxane (20 mL) and H2O (5 mL) was added Pd(dppf)Ch (366 mg, 0.5 mmol), the mixture was stirred at 70 °C for 16 h under N2. After the reaction was cooled to room temperature, the reaction mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 100 mL). The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: PE/EtOAc=l 0/1 to 6/1) to give methyl 5-(pyridin-2-yl)-2-naphthoate (740 mg, yield: 56%) as a yellow solid. ESI-MS [M +H]+: 264.2.
[0531] Synthesis of (5-(pyridin-2-yl)naphthalen-2-yl)methanol. To a mixture of methyl 5-
(pyridin-2-yl)-2-naphthoate (430 mg, 1.63 mmol) in THF (4 mL) and MeOH (1 mL) was added LiBHi (216 mg, 9.81 mmol). After the reaction mixture was stirred at room temperature for 16 h, the reaction was quenched with NH4CI (sat. aq., 30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give (5-(pyridin-2-yl)naphthalen-2-yl)methanol (360 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS [M +H]+: 236.2. [0532] Synthesis of 2-(6-(chloromethyl)naphthalen-l-yl)pyridine. To a mixture of (5-
(pyridin-2-yl)naphthalen-2-yl)methanol (360 mg, crude) in DCM (10 mL) was added SOCh (2 mL), the reaction mixture was stirred at room temperature for 2 h under N2. Then the reaction was concentrated to give 2-(6-(chloromethyl)naphthalen-l-yl)pyridine (350 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS [M +H]+: 254.2.
[0533] Synthesis of (5-(pyridin-2-yl)naphthalen-2-yl)methanamine. A solution of 2-(6-
(chloromethyl)naphthalen-l-yl)pyridine (350 mg, crude) in NH3 in MeOH (7M, 5 mL) in a sealed tube was stirred at 60 °C for 16 h. After cooled to room temperature, the reaction was concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH=15/l) to give the (5-(pyridin-2-yl)naphthalen-2-yl)methanamine (150 mg, yield: 39% over 3 steps) as a yellow solid. ESI-MS [M +H]+: 235.2.
Synthesis of (5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanannne
Figure imgf000232_0001
[0534] Synthesis of 2-(chloromethyl)-5-cyclopropylthieno[2,3-b]pyridine. To a mixture of (5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanol (100 mg, 0.49 mmol) in DCM (2 mL) was added SOCh (0.5 mL). The mixture reaction was stirred at room temperature for 3 h then concentrated to give 2-(chloromethyl)-5-cyclopropylthieno[2,3-b]pyridine (108 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS [M +H]+: 224.1.
[0535] Synthesis of (5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanamine. A mixture of 2- (chloromethyl)-5-cyclopropylthieno[2,3-b]pyridine (108 mg, crude) in NH (2M in z-PrOH, 5 mL) in a sealed tube was stirred at 60 °C for 16 h. After cooled to room temperature, the reaction was concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH=15/l) to give the (5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanamine (70 mg, yield: 70% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 205.2. Synthesis of (5-cyclopropylpyrazolo[l , 5-a]pyridin-2-yl)methananiine
Figure imgf000233_0001
[0536] Synthesis of methyl 5-cyclopropylpyrazolo[l ,5-a]pyridine-2-carhoxylate. To a solution of 5-cyclopropylpyrazolo[l,5-a]pyridine-2-carboxylic acid (600 mg, 3 mmol) (synthesis reported in WO 2019/178129) in MeOH (10 mL) was added SOCh (2 mL) at 0 °C. The reaction mixture was warmed to 80 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and concentrated, the residue was purified by silica gel column (DCM: MeOH = 20: 1) to afford methyl 5-cyclopropylpyrazolo[l,5-a]pyridine-2-carboxylate (450 mg, yield: 70%) as yellow oil. ESI-MS [M + H] +: 217.2.
[0537] Synthesis of (5-cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methanol. To a solution of methyl 5-cyclopropylpyrazolo[l,5-a]pyridine-2-carboxylate (400 mg, 1.85 mmol) in THF (20 mL) was added LiAlH4 (210 mg, 5.55 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 1 h. The mixture was then quenched by adding Na2SO4*10H2O (2 g) and filtered. The filter cake was washed by MeOH (20 mL) and the filtrate was concentrated to give the crude, which was purified by silica gel column (DCM: MeOH = 10: 1) to afford (5- cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methanol as a solid (190 mg, yield: 55%). ESI-MS [M + H] + : 189.1.
[0538] Synthesis of 2-(chloromethyl)-5-cyclopropylpyrazolo[l,5-a]pyridine. To a solution of (5-cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methanol (190 mg, 1.01 mmol) in DCM (2 mL) was added SOCh (0.5 mL) slowly at 0 °C. After the mixture was stirred at room temperature overnight, the mixture was concentrated and used in the next step without further purification (125 mg, crude). ESI-MS [M + H] +: 207.1.
[0539] Synthesis of 2-(azidomethyl)-5-cyclopropylpyrazolo[l,5-a]pyridine. To a solution of
2-(chloromethyl)-5-cyclopropylpyrazolo[l,5-a]pyridine (125 mg, crude) in DMF (4 mL) was added NaN (118 mg, 1.82 mmol). The mixture stirred at 80 °C overnight. After cooled to room temperature, the reaction mixture was quenched with water (30 mL) and then extracted by ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give 2-(azidomethyl)-5-cyclopropylpyrazolo[l,5-a]pyridine (100 mg, crude) as a white solid. ESI-MS [M + H] +: 214.2.
[0540] Synthesis of (5-cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methanamine. A solution of 2-(azidomethyl)-5-cyclopropylpyrazolo[l,5-a]pyridine (100 mg, crude) and PPhs (314 mg, 1.2 mmol) in THF/H2O (V:V = 1: 1, 4 mL) was stirred at 40 °C overnight. After cooled to room temperature, the reaction was diluted with water (20 mL) and then extracted by ethyl acetate (20 mL x 3). The organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated and purified by silica gel column (DCM:MeOH = 10: 1) to afford (5-cyclopropylpyrazolo[l,5- a]pyridin-2-yl)methanamine (80 mg, yield: 42% over 3 steps) as a white solid. ESI-MS [M + H] “: 188.2.
Synthesis of l-(6-(aminomethyl)naphthalen-l-yl)pyridin-2(lH)-one
Figure imgf000234_0001
[0541] Synthesis of methyl 5-(2-oxopyridin-l(2H)-yl)-2-naphthoate. Methyl 5-bromo-2- naphthoate (1 g, 3.8 mmol), pyridin-2(lH)-one (722 mg, 7.6 mmol), 4,7-dimethoxy-l,10- phenanthroline (182 mg, 0.76 mmol), Cui (289 mg, 1.52 mmol), Nal (566 mg, 3.8 mmol) and K2CO3 (1.6 g, 11.4 mmol) in DMSO (20 mL) was stirred at 140 °C for 20 h under N2. After cooled to room temperature, the reaction was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-30% EtOAc in PE to methyl 5-(2-oxopyridin- l(2H)-yl)-2-naphthoate (150 mg, 14%) as a yellow solid. ESI-MS [M +H]+: 280.2. [0542] Synthesis of l-(6-(hydroxymethyl)naphthalen-l-yl)pyridin-2(lH)-one. A mixture of methyl 5-(2-oxopyridin-l(2H)-yl)-2-naphthoate (150 mg, 0.54 mmol) and LiBH4 (36 mg, 1.62 mmol) in MeOH/THF (2 mL/8 mL) was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was quenched with NH4CI (25 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 20/1) to give l-(6-(hydroxymethyl)naphthalen-l-yl)pyridin-2(lH)-one (110 mg, 81%) as a white solid. ESI-MS [M +H]+: 252.3.
[0543] Synthesis of l-(6-(chloromethyl)naphthalen-l-yl)pyridin-2(lH)-one. To a solution of l-(6-(hydroxymethyl)naphthalen-l-yl)pyridin-2(lH)-one (110 mg, 0.44 mmol) in DCM (5 mL) was added SOCh (0.5 mL) at 0 °C. The resulting reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo to give l-(6-(chloromethyl)naphthalen-l- yl)pyridin-2(lH)-one (130 mg, crude) as yellow oil, which was used into next step without further purification. ESI-MS [M +H]+: 270.2.
[0544] Synthesis of l-(6-(aminomethyl)naphthalen-l-yl)pyridin-2(lH)-one. A solution of l-(6-(chloromethyl)naphthalen-l-yl)pyridin-2(lH)-one (130 mg, crude) in NH3 (5 mL, 7 M solution in MeOH) in a sealed tube was stirred at 65 °C for 12 h. After cooled to room temperature, the reaction was concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give l-(6-(aminomethyl)naphthalen-l-yl)pyridin- 2(lH)-one (85 mg, 77% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 251.2.
Synthesis of (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanamine.
Figure imgf000235_0001
[0545] Synthesis of 5-(lH-pyrazol-l-yl)-2-naphthoic acid. A mixture of methyl 5-bromo-2- naphthoate (1 g, 3.8 mmol), IH-pyrazole (775 mg, 11.4 mmol), t-BuONa (730 mg, 7.6 mmol) and Cu2O (107 mg, 0.76 mmol) in NMP (10 mL) was degassed with N2 for 10 min, sealed and heated to 120 °C under microwave for 12 h. After cooled to room temperature, the reaction was diluted with H2O (100 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-10% MeOH in DCM to give 5-(lH-pyrazol-l-yl)-2-naphthoic acid (530 mg, 58%) as a yellow solid. ESLMS [M +H]+: 239.2.
[0546] Synthesis of methyl 5-(lH-pyrazol-l-yl)-2-naphthoate. A solution of 5-(lH-pyrazoL l-yl)-2-naphthoic acid (530 mg, 2.2 mmol) and SOCI2 (772 mg, 6.6 mmol) in MeOH (20 mL) was stirred at 50 °C for 6 h. After cooled to room temperature, the reaction was concentrated in vacuo. The residue was washed with NaHCO- (sat. aq., 40 mL), extracted with extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to give methyl 5-(lH-pyrazol-l- yl)-2-naphthoate (410 mg, 74%) as a yellow solid. ESLMS [M +H]+: 253.3.
[0547] Synthesis of (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanol. A mixture of methyl 5- (lH-pyrazol-l-yl)-2-naphthoate (410 mg, 1.62 mmol) and LiBHi (107 mg, 4.86 mmol) in MeOH/THF (2 mL/10 mL) was stirred at 70 °C for 14 h. After cooled to room temperature, the reaction was quenched with NH4CI (sat. aq., 35 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-70% EtOAc in PE to give (5-(lH-pyrazoLl-yl)naphthalen-2-yl)methanol (305 mg, 84%) as a yellow solid. ESLMS [M +H]+: 225.3.
[0548] Synthesis of l-(6-(chloromethyl)naphthalen-l-yl)-lH-pyrazole. To a solution of (5- (lH-pyrazol-l-yl)naphthalen-2-yl)methanol (305 mg, 1.4 mmol) in DCM (10 mL) was added SOCI2 (1 mL) at 0 °C. The resulting reaction was stirred at room temperature for 3 h, then was concentrated in vacuo to give L(6-(chloromethyl)naphthalen-l-yl)-lH-pyrazole (310 mg, crude) as yellow oil, which was used into next step without further purification. ESLMS [M +H]+: 243.2.
[0549] Synthesis of (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanamine. A solution of l-(6- (chloromethyl)naphthalen-l-yl)-lH-pyrazole (310 mg, crude) in NH3 (10 mL, 7 M solution in MeOH) in a sealed tube was stirred at 65 °C for 12 h. After cooled to room temperature, the reaction was concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanamine (230 mg, 73% over 2 steps) as a yellow solid. ESLMS [M +H]+: 224.2.
Synthesis of naphthalen-2-ylmethanol
Figure imgf000237_0001
[0550] To a solution of methyl 2-naphthoate (1 g, 5.4 mmol) in THF (20 mL) was added LiAlHi (IM solution in THF, 16.2 mL, 16.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h under N2. The reaction was quenched with NH4CI (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give naphthalen-2-ylmethanol (730 mg, yield: 86%) as a yellow oil. ESLMS [M +H]+: 159.2.
Synthesis of 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l, 5-a]pyridin- 7-yl)oxazolidin-2-one
Figure imgf000237_0002
[0551] Synthesis of 3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l, 5- a]pyridin- 7-yl)oxazolidin-2-one. A mixture of 7 -bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridine (395 mg, 1.04 mmol) (synthesis reported in WO 2019/178129), oxazolidin-2-one (181 mg, 2.08 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), Xantphos (60 mg, 0.1 mmol) and CS2CO3 (1.02 g, 3.12 mmol) in 1,4-dioxane (8 mL) was stirred at 105 °C for 1 h under microwave. After cooled to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography (PE / EtOAc = 0 ~ 20%) to give 3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)oxazolidin-2-one as a white solid (300 mg, yield: 75%). ESI-MS [M +H]+: 388.2.
[0552] Synthesis of 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l, 5-a]pyridin- 7- yl)oxazolidin-2-one. To a solution of 3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)oxazolidin-2-one (300 mg, 0.78 mmol) in THF (10 mL) was added TBAF (IM solution in THF, 1.56 mL, 1.56 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 3 h under N2. The mixture was quenched with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give 3-(5-cyclopropyL2- (hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)oxazolidin-2-one (120 mg, yield: 56%) as a yellow solid. ESI-MS [M +H]+: 274.2.
Synthesis of 3-(6-cyclopropyl-2-(hydroxymethyl)imidazo[I,2-a]pyridin-8-yl)oxetan-3-ol
Figure imgf000238_0001
[0553] To a solution of 3-(2-(chloromethyl)-6-cyclopropylimidazo[l,2-a]pyridin-8- yl)oxetan-3-ol (203 mg, 0.73 mmol) in THF/H2O (lOmL/lOmL) was added Na2CC>3 (230 mg, 2.19 mmol) at room temperature. The mixture was stirred at 90 °C for 16 h. After cooled to room temperature, the reaction was diluted with H2O (40 mL, extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH = 20/1) to give the 3-(6-cyclopropyl-2-(hydroxymethyl)imidazo[l,2-a]pyridin-8-yl)oxetan-3-ol (70 mg, yield: 37%) as a yellow solid. ESI-MS [M +H]+: 261.2. Synthesis of (6-cyclopropyl-8-(3,5-dimethyl-4H-l ,2,4-triazol-4-yl)imidazo[l ,2-a]pyridin-2- y I) methanol
Figure imgf000239_0001
[0554] Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine. To a solution of 5- cyclopropylpyridin-2-amine (5 g, 37.31 mmol) in CH3CN (50 mL) was added NBS (7 1 g, 41.04 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. Water (100 mL) was added and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (DCM/MeOH = 50/1) to give 3- bromo-5-cyclopropylpyridin-2-amine as a yellow solid (4 g, yield: 51 %). ES MS [M +H]+: 213.1.
[0555] Synthesis of ethyl 8-bromo-6-cyclopropylimidazo[l,2-a]pyridine-2-carboxylate. To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (2 g, 9.4 mmol) in EtOH (60 mL) was added ethyl 3-bromo-2-oxopropanoate (10.10 g, 52. 1 mmol) at room temperature. The mixture was stirred at 95 °C for 16 h under N2. After cooled to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography (DCM/MeOH = 0~5%) to give ethyl 8-bromo-6-cyclopropylimidazo[l,2-a]pyridine-2-carboxylate as a light yellow solid (1.8 g, yield: 62 %). ESLMS [M +H]+: 309.1.
[0556] Synthesis of ethyl 8-bromo-6-cyclopropylimidazo[l,2-a]pyridine-2-carboxylate. To a solution of ethyl 8-bromo-6-cyclopropylimidazo[l,2-a]pyridine-2-carboxylate (500 mg, 1.62 mmol) in 1,4-dioxane (20 mL) was added NH2B0C (282 mg, 2.43 mmol), Pd(OAc)2 (36 mg, 0.16 mmol), Xantphos (92 mg, 0.16 mmol) and CS2CO3 (1.3 g, 4.05 mmol) at room temperature. The mixture was stirred at 95 °C for 16 h under N2. Then the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH = 0 ~ 10%) to give ethyl 8-bromo-6-cyclopropylimidazo[l,2-a]pyridine-2- carboxylate as a borrow solid (350 mg, yield: 63%). ESI-MS [M +H]~: 346.2.
[0557] Synthesis of ethyl 8-amino-6-cyclopropylimidazo[l,2-a]pyridine-2-carboxylate. A mixture of ethyl 8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[l,2-a]pyridine-2- carboxylate (500 mg, 1.45 mmol) in HC1 (4 M in 1.4-dioxane) (10.0 mL) was stirred at room temperature for 2.5 h. The reaction mixture was concentrated to give ethyl 8-amino-6- cyclopropylimidazo[l,2-a]pyridine-2-carboxylate (360 mg, crude) as a yellow solid, which was used for the next step directly without purification. ESI-MS [M +H]+: 256.1.
[0558] Synthesis of ethyl 6-cyclopropyl-8-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)imidazo[l,2- a]pyridine-2-carboxylate. A solution of ethyl 8-amino-6-cyclopropylimidazo[l,2-a]pyridine-2- carboxylate (360 mg, crude) and 1 , 1 , 1 -trimethoxy ethane (1.74 g, 14.5 mmol) in CH CN (10 mL) was stirred at 85 C° for 7 h under N2. Then the mixture was cooled to room temperature, HO Ac (5 mL) was added followed by the addition of acetohydrazide (1.07 g, 14.5 mmol). The mixture was stirred at 85 °C for another 16 h under N2. After cooled to room temperature, the mixture was concentrated and purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give ethyl 6- cyclopropyl-8-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)imidazo[l,2-a]pyridine-2-carboxylate (180 mg, yield: 38% over 2 steps) as a yellow solid. ESLMS [M +H]+: 326.1.
[0559] Synthesis of (6-cyclopropyl-8-(3,5-dinethyl-4H-l,2,4-triazol-4-yl)imidazo[l,2- a]pyridin-2-yl)methanol. To a solution of ethyl 6-cyclopropyl-8-(3,5-dimethyl-4H-l,2,4-triazol- 4-yl)imidazo[l,2-a]pyridine-2-carboxylate (180 mg, 0.55 mmol) in THF (10.0 mL) was added DIBAL-H (IM in hexane, 1.67 mL, 1.67 mmol) drop-wise at 0 °C under N2. After the mixture was stirred at 0 °C for 1.0 h under N2, the reaction mixture was quenched with Na2SO4*10H2O (2 g) and stirred for another 30 min. The mixture was filtered, and the filter cake was washed by EtOAc (30 mL). The filtrate was concentrated and purified by Prep-TLC to give (6-cyclopropyl- 8-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)imidazo[l,2-a]pyridin-2-yl)methanol (100 mg, yield: 64%) as a light yellow solid. ESI-MS [M +H]+: 284.2.
Figure imgf000241_0001
[0560] Synthesis of (8-bromo-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol To a solution of ethyl 8-bromo-6-cyclopropylimidazo[l,2-a]pyridine-2-carboxylate (230 mg, 0.75 mmol) in THF (10 mL) was added DIB AL -H (IM in hexane, 2.25 mL, 2.25 mmol) at 0 °C under N2. After the mixture was stirred at 0 °C for 2 h under N2, the reaction mixture was quenched with Na2SO4*10H2O (2 g) and stirred for another 10 min. The mixture was fdtered, and the filter cake was washed by EtOAc (30 mL). The filtrate was concentrated to give (8-bromo-6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol as a white solid (200 mg, crude), which was used in the next step without purification. ES MS [M +H]+: 267.2.
[0561] Synthesis of l-(6-cyclopropyl-2-(hydroxymethyl)imidazo[l,2-a]pyridin-8- yl)pyrrolidin-2-one. A mixture of (8-bromo-6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol (200 mg, crude), pyrrolidin-2-one (96 mg, 1.13 mmol), Pd(OAc)2 (17 mg, 0.075 mmol), Xantphos (43.4 mg, 0.075 mmol) and CS2CO3 (611 mg, 1.87 mmol) in dioxane (10 mL) was stirred at 100 °C for 16 h under N2. The mixture was concentrated and purified by Prep-TLC (DCM/MeOH = 10/1) to give l-(6-cyclopropyl-2-(hydroxymethyl)imidazo[l,2-a]pyridin-8- yl)pyrrolidin-2-one (130 mg, 64 % over 2 steps) as a yellow solid. ESLMS [M +H]+: 272.1.
Synthesis of ethyl 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)propanoate
Figure imgf000241_0002
[0562] Synthesis of 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridine. To a solution of (7-bromo-5-cyclopropylpyrazolo[l,5- a]pyridin-2-yl)methanol (1.49 g, 5.6 mmol) (reported in WO 2019/178129) in dry DCM (50 mL) was added TBSC1 (1.26 g, 8.4 mmol) and Imidazole (1.1 g, 16.8 mmol) at 0 °C. After the reaction was stirred at room temperature for 16 h, the reaction was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE/EtOAc = 5/1 ) to give to give 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridine (1.5 g, yield: 70%) as a yellow oil. ESLMS [M +H]+: 381.1.
[0563] Synthesis of ethyl (E)-3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)(icrylate. To a solution of 7-bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridine (2.5 g, 6.58 mmol) in dry 1,4-dioxane (80 mL) was added ethyl acrylate (6.5 g, 65.8 mmol), Pd(OAc)2 (294 mg, 1.3 mmol), PPhs (341 mg, 1.3 mmol) and TEA (6.6 g, 65.8 mmol). The reaction mixture was stirred at 95 °C for 16 h under N2. After cooled to room temperature, the reaction was concentrated, and the residue was diluted with water (70 mL), extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (100 mL), dried with Na2SOr, concentrated in vacuo to give the crude, which was purified by silica gel column chromatography (PE/EtOAc = 5/1) to give ethyl (E)-3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin- 7-yl)acrylate (1.5 g, yield: 57%) as yellow oil. ESLMS [M +H]+: 401.2.
[0564] Synthesis of ethyl 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l ,5-a]pyridin-7- yl)propanoate. To a solution of ethyl (E)-3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)acrylate (800 mg, 2 mmol) in MeOH (30 mL) and THF (30 ml) was added Pd/C (150 mg, 0.1 mmol). After the reaction was stirred at room temperature for 1 h under H2 atmosphere, the reaction mixture was filtered through celite® , filter cake was washed with MeOH (40 mL x 2). The filtrate was concentrated and purified by silica gel column chromatography (PE/EtOAc = 2/1) to give ethyl 3-(5-cyclopropyl-2- (hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)propanoate (450 mg, yield: 78%) as yellow oil. ESLMS [M +H]+: 289.1.
Figure imgf000243_0001
[0565] Synthesis of l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethan-l-one. A mixture of l-(4- (bromomethyl)phenyl)ethan-l-one (2 g, 9.4 mmol), IH-pyrazole (639 mg, 9.4 mmol) and KzCCh (2.6 g, 18.8 mmol) in CHAIN (30 mL) was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature. The mixture was quenched with water (100 mL) and extracted with EtOAc (70 mL X 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 50/1) to give l-(4-((lH-pyrazol-l- yl)methyl)phenyl)ethan-l-one (1.6 g, yield: 85%) as a white solid. ESI-MS [M +H]+: 201.2.
[0566] Synthesis of l-(4-((lH-pyrazol-l-yl)niethyl)phenyl)ethan-l-ol. To a solution of 1- (4-((lH-pyrazol-l-yl)methyl)phenyl)ethan-l-one (1.6 g, 8 mmol) in MeOH (20 mL) was added NaBH4 (608 mg, 16 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16h. The reaction was quenched with water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethan-l-ol (1.4 g, yield: 86%) as a yellow solid. ESI-MS [M +H]+: 203.2.
Synthesis of ( 5-cyclopropylthieno[2,3-b]pyridin-2-yl) methanol.
Figure imgf000243_0002
[0567] Synthesis of ethyl 5-bromothieno[2,3-b]pyridine-2-carboxylate. To a solution of 5- bromo-2-fluoronicotinaldehyde (10 g, 49.5 mmol) in DMSO (100 mL) was added ethyl 2- mercaptoacetate (6.48 g, 54 mmol) and EtjN (5.45 g, 54 mmol). The reaction mixture was stirred for 16 h at 80 °C. Then the reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (130 mL), dried over NaiSCL and concentrated to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc = 10/1) to give ethyl 5-bromothieno[2,3- b]pyridine-2-carboxylate (11 g, yield: 78%) as a white solid. ESI-MS [M +H]+: 286.1, 288.1. [0568] Synthesis of ethyl 5-cyclopropylthieno[2,3-b]pyridine-2-carboxylate. To a solution of ethyl 5-bromothieno[2,3-b]pyridine-2-carboxylate (5 g, 17.5 mmol) in toluene/LLO (100 mL / 5 mL) was added cyclopropylboronic acid (4.5 g, 52.4 mmol), Pd(OAc)2 (392 mg, 1.75 mmol), Sphos (1.43 g, 3.49 mmol) and K3PO4 (12.98 g, 61.15 mmol). The reaction mixture was stirred at 95 °C for 14 h under nitrogen. Then the mixture was cooled to room temperature and concentrated in vacuo. Water (100 mL) was added, and the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc= 15/1) to give the ethyl 5- cyclopropylthieno[2,3-b]pyridine-2-carboxylate as a yellow oil (3 g, yield: 69%). ESLMS [M +H]+: 248.1.
[0569] Synthesis of (5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanol. To a solution of ethyl 5-cyclopropylthieno[2,3-b]pyridine-2-carboxylate (785 mg, 3.17 mmol) in THF (10 ml) was added LiAlH4 (120 mg, 3.17 mmol) slowly. The mixture was stirred for 2 h at 0 °C. Then the reaction was quenched with water (2 mL) and aqueous NaOH (10%, 4 mL) and the resulting mixture was filtered through celite®. The filter cake was washed with MeOH (50 mL), and the filter was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc = 2/1) to give (5-cyclopropylthieno[2,3-b]pyridin-2- yl)methanol (210 mg, yield: 32%) as a yellow oil. ESI-MS [M -H]+: 206.0.
Figure imgf000245_0001
[0570] Synthesis of 5-cyclopropylbenzo[d]thiazole. A mixture of 5-bromobenzo[d]thiazole (1 g, 4.7 mmol), cyclopropylboronic acid (606 mg, 7.05 mmol), Pd(dppf)C12 (344 mg, 0.47 mmol) and K2CO3 (2.6 g, 18.8 mmol) in 1,4-dioxane (30 mb) / H2O (5 mL) was stirred at 100 °C for 16 hrs under N2. After cooled to room temperature, the reaction was quenched with water (100 mL), extracted by EtOAc (100 mL x 3). The combined organic layers were washed by brine (100 mL). The solvent was concentrated to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc= 3/1) to give the compound 5- cyclopropylbenzo[d]thiazole (410 mg, yield: 49.8%) as oil. ESLMS [M +H]+: 176.1.
[0571] Synthesis of 5-cyclopropylbenzo[d]thiazole-2-carbaldehyde. To a solution of 5- cyclopropylbenzo[d]thiazole (500 mg, 2.86 mmol) in THF (10 mL) was added n-BuLi (1.3 mL, 3.12 mmol, 2.4 M solution in hexane) dropwise at -78 °C, The mixture was stirred at -78 °C for 30 min, then DMF (313 mg, 4.29 mmol) was added, the resulting reaction mixture was stirred at -78 °C for 1 h. After completed, the reaction was quenched with NI LCl (sat. aq., 30 mL), and extracted by EtOAc (30 mL x 3). The combined organic layers were washed by brine (50 mL), dried over Na2SOr, filtered, and concentrated to give the crude product, which was purified by Prep-TLC (PE / EtOAc = 5 / 1) to give the product 5-cyclopropylbenzo[d]thiazole-2- carbaldehyde (420 mg, yield: 72%) as yellow solid. ESI-MS [M +H]+: 204.1.
[0572] Synthesis of (5-cyclopropylbenzo[d]thiazol-2-yl)methanol. To a solution of 5- cyclopropylbenzo[d]thiazole-2-carbaldehyde (420 mg, 2.06 mmol) in MeOH (10 mL) was added NaBH4 (236 mg, 6.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. Water (30 mL) was added and extracted by EtOAc (30 mL x 3), and the combined organic layers were washed by brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-TLC (PE: EtOAc = 5:1) to give the product (5-cyclopropylbenzo[d]thiazol-2-yl)methanol (380 mg, yield: 90%) as a yellow solid. ESI-MS [M +H]+: 206.1.
[0573] Synthesis of 6-bromo-3-fluoro-lH-pyrrolo[3,2-c]pyridine. To a stirred solution of 6-bromo-lH-pyrrolo[3,2-c]pyridine (1.5 g, 7.61 mmol) in pyridine(5 mL) and CH CN (20 mL) was added selectfluor® (2.7 g, 7.61 mmol) in portions over 10 min at 0 °C and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated and purified by silica gel column chromatography (EtOAc /PE = 1/2) to give 6-bromo-3-fluoro-lH-pyrrolo[3,2-c]pyridine (260 mg, yield: 16%) as a yellow solid. ESI-MS [M +H]+: 215.0.
Synthesis of (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanethiol
Figure imgf000246_0001
[0574] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[l,2-a]pyridine. To a solution of 5-cyclopropylpyridin-2-amine (2 g, 14.9 mmol) in DME (20 mL) was added 1,3- dichloropropan-2-one (5.63 g, 44.7 mmol). The mixture was stirred at 90 °C for 16 h. After cooled to room temperature, the reaction was washed with NaHCCh (sat, aq., 50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SC>4, and concentrated to give the crude product, which was purified by column chromatography (eluent:PE/EtOAc=4/l to 1/1) to give 2-(chloromethyl)-6- cyclopropylimidazo[l,2-a]pyridine (600 mg, 20%) as a yellow oil. ESLMS [M +H]+: 207.1.
[0575] Synthesis of S-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl) ethanethioate. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[l,2-a]pyridine (500 mg, 2.43 mmol) in DCM (10 mL) was added ethanethioic S-acid (222 mg, 2.92 mmol). After the mixture was stirred at room temperature for 72 h, the reaction was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), concentrated to give the crude product, which was purified by column chromatography (eluent:EtOAc/PE=l/l) to give S-((6-cy cl opropylimidazo[l,2-a]pyri din-2 -yl)methyl) ethanethioate (265 mg, 44%) as yellow oil. ESI-MS [M +H]+: 247.1.
[0576] Synthesis of (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)niethanethiol. To a solution of S-((6-cy cl opropylimidazo[l,2-a]pyri din-2 -yl)methyl) ethanethioate (265 mg, 1.08 mmol) in THF (3 mQ/HiO (1 mL)/MeOH (3 mL) was added LiOH’EEO (136 mg, 3.24 mmol). The reaction mixture was stirred at room temperature for 30 min. pH of the reaction was adjusted to 6 by 1 N HC1, the mixture was then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated to give (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanethiol (200 mg, crude) as brown oil, which was used in the next step without purification. ESLMS [M +H]+: 205.2.
[0577] The required 6-chloropyrimdine intermediate, in Table 4, was synthesized following a similar procedure for the synthesis of 6-chloro-2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5- methylimidazo[l,2-a]pyridine.
Table 4
Figure imgf000247_0002
Synthesis of 6-chloro-N-methyl-N-(quinolin-6-ylmethyl)pyrimidin-4-annne
Figure imgf000247_0001
[0578] DIPEA (0.42 mL, 2.4 mmol) was added to a stirred solution of 4,6- dichloropyrimidine (107 mg, 0.72 mmol) and N-methyl-l-(quinolin-6-yl)methanamine hydrochloride (125 mg, 0.6 mmol) in zPrOH (5.0 mL) and stirred at 60 °C for 18 h. The reaction concentrated in vacuo, the residue was diluted with water (25 mL) and EtOAc (20 mL), the layers were separated and the aqueous layer was then further extracted with EtOAc (2 x 20 mL) the organics were combined, dried (MgSCh) and concentrated in vacuo to give the title compound (186 mg) carried forward to next step without further purification. ESI-MS (M+H)+: 285.0, 'H NMR (400 MHz, CDCh) 5 8.91 (dd, J=1.7, 4.2 Hz, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.13
- 8.08 (m, 2H), 7.60 - 7.56 (m, 2H), 7.42 (dd, J=4.3, 8.3 Hz, 1H), 6.50 (d, J=0.7 Hz, 1H), 5.03 (s, 2H), 3.10 (s, 3H).
[0579] The compounds in Table 5 were synthesised following a similar procedure for the synthesis of 6-chloro-7V-methyl-jV-(quinolin-6-ylmethyl)pyrimidin-4-amine from dichloropyrimidine and an appropriate coupling partner.
Table 5
Figure imgf000248_0001
Figure imgf000249_0002
Synthesis of 4-(((6-chloropyrinudin-4-yl)amino)methyl)phenol
Figure imgf000249_0001
[0580] 4-(Aminomethyl)phenol (5.0 g, 41 mmol) and 4,6-dichloropyrimidine (7.3 g, 49 mmol) were suspended in z'PrOH (85 mL) and NEts (14 mL, 100 mmol) was added. The reaction mixture was placed under N2 and stirred at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, diluted with water (70 mL) and extracted with DCM (2 * 100 mL). A precipitate formed in the aqueous layer and was collected by filtration. The combined organics were passed through a hydrophobic frit and concentrated in vacuo. This residue was combine with the previously collected precipitate then triturated with DCM to give the title compound (8.7 g, 91%) as an off white solid. ESLMS (M+H)+: 236.2, 'HNMR (400 MHz, DMSO) 5 9.34 (s, 1H), 8.30 (s, 1H), 8.07 - 8.07 (m, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.73 (d, J=8.5 Hz, 2H), 6.55 (s, 1H), 4.43 - 4.43 (m, 1H), 4.34 (s, 1H).
Synthesis of ethyl 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)acetate
Figure imgf000250_0001
[0581] 4-(((6-Chloropyrimidin-4-yl)amino)methyl)phenol (2.7 g, 11 mmol) was dissolved in DMF (50 mL), K2CO3 (1.6 g, 12 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. Ethyl 2-bromoacetate (1.2 mL, 11 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organics were dried over a MgSO4 and concentrated in vacuo to give the title compound (3.6 g, quant.) as a brown oil. ESIMS (M+H)+: 322.2, >HNMR (400 MHz, DMSO) 5 8.29 (s, 1H), 8.14 (s, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.56 (s, 1H), 4.76 (s, 2H), 4.49 - 4.49 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.22 (dd, J=7.2, 7.2 Hz, 3H).
Synthesis of 2-(4-(((6-chloropyrimidin-4-yl)aniino)methyl)phenoxy)acetic acid
Figure imgf000250_0002
[0582] Ethyl 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)acetate (3.4 g, 11 mmol) was dissolved in THF (65 mL). NaOH (1 M, aq., 12 mL, 12 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with DCM (100 mL) then the combined organics were dried over MgSCh and concentrated in vacuo. The aqueous phase was acidified with HC1 (1 M aq.) to pH 2-3. A precipitate formed which was collected by filtration, washed with water (100 mL) and dried in a desiccator for 72 h. The previously isolated residue from the DCM layer was combined with the dried precipitate to give the title compound (2.6 g, 84%) as an off white solid. ESLMS (M+H)+: 294.1. 'H NMR (400 MHz, DMSO) 8 12.99 - 12.99 (m, 1H), 8.29 (s, 1H), 8.14 - 8.13 (m, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 6.56 (s, 1H), 4.66 (s, 2H), 4.48 - 4.48 (m, 2H).
Synthesis of l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(((6-chloropyrimidin-4- yl)anuno)methyl)phenoxy)ethan-l-one
Figure imgf000251_0001
[0583] A solution of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)acetic acid (200 mg, 0.68 mmol), HATU (260 mg, 0.68 mmol) and DIPEA (0.22 mL, 1.2 mmol) in DMF (6.2 mL) was stirred at room temperature for 10 min. 3-Azabicyclo[3.1.0]hexane hydrochloride (74 mg, 0.62 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Additional 3-azabicyclo[3.1.0]hexane hydrochloride (7.4 mg, 0.06 mmol) was added and the reaction mixture was stirred at room temperature for further 2 h. The reaction mixture was diluted with a NaHCCh (sat. aq., 15 mL) and extracted with DCM (3 x 25 mL). The combined organics were washed with water (20 mL), passed through a hydrophobic frit then concentrated in vacuo. The residue was triturated with water then in EtiO and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-70% EtOAc in isohexane to give the title compound (54 mg, 24%) as a colourless oil. ESI-MS (M+H)+: 403.3, >H NMR (400 MHz, DMSO) 8 8.26 (s, 1H), 8.10 (s, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.54 (s, 1H), 4.40 - 4.37 (m, 2H), 3.63 - 3.50 (m, 3H), 3.17 (d, J=5 3 Hz, 1H), 1.66 - 1.48 (m, 2H), 0.73 - 0.65 (m, 1H), 0.08 (q, J=4.1 Hz, 1H).
[0584] Using a similar procedure to that used for l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4- (((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)ethan-l-one, the compounds in Table 6 were prepared from 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)acetic acid and an appropriate amine coupling partner. Table 6
Figure imgf000252_0002
Figure imgf000252_0001
[0585] Synthesis of 4-(aminomethyl)-2,6-dimethylphenol To a solution of 4-hydroxy-3,5- dimethylbenzonitrile (2.5 g, 17 mmol) in THF (175 mL) was added a solution of BH3 (1 M in THF, 68 mL, 68 mmol). The reaction mixture was stirred at reflux for 16 h then cooled to 0 °C. A fresh batch of BH3 (1 M in THF, 50 mL, 50 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h, then at reflux for 4 h. HC1 (6 N, aq., 80 mL) was added and the reaction mixture was stirred at reflux for 1 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in DCM and loaded onto a SCX cartridge which was washed with DCM then MeOH then eluted with (7N NH3 in MeOH) in DCM. The product-containing eluent was concentrated in vacuo to give the title compound (2.3 g, 90%) as a brown solid. ESI-MS (M+H)+: 150.1, 'H NMR (400 MHz, CDCh) 5 6.91 (s, 2H), 3.73 (s, 2H), 2.23 (s, 6H), exchangeable protons not visible.
[0586] Synthesis of 4-(((6-chloropyrimidin-4-yl)amino)niethyl)-2,6-dimethylphenol. 4- (Aminomethyl)-2,6-dimethylphenol (2.2 g, 15 mmol) and 4,6-dichloropyrimidine (2.6 g, 18 mmol) were suspended in /PrOH (40 mL) and tri ethylamine (2.4 mL, 18 mmol) was added. The reaction mixture was placed under a N2 atmosphere and stirred at reflux for 4 h. The reaction mixture was allowed to cool to room temperature then concentrated in vacuo. The residue was triturated with water/DCM then collected by fdtration. The obtained solid was further washed with water/DCM and dried in a vacuum desiccator for 24 h to give the title compound (2.9 g, 76%) as an off-white solid. ESI-MS (M+H)+: 264.2, 'H NMR (400 MHz, DMSO) 5 8.29 (s, 1H), 8.15 (s, 1H), 8.01 - 8.01 (m, 1H), 6.87 (s, 2H), 6.55 (s, 1H), 4.42 - 4.34 (m, 2H), 2.15 (s, 6H).
Figure imgf000253_0001
[0587] A mixture of 4-(((6-chloropyrimidin-4-yl)amino)methyl)phenol (100 mg, 0.42 mmol), 2-(bromomethyl)pyridine hydrobromide (110 mg, 0.42 mmol) and K2CO3 (240 mg, 1.7 mmol) in MeCN (2.0 mL) was placed under a N2 atmosphere and stirred at reflux for 16 h. Additional 2-(bromomethyl)pyridine hydrobromide (53 mg, 0.21 mmol) was added and the mixture was stirred at reflux for a further 2 h. The reaction mixture was allowed to cool to room temperature, diluted with water(10 mL) and extracted with DCM (2 x 50 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-55% EtOAc in DCM to give the title compound (31 mg, 22%) as a white solid. ESI-MS (M+H)+: 327.1, ’H NMR (400 MHz, CDCh) 5 8.60 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 7.74 - 7.69 (m, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.25 - 7.21 (m, 3H), 6.98 (d, J=8.8 Hz, 2H), 6.34 (s, 1H), 5.21 (s, 2H), 4.45 - 4.45 (m, 2H), exchangeable proton not visible. Synthesis of 6-chloro-N-(4-(oxazol-2-ylmethoxy)benzyl)pyrimidin-4-anune
Figure imgf000254_0001
[0588] 4-(((6-Chloropyrimidin-4-yl)amino)methyl)phenol (100 mg, 0.42 mmol) and 2- (chloromethyl)oxazole (50 mg, 0.42 mmol) were dissolved in DMF (2.2 mL). K2CO3 (240 mg, 1.7 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 50 mL). The combined organics were passed through a hydrophobic frit then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc in DCM to give the title compound (120 mg, 91%) as a white solid. ESLMS (M+H)+: 317.0, 'H NMR (400 MHz, CDCI3) 8 8.37 (s, 1H), 7.69 (s, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 7.01 (d, J=8.7 Hz, 2H), 6.34 (s, 1H), 5.16 (s, 2H), 4.46 - 4.46 (m, 2H), one exchangeable proton not visible and one aromatic proton hidden under CDCh peak.
Synthesis of 6-chloro-N-(4-(thiazol-2-ylmethoxy)benzyl)pyrimidin-4-amine
Figure imgf000254_0002
[0589] DEAD (0.16 mL, 1.0 mmol) was added dropwise to a mixture of 4-(((6- chloropyrimidin-4-yl)amino)methyl)phenol (100 mg, 0.42 mmol), thiazol-2-ylmethanol (59 mg, 0.51 mmol) and PPI13 (130 mg, 0.51 mmol) in THF (5.0 mL) and the reaction mixture was stirred at room temperature for 16 h. Additional thiazol-2-ylmethanol (15 mg, 0.13 mmol), PPI13 (34 mg, 0.13 mmol) and DEAD (0.02 mL, 0.13 mmol) were added and the reaction mixture was stirred at room temperature for a further 4.5 h then concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with water (25 mL). The organics were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-30% EtOAc in DCM to give the title compound (90 mg, 64%) as an off-white solid. ESLMS (M+H)+: 333.0, XH NMR (400 MHz, DMSO) 8 8.27 (s, 1H), 8.12 (s, 1H), 7.84 - 7.79 (m, 1H), 7.77 - 7.75 (m, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.06 - 7.00 (m, 2H), 6.55 (s, 1H), 5.42 (s, 2H), 4.48 (s, 2H).
Synthesis of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-2,2-difhioro-N,N- dimethylacetamide
Figure imgf000255_0001
[0590] Synthesis of ethyl 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-2,2- difluoroacetate. 4-(((6-Chloropyrimidin-4-yl)amino)methyl)phenol (1.0 g, 4.2 mmol) was dissolved in DMF (22 mL) and K2CO3 (1.5 g, 11 mmol) was added. The reaction mixture was stirred at room temperature for 10 min. Ethyl 2-bromo-2,2-difluoroacetate (2.1 mL, 16 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 75 mL). The combined organics were washed with water (3 x 50 mL) then brine (60 mL), passed through a hydrophobic frit then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-10% EtOAc in DCM to give the title compound (250 mg, 17%) as a yellow oil. ESLMS (M+H)+: 358.0, 'H NMR (400 MHz, DMSO) 6 8.30 (s, 1H), 8.25 - 8.24 (m, 1H), 7.42 - 7.34 (m, 2H), 7.26 - 7.19 (m, 2H), 6.60 (s, 1H), 4.58 - 4.53 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 1.32 - 1.17 (m, 3H).
[0591] Synthesis of 2-(4-(((6-chloropyrinndin-4-yl)amino)methyl)phenoxy)-2,2-difluoro-
N,N-diniethylacetamide. Ethyl 2-(4-(((6.-chloropyrimidin-4-yl)amino)methyl)phenoxy)-2,2- difluoroacetate (250 mg, 0.70 mmol) was dissolved in THF (7 mL), NaOH (1 M, aq., 0.77 mL,
O.77 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in a water/Et2O (50 mL) and separated. The aqueous phase was acidified with HC1 (1 M aq.) to pH 2 and extracted with DCM (3 x 60 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to give a crude product (91 mg) which was used directly in the next step without further purification. The aqueous phase was concentrated in vacuo. The resulting crude product (140 mg) was also used directly in the next step without further purification. Both crude products were separately subjected to identical reaction conditions. One portion of crude acid (140 mg) was suspended in DMF (2.8 mL) and HATU (140 mg, 0.37 mmol) and DIPEA (99 pL, 0.57 mmol) was stirred at room temperature for 10 min. NHMe2 (2 M in THF, 180 pL, 0.37 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Additional HATU (160 mg, 0.42 mmol) and DIPEA (110 pL, 0.42 mmol) were added and the reaction mixture was stirred at room temperature for 5 min and NHMe2 (2 M in THF, 210 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for a further 2 h. Contemporaneously, the remaining crude acid was treated in a similar fashion. The two separate reaction mixtures were combined, diluted with water (20 mL) and extracted with EtOAc (2 >< 30 mL). The combined organics were washed with water (3 x 30 mL) then brine (50 ml), passed through a hydrophobic frit then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc in z.whexane to give the title compound (92 mg, 47%). ESLMS (M+H)+: 357.0, >HNMR (400 MHz, DMSO) 6 8.30 (s, 1H), 8.25 (s, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 6.60 (s, 1H), 4.58 - 4.58 (m, 2H), 3.23 (s, 3H), 2.97 (s, 3H).
Synthesis of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-N,N,2- trimethylpropanamide
Figure imgf000256_0001
[0592] Synthesis of methyl 2-(4-(((6-chloropyrimidin-4-yl) amino) methyl)phenoxy)-2- methylpropanoate. 4-(((6-Chloropyrimidin-4-yl)amino)methyl)phenol (200 mg, 0.85 mmol) was dissolved in DMF (4.3 mL) and K2CO3 (350 mg, 2.6 mmol) was added. The reaction mixture was stirred at room temperature for 10 min. Methyl 2-bromo-2-methylpropanoate (120 pL, 0.94 mmol) was added and the reaction mixture was stirred at 60 °C for 16 h. Additional methyl 2-bromo-2-methylpropanoate (110 pL, 0.85 mmol) was added and the reaction mixture was stirred at 60 °C for 90 min. Further methyl 2-bromo-2-methylpropanoate (110 pL, 0.85 mmol) was added and the reaction mixture was stirred at 60 °C for 1 h then at 80 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were washed with water (3 x 50 mL) and brine (40 mL), dried over MgSCU and concentrated in vacuo to give the title compound (280 mg, 98%) as a yellow oil. ESLMS (M+H)+: 336.0, 'H NMR (400 MHz, DMSO) 8 8.30 (s, 1H), 8.14 (s, 1H), 7.23 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 6.57 (s, 1H), 4.49 - 4.49 (m, 2H), 3.70 (s, 3H), 1.52 (s, 6H).
[0593] Synthesis of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-2- methylpropanoic acid. Methyl 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-2- methylpropanoate (280 mg, 0.83 mmol) was dissolved in THF (8 mL). NaOH (2 N, aq., 0.92 mL, 1.8 mmol) was added and the reaction mixture was stirred at room temperature for 1 h then at 60 °C for 2 h. Additional NaOH (2 N, aq., 0.21 mL, 0.42 mmol) was added and the reaction mixture was stirred at 60 °C for a further 30 min. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 mL) and washed with Et2O (2 x 50 mL). The aqueous phase was acidified to pH 4-5 and extracted with EtOAc (2 x 60 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The aqueous phase was further acidified to pH 3-4 and extracted with EtOAc (2 x 60 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. All residues were combined to give the title compound (150 mg, 55%) as a white solid. ESLMS (M+H)+: 322.0, ’H NMR (400 MHz, DMSO) 8 8.30 (s, 1H), 8.13 (s, 1H), 7.22 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 6.57 (s, 1H), 4.48 - 4.48 (m, 2H), 1.50 (s, 6H).
[0594] Synthesis of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-N,N,2- trimethylpropanamide. To a solution of 2-(4-(((6-chloropyrimidin-4- yl)amino)methyl)phenoxy)-2-methylpropanoic acid (150 mg, 0.46 mmol) in DMF (4.6 mL) was added HATU (230 mg, 0.60 mmol) and DIPEA (160 pL, 0.91 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. NHMe2 (2 M in THF, 0.3 mL, 0.60 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2x30 mL). The combined organics were washed with water (2 x 30 mL), brine (50 ml), dried over MgSO4 and concentrated in vacuo to give the title compound (92 mg, 87%) as a brown solid. ESI-MS (M+H)+: 349.1, 'H NMR (400 MHz, DMSO) 5 8.30 (s, 1H), 8.12 (s, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 6.57 (s, 1H), 4.48 - 4.48 (m, 2H), 3.11 (s, 3H), 2.85 (s, 3H), 1.52 (s, 6H).
Synthesis of l-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-N,N- dimethylcyclopropane-l-carboxamide
Figure imgf000258_0001
[0595] Synthesis of methyl 4-bromo-2-(4-(((6-chloropyrimidin-4- yl) amino) methyl)phenoxy)butanoate. 4-(((6-Chloropyrimidin-4-yl)amino)methyl)phenol (500 mg, 2.1 mmol) was dissolved in DMF (10 mL) and K2CO3 (350 mg, 2.6 mmol) was added. The reaction mixture was stirred at room temperature for 10 min. Methyl 2,4-dibromobutanoate (360 pL, 2.6 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. Additional methyl 2,4-dibromobutanoate (300 pL, 2.1 mmol) was added and the reaction mixture was stirred at room temperature for a further 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 * 100 mL). The combined organics were washed with water (2 x 50 mL) then brine (70 mL), dried over MgSOi and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in DCM to give the title compound (440 mg, 50%). ESI-MS (M+H)+: 414.0, 416.0, 'H NMR (400 MHz, DMSO) 5 8.29 (s, 1H), 8.15 - 8.14 (m, 1H), 7.26 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.57 (s, 1H), 4.94 (dd, J=4.6, 8.2 Hz, 1H), 4.49 - 4.49 (m, 2H), 3.74 - 3.60 (m, 5H), 2.44 - 2.37 (m, 2H).
[0596] Synthesis of methyl l-(4-(((6-chloropyrimidin-4- yl)amino)methyl)phenoxy)cyclopropane-l-carboxylate. A solution of ethyl 4-bromo-2-(4-(((6- chloropyrimidin-4-yl)amino)methyl)phenoxy)butanoate (430 mg, 1.0 mmol) in THF (5.0 mL) was cooled to 0 °C. KO'Bu (130 mg, 1.1 mmol) was added and the reaction mixture was stirred at 0 °C for 10 min, then at room temperature for 1 h. The reaction mixture was quenched with NH4CI (sat. aq., 15 mL) and extracted with DCM (2 x 40 mL). The combined organics were washed with water (30 mL), passed through a hydrophobic frit and concentrated in vacuo to give the title compound (310 mg, 89%) as an oil. ESI-MS (M+H)+: 334.0, 'H NMR (400 MHz, DMSO) 3 8.29 (s, 1H), 8.14 - 8.14 (m, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 6.57 (s, 1H), 4.49 - 4.43 (m, 2H), 3.64 (s, 4H), 1.80 - 1.76 (m, 1H), 1.58 - 1.53 (m, 1H), 1.32 - 1.27 (m, 1H).
[0597] Synthesis of l-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)cyclopropane-l- carboxylic acid. Methyl l-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)cyclopropane- 1-carboxylate (310 mg, 0.91 mmol) was dissolved in THF (9 mL), NaOH (2N, aq., 0.90 mL, 1.8 mmol) was added and the reaction mixture was stirred at 60 °C for 20 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and washed with Et2O (2 x 40 mL). The aqueous phase was acidified to pH 2. The resulting precipitate was filtered, washed with water (60 mL) and dried in a vacuum desiccator for 16 h to give the title compound (180 mg, 62%) as a white solid. ESI-MS (M+H)+: 338.0, 'H NMR (400 MHz, DMSO) 8 12.94 - 12.94 (m, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.25 (d, J=8.3 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.56 (s, 1H), 4.48 - 4.47 (m, 2H), 1.54 - 1.47 (m, 2H), 1.25 - 1.19 (m, 2H).
[0598] Synthesis of l-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenoxy)-N,N- dimethylcyclopropane-l-carboxanude. To a solution of l-(4-(((6-chloropyrimidin-4- yl)amino)methyl)phenoxy)cyclopropane-l-carboxylic acid (170 mg, 0.54 mmol) in DMF (5.4 mL) was added HATU (270 mg, 0.70 mmol) and DIPEA (220 pL, 1.2 mmol) and the reaction mixture was stirred at room temperature for 10 min. NHMe2 (2 M in THF, 0.4 mL, 0.70 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organics were washed with water (2 x 30 mL) then brine (50 ml), dried over MgSCL and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-49% EtOAc in DCM to give the title compound (130 mg, 70%) as an off-white solid. ESI- MS (M+H)+: 347.1, >HNMR (400 MHz, DMSO) 8 8.29 (s, 1H), 8.12 - 8.12 (m, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 6.56 (s, 1H), 4.47 - 4.47 (m, 2H), 3.15 - 3.15 (m, 3H), 2.78 - 2.73 (m, 3H), 1.34 - 1.29 (m, 2H), 1.11 - 1.06 (m, 2H).
Synthesis of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)-2,6-dimethylphenoxy)-N,N- dimethylacetamide
Figure imgf000260_0001
[0599] A mixture of 4-(((6-chloropyrimidin-4-yl)amino)methyl)-2,6-dimethylphenol (200 mg, 0.76 mmol) and K2CO3 (120 mg, 0.83 mmol) in DMF (3.6 mL) were stirred at room temperature for 10 min. 2-Chloro-A,A-dimethylacetamide (78 pL, 0.76 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Additional 2-chloro-AA- dimethylacetamide (78 pL, 0.76 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 40 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried over MgSCU and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-55% EtOAc in DCM to give the title compound (184 mg, 70%) as a colourless oil. ESLMS (M+H)+: 349.0, ’H NMR (400 MHz, DMSO) 8 8.29 (s, 1H), 8.12 (s, 1H), 6.98 (s, 2H), 6.57 (s, 1H), 4.39 (d, J=52.1 Hz, 4H), 2.99 (s, 3H), 2.88 (s, 3H), 2.21 (s, 6H).
S
Figure imgf000260_0002
[0600] K2CO3 (210 mg, 1.5 mmol) was added to a solution of 4-(((6-chloropyrimidin-4- yl)amino)methyl)-2,6-dimethylphenol (100 mg, 0.38 mmol) and 2-(bromomethyl)pyridine hydrobromide (96 mg, 0.38 mmol) in DMF (2.0 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (60 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc in DCM to give the title compound (130 mg, 96%) as a white solid. ESI-MS (M+H)+: 355.1, 'H NMR (400 MHz, CDCh) 5 8.59 (d, J=4.0 Hz, 1H), 8.33 (s, 1H), 7.81 - 7.75 (m, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.26 - 7.25 (m, 1H), 6.97 (s, 2H), 6.36 (s, 1H), 5.67 - 5.66 (m, 1H), 4.94 (s, 2H), 4.49 - 4.35 (m, 2H), 2.29 (s, 6H).
Synthesis of 6-chloro-N-(3>5-dimethyl-4-(thiazol-2-ylmethoxy)benzyl)pyrimidin-4-amine
Figure imgf000261_0001
[0601] DEAD (0.16 mL, 1.0 mmol) was added dropwise to a mixture of 4-(((6- chloropyrimidin-4-yl)amino)methyl)-2,6-dimethylphenol (110 mg, 0.42 mmol), thiazol-2- ylmethanol (59 mg, 0.51 mmol) and PPhs (130 mg, 0.51 mmol) in THF (5.0 mL) and the reaction mixture was stirred at room temperature for 16 h. Additional thiazol-2-ylmethanol (15 mg, 0.13 mmol), PPh3 (34 mg, 0.13 mmol) and DEAD (0.02 mL, 0.13 mmol) were added and the reaction mixture was stirred at room temperature for a further 4.5 h then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-25% EtOAc in DCM. The product containing fractions were concentrated in vacuo then the residue was dissolved in DCM and loaded onto a SCX cartridge. The cartridge was washed with DCM then MeOH and eluted with (7N NH3 in MeOH) in DCM. The eluent was concentrated in vacuo to give the title compound (61 mg, 40%) as an off-white solid. ESI-MS (M+H)+: 361.0, ’H NMR (400 MHz, MeOD) 5 8.24 (s, 1H), 7.81 (d, J=3.3 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H), 7.02 (s, 2H), 6.53 (s, 1H), 5.11 (s, 2H), 4.97 (s, 2H), 2.26 (s, 6H).
Synthesis of 6-chloro-N-(4-(thiazol-4-ylmethyl)benzyl)pyrimidin-4-amine
Figure imgf000261_0002
[0602] To a suspension of (4-(thiazol-4-ylmethyl)phenyl)methanamine hydrochloride (300 mg, 1.3 mmol) in zPrOH (6.0 mL) was added triethylamine (440 pL, 3.2 mmol). The reaction mixture was stirred at room temperature for 10 min. 4,6-Dichloropyrimidine (230 mg, 1.5 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was triturated with Et2O, fdtered and washed with DCM/water (40 mL) to give the title compound (99 mg, 25%) as a brown solid. ESI-MS (M+H)+: 317.0, ’H NMR (400 MHz, DMSO) 5 9.02 (d, J=1.6 Hz, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.35 (s, 1H), 7.24 (s, 4H), 6.57 (s, 1H), 4.52 - 4.52 (m, 2H), 4.09 (s, 2H).
Synthesis ofN-(4-((lH-pyrazol-l-yl)niethyl)benzyl)-6-chloropyrimidin-4-amine
Figure imgf000262_0001
[0603] A mixture of (4-((l/7-pyrazol-l-yl)methyl)phenyl)methanamine (140 mg, 0.74 mmol), NEt3 (260 pL, 1.9 mmol) and 4,6-dichloropyrimidine (130 mg, 0.89 mmol) in /PrOH (20 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (60 mL) and washed with water (50 mL). The organics were passed through a hydrophobic frit and concentrated in vacuo to give the title compound (220 mg, 99%) as a white solid. ESI-MS (M+H)+: 300, >H NMR (400 MHz, CDCk) 8 8.37 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 6.35 (s, 1H), 6.29 (dd, J=2.0, 2.0 Hz, 1H), 5.32 (s, 2H), 4.52 - 4.51 (m, 2H), NH not visible.
Synthesis of N-benzyl-6-chloropyrimidin-4-atnine
Figure imgf000262_0002
[0604] Using a similar procedure to that used for 7V-(4-((17/-pyrazol-l-yl)methyl)benzyl)-6- chloropyrimidin-4-amine, the title compound was prepared from 4,6-dichloropyrimidine and benzylamine (0.22 g, quant.). ESI-MS (M+H)+: 220. 1, ’H NMR (400 MHz, DMSO) 5 8.27 (s, 1H), 8.19 (s, 1H), 7.35 - 7.25 (m, 5H), 6.61 - 6.55 (m, 1H), 4.59 - 4.49 (m, 2H).
Figure imgf000262_0003
[0605] A suspension of (4-(pyrazin-2-ylmethyl)phenyl)methanamine (150 mg, 0.75 mmol), 4,6-dichloropyrimidine (110 mg, 0.75 mmol) and DIPEA (390 pL, 2.3 mmol) in zPrOH (7.0 mL) was stirred at 75 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-10% MeOH in DCM to give the title compound (89 mg, 39%). ESLMS (M+H)+: 312.1
[0606] Using a similar procedure to that used for 6-chloro-A-(4-(pyrazin-2- ylmethyl)benzyl)pyrimidin-4-amine, the compounds in Error! Reference source not found. 7 were prepared from 4,6-dichloropyrimidine and an appropriate coupling partner.
Table 7
Figure imgf000263_0001
Figure imgf000264_0001
[0607] Synthesis of tert-butyl (4-hydroxybenzyl) carbamate. To a mixture of 4- (aminomethyl)phenol (1 g, 8.1 mmol) and (Boc)2O (2.7 g, 12.2 mmol) in MeOH (20 mL) was added NaHCOi (2 g, 24 mmol), the reaction was stirred at room temperature for 16 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give tert-butyl (4-hydroxybenzyl)carbamate (1.6 g, yield: 89%) as a white solid. ESIMS [M +H]+: 224.2.
[0608] Synthesis of tert-butyl (4-(2-(dimethylamino)-2-oxoethoxy)benzyl)carbamate. A mixture of tert-butyl (4-hydroxybenzyl)carbamate (1.6 g, 7.2 mmol), 2-bromo-N,N- dimethylacetamide (1.78 g, 10.8 mmol) and CS2CO3 (3.3 g, 10 mmol) in DMF (20 mL) was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: DCM/MeOH = 40/1) to give tert-butyl (4-(2- (dimethylamino)-2-oxoethoxy)benzyl)carbamate (1.2 g, yield: 54%) as a yellow solid. ESI-MS [M +H]+: 309.2.
[0609] Synthesis of 2-(4-(aminomethyl)phenoxy)-N,N-dimethylacetamide. To a solution of tert-butyl (4-(2-(dimethylamino)-2-oxoethoxy)benzyl)carbamate (1.2 g, 3.9 mmol) in MeOH (10 mL) was added HC1 (4M solution in 1,4-dioxane, 10 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, quenched with NH3 (7M solution in MeOH, 10 mL) and concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 10/1) to give l-(4-2-(4-(aminomethyl)phenoxy)-N,N- dimethylacetamide (720 mg, yield: 89%) as a yellow solid. ESLMS [M +H]+: 209.2. Synthesis of 2-(4-(aminomethyl)phenyl)-N,N-dimethylacetamide
Figure imgf000265_0001
[0610] Synthesis of 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide. A mixture of 2-
(4-(hydroxymethyl)phenyl)acetic acid (120 mg, 0.72 mmol), dimethylamine hydrochloride (58 mg, 0.72 mmol), and HATU (410 mg, 1.08 mmol) and DIPEA (279 mg, 2.16 mmol) in DMF (2 mL) was stirred at room temperature for 12 h. The reaction was diluted with water (20 mL) and extracted by EtOAc (30 mL x 3). The combined organic layers were washed by brine (30 mL), dried over Na2SC>4, concentrated to give the crude, which was purified by column flash (EtOAc in PE = 70%) to get 2-(4- hydroxymethyl)phenyl)-N,N-dimethylacetamide (100 mg, yield: 72%) as yellow oil, ESI-MS [M +H]+: 194.1.
[0611] Synthesis of 2-(4-(chloromethyl)phenyl)-N,N-dimethylacetamide. To a solution of
2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide(100 mg, 0.52 mmol) was added SOCh (305 mg, 2.56 mmol) slowly at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated to afford 2-(4-(chloromethyl)phenyl)-N,N- dimethylacetamide(l 10 mg, crude) as yellow oil, which was used into next step without further purification. ESI-MS [M +H]+:212.1.
[0612] Synthesis of2-(4-(aminomethyl)phenyl)-N,N-diniethylacetamide. To a solution of 2-(4-(chloromethyl)phenyl)-N,N-dimethylacetamide(l 10 mg, crude) was added NHs(7 M in MeOH, 4 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated and purified by Prep-TLC(DCM/MeOH=20/l) to afford 2-(4- (aminomethyl)phenyl)-N,N-dimethylacetamide(75 mg, yield: 75% over 2 steps) as yellow oil. ESI-MS [M +H]+: 193.1.
Synthesis of 2-(4-(aminomethyl)phenyl)-l-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-l-one
Figure imgf000265_0002
[0613] Synthesis of l-(3-az.(ibicyclo[3.1.0]hexan-3-yl)-2-(4-(chloromethyl)phenyl)ethan-l- one. To a solution of l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(hydroxymethyl)phenyl)ethan-l- one (300 mg, 1.3 mmol) in dry DCM (10 mL) was added SOCI2 (770 mg, 6.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated to get 1- (3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(chloromethyl)phenyl)ethan-l-one (300 mg, crude) as a yellow solid, which was used in the next step without purification. ESLMS [M +H]+:250.2.
[0614] Synthesis of 2-(4-(aminomethyl)phenyl)-l-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-l- one. A mixture of l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(chloromethyl)phenyl)ethan-l-one (300 mg, crude) in NH4OH (10 mL) was stirred at room temperature for 10 h. The reaction mixture was concentrated and purified by Prep-TLC (DCM/MeOH=20/l) to afford 2-(4- (aminomethyl)phenyl)-l-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-l-one (250 mg, yield: 84% over 2 steps) as a yellow solid. ESLMS [M +H]+:231.2.
Synthesis ofN-(4-((lH-pyrazol-l-yl)methyl)-2-(trifluoromethyl)benzyl)-6-chloropyrimidin-4- amine.
Figure imgf000266_0001
[0615] Synthesis of 2-(trifluoromethyl)-4-vinylbenzonitrile. A mixture of 4-bromo-2- (trifluoromethyl)benzonitrile (4.0 g, 20 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (3.85 g, 25 mmol), Pd(dppf)C12 (732 mg, 1.0 mmol) and K2CO3 (8.28 g, 60 mmol) in 1,4- dioxane (50 mL) and water (5 mb) was stirred at 90 °C for 6 h under N2. The reaction mixture was cooled to room temperature. The reaction mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 100 mL). The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: PE/EtOAc = 10/1) to give 2- (trifluoromethyl)-4-vinylbenzonitrile (3 g, yield: 76%) as a yellow solid. ESI-MS [M +H]+: 198.2.
[0616] Synthesis of 4-cyano-3-(trifluoromethyl)benzoic acid. A mixture of 2- (trifluoromethyl)-4-vinylbenzonitrile (3 g, 15 mmol), KMnCh (4.7 g, 30 mmol) , NaIO4 (6.4 g, 30 mmol) and K2CO3 (4.1 g, 30 mmol) in Z-BuOI I (50 mL) and water (10 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with HC1 (IM solution in water, 50 mL) and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 10/1) to give 4-cyano-3-(trifluoromethyl)benzoic acid (1.5 g, yield: 47%) as a yellow oil. ESI-MS [M +H]+: 216.2.
[0617] Synthesis of (4-(aminomethyl)-3-(trifluoromethyl)phenyl)methanol. To a mixture of 4-cyano-3-(trifluoromethyl)benzoic acid (1.0 g, 4.7 mmol) in THF (30 mL) was added BH3 (IM solution in THF, 20 mL). The reaction mixture was stirred room temperature for 16 h. The reaction mixture was quenched with MeOH (30 mL) and stirred at room temperature for 1 h. The mixture was concentrated, the residue was diluted with water (100 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NazSCL, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 10/1) to give (4-(aminomethyl)-3- (trifluoromethyl)phenyl)methanol (860 mg, yield: 89%) as a yellow oil. ESI-MS [M +H]+: 206.2.
[0618] Synthesis of (4-(((6-chioropyrimidin-4-yi)amino)methyl)-3- (trifluoromethyl)phenyl)methanol. A mixture of (4-(aminomethyl)-3- (trifluoromethyl)phenyl)methanol (860 mg, 4.2 mmol), 4,6-dichloropyrimidine (932 mg, 6.3 mmol) and DIPEA (1.63 g, 12.6 mmol) in z-PrOH (20 mL) was stirred at 60 °C for 8 h. The mixture was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give (4-(((6-chloropyrimidin-4-yl)amino)methyl)-3- (trifluoromethyl)phenyl)methanol (1.0 g, yield: 75%) as a yellow solid. ESI-MS [M +H]+: 318.2. [0619] Synthesis of 6-chloro-N-(4-(chloroniethyl)-2-(trifluoromethyl)benzyl)pyrimidin-4- amine. To a solution of (4-(((6-chloropyrimidin-4-yl)amino)methyl)-3- (trifluoromethyl)phenyl)methanol (1.0 g, 3.2 mmol) in DCM (20 mL) was added SOCh (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated to give 6-chloro-N-(4-(chloromethyl)-2-(trifluoromethyl)benzyl)pyrimidin-4-amine (1.1 g, crude) as a yellow solid, which was used in the next step without further purification. ESLMS [M +H]+: 336.1.
[0620] Synthesis of N-(4-((lH-pyrazol-l-yl)methyl)-2-(trifluoromethyl)benzyl)-6- chloropyrimidin-4-aniine. A mixture of 6-chloro-N-(4-(chloromethyl)-2-
(trifluoromethyl)benzyl)pyrimidin-4-amine (1.1 g, crude), IH-pyrazole (286 mg, 4.2 mmol) and CS2CO3 (2.7 g, 8.4 mmol) in DMF (20 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL X 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give N-(4-((lH-pyrazol-l-yl)methyl)- 2-(trifluoromethyl)benzyl)-6-chloropyrimidin-4-amine (800 mg, yield: 68% over 2 steps) as a white solid. ESLMS [M +H]+: 368.2.
Synthesis of 6-chloro-N-(4-(difluoro(lH-pyrazol-l-yl)methyl)benzyl)pyrimidin-4-amine
Figure imgf000268_0001
[0621] Synthesis of 4-(difluoromethyl)benzonitrile. To a solution of 4-formylbenzonitrile (2.0 g, 15.3 mmol) in DCM (20 mL) was added a solution of DAST (7.4 g, 45.9 mmol) in DCM (20 mL) at 0 °C under N2. The mixture was stirred at room temperature for 2 h. The mixture was quenched with NaHCOi (sat. aq., 50 mL) and extracted with DCM (30 mL X 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 20/1) to give 4-(difluoromethyl)benzonitrile (1.4 g, yield: 60%) as a yellow oil. ESLMS [M +H]+: 154.2.
[0622] Synthesis of 4-(bromodifluoromethyl)benzonitrile. A mixture of 4- (difluoromethyl)benzonitrile (1.4 g, 9.2 mmol), NBS (1.6 g, 9.2 mmol) and benzoyl peroxide (223 mg, 0.92 mmol) in CCI4 (30 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 10/1) to give 4-(bromodifluoromethyl)benzonitrile (1.0 g, yield: 47%) as a yellow oil. ESI-MS [M +H]+: 232.2.
[0623] Synthesis of 4-(difluoro(lH-pyrazol-l-yl)niethyl)benzonitrile. A mixture of 4- (bromodifluoromethyl)benzonitrile (1.0 g, 4.3 mmol), IH-pyrazole (585 mg, 8.6 mmol) and CS2CO3 (4.2 g, 12.9 mmol) in DMF (20 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature. The mixture was quenched with water (70 mL) and extracted with EtOAc (60 mL X 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 5/1) to give 4-(difluoro(lH-pyrazol-l- yl)methyl)benzonitrile (850 mg, yield: 90%) as a white solid. ESI-MS [M +H]+: 220.2.
[0624] Synthesis of (4-(difluoro(lH-pyrazol-l-yl)methyl)phenyl)methanamine. A mixture of 4-(difluoro(lH-pyrazol-l-yl)methyl)benzonitrile (850 mg, 3.8 mmol) and Raney Ni (100 mg) in NEE (7M solution in MeOH, 20 mL) was stirred at room temperature for 1 h under H2. The mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give (4-(difluoro(lH-pyrazol-l- yl)methyl)phenyl)methanamine (770 mg, yield: 82%) as a yellow solid. ESI-MS [M +H]+: 224.2.
[0625] Synthesis of 6-chloro-N-(4-(difluoro(lH-pyrazol-l-yl)methyl)benzyi)pyrimidin-4- amine. A mixture of (4-(difluoro(lH-pyrazol-l-yl)methyl)phenyl)methanamine (770 mg, 3.5 mmol), 4,6-dichloropyrimidine (784 mg, 5.3 mmol) and DIPEA (1.35 g, 10.5 mmol) in z-PrOH (20 mL) was stirred at 65 °C for 16 h. The mixture was cooled to room temperature and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give 6-chloro-N-(4-(difluoro(lH-pyrazol-l-yl)methyl)benzyl)pyrimidin- 4-amine (650 mg, yield: 55%) as a white solid. ESI-MS [M +H]+: 336.2. Synthesis ofN-(4-((lH-pyrazol-l-yl)niethyl)-3-(trifluoromethyl)benzyl)-6-chloropyrimidin-4- amine
Figure imgf000270_0001
[0626] Synthesis of 4-(bromomethyl)-3-(trifluoromethyl)benzonitrile. A mixture of 4- methyl-3-(trifluoromethyl)benzonitrile(2.5 g, 13.5 mmol), NBS (2.4 g, 13.5 mmol) and benzoyl peroxide (327 mg, 1 .35 mmol) in CCk (50 mL) was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 10/1) to give 4-(brom om ethyl )-3- (trifluoromethyl)benzonitrile (1.5 g, yield: 42%) as a white solid. ESI-MS [M +H]+: 264.2.
[0627] Synthesis of 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethyl)benzonitrile. A mixture of 4-(bromomethyl)-3-(trifluoromethyl)benzonitrile (1.5 g, 5.7 mmol), IH-pyrazole (581 mg, 8.55 mmol) and CS2CO3 (3.7 g, 11.4 mmol) in DMF (30 mL) was stirred at room temperature for 16 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 5/1) to give 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethyl)benzonitrile (1.1 g, yield: 77%) as a white solid. ESLMS [M +H]+: 252.2.
[0628] Synthesis of (4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethyl)phenyl)methanamine.
A mixture of 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethyl)benzonitrile (1.1 g, 4.38 mmol) and Raney Ni (110 mg) in NH3 (7M solution in MeOH, 20 mL) was stirred at room temperature for 1 h under H2. The mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give (4-((lH-pyrazol-l-yl)methyl)- 3-(trifluoromethyl)phenyl)methanamine (1.0 g, yield: 89%) as a yellow solid. ESLMS [M +H]+: 256.2.
[0629] Synthesis of N-(4-((lH-pyrazol-l-yl)methyI)-3-(trifluoromethyl)benzyl)-6- chloropyrimidin-4-amine. A mixture of (4-((lH-pyrazol-l-yl)methyl)-3- (trifluoromethyl)phenyl)methanamine (1.0 g, 3.9 mmol), 4,6-dichloropyrimidine (873 mg, 5.9 mmol) and DIPEA (1.5 g, 11.7 mmol) in z-PrOH (20 mL) was stirred at 65 °C for 16 h. The mixture was cooled to room temperature and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give N-(4-((lH-pyrazoLl- yl)methyl)-3-(trifluoromethyl)benzyl)-6-chloropyrimidin-4-amine (830 mg, yield: 58%) as a white solid. ESI-MS [M +H]+: 368.2.
Figure imgf000271_0001
[0630] Synthesis of (4-(aminomethyl)-3-fluorophenyl)methanol. To a solution of 4-cyano- 3 -fluorobenzoic acid (495 mg, 3 mmol) in THF (20 mL) was added dropwise BH3 (IM in THF, 9 mL, 9 mmol). The mixture was stirred at room temperature for 12 h. The reaction was quenched with MeOH (20 mL) and stirred at room temperature for another 2 h. Then the reaction was concentrated to give the crude (4-(aminomethyl)-3-fluorophenyl)methanol (480 mg, crude) as colourless oil, which was used in the next step without purification. ES MS [M +H]+: 156.2. [0631] Synthesis of (4f((6-chloropyrinudin-4-yl)anuno)niethyl)-3-fluorophenyl)methanol. To a solution of (4-(aminomethyl)-3-fluorophenyl)m ethanol (480 mg, crude) in /-PrOH (20 mL) was added 4,6-dichloropyrimidine (596 mg, 4 mmol) and DIPEA (1.98 mL, 12 mmol). After the reaction mixture was stirred at 60 °C for 12 h, the reaction was cooled to room temperature and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with petroleum ether : ethyl acetate = 2 : 1) to afford the (4-(((6-chloropyrimidin-4- yl)amino)methyl)-3 -fluorophenyl )m ethanol (547 mg, 68% over two steps). ESLMS [M +H]+:268.2.
[0632] Synthesis of 6-chloro-N-(4-(chloroniethyl)-2-fluorobenzyl)pyrimidin-4-amine. To a solution of (4-(((6-chloropyrimidin-4-yl)amino)methyl)-3-fluorophenyl)methanol (355 mg, 1.3 mmol) in DCM (10 mL) was added SOCh (2 mL). The reaction mixture was stirred for 12 h at room temperature. The reaction was concentrated to give the crude, which was purified by silica gel column chromatography (eluting with PE / EtOAc = 2 / 1) to afford the 6-chloro-N-(4- (chloromethyl)-2-fluorobenzyl)pyrimidin-4-amine (300 mg, yield: 80%). ESLMS [M +H]+:286.1.
[0633] Synthesis of N-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-6-chloropyrimidin-4- amine. To a solution of 6-chloro-N-(4-(chloromethyl)-2-fluorobenzyl)pyrimidin-4-amine (300 mg, 1.05 mmol) in DMF (5 mL) was added pyrazole (167 mg, 2.46 mmol) and Cesium carbonate (1.21 g, 3.69 mmol). The reaction mixture was stirred at room temperature for 2 h. Water (30 mL) was added and extracted with ethyl acetate (30 mL * 3), washed with brine (40 mL), dried over NazSCU and concentrated to give the crude, which was purified by silica gel column chromatography (eluting with PE / EtOAc = 2 : 1) to afford N-(4-((lH-pyrazol-l-yl)methyl)-2- fluorobenzyl)-6-chloropyrimidin-4-amine (300 mg, 90%) as white solid. ESLMS [M +H]+:318.1.
Synthesis of 6-chloro-N-(4-(chloromethyl)-2-fluorobenzyl)pyridazin-4-amine
Figure imgf000272_0001
[0634] Synthesis of (4-(aminomethyl)-3-fluorophenyl)methanol. To a solution of 4-cyano- 3 -fluorobenzoic acid (990 mg, 6 mmol) in THF (10 mL) was added dropwise BH3 (IM in THF, 18 mL, 18 mmol). After the reaction mixture was stirred at room temperature for 12 h, the reaction was quenched with MeOH (20 mL) and stirred at room temperature for another 2 h. And then the mixture was concentrated to give the (4-(aminomethyl)-3-fluorophenyl)methanol (1.17 g, crude) as colourless oil. ESLMS [M +H]+: 156.2.
[0635] Synthesis of (4-(((6-chloropyridazin-4-yl)amino)methyl)-3-fhiorophenyl)methanol.
To a solution of (4-(aminomethyl)-3-fluorophenyl)methanol (1.17 g, crude) in z-PrOH (30 mL) was added DIPEA (2.9 g, 22.5 mmol) and 3,5-dichloropyridazine (1.24 g, 8.3 mmol). The reaction mixture was stirred at 60 °C for 12 h and then cooled to room temperature and concentrated to give the crude, which was purified by silica gel column chromatography (eluting with PE / EtOAc = 2 / 1) to afford the (4-(((6-chloropyridazin-4-yl)amino)methyl)-3- fluorophenyl)methanol (712 mg, 44% over two steps). ESI-MS [M +H]+:268.1.
[0636] Synthesis of 6-chloro-N-(4-(chloroniethyl)-2-fluorobenzyl)pyridazin-4-amine. To a solution of (4-(((6-chloropyridazin-4-yl)amino)methyl)-3-fluorophenyl)methanol (603 mg, 2.24 mmol) in DCM (20 mL) was added SOCk (4 m ). The reaction mixture was stirred for 12 h at room temperature. The reaction was concentrated and the residue was neutralized with NaHCOs (sat. aq., 25 mL), extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude, which was purified by silica gel column chromatography (eluting with PE / EtOAc = 2 / 1) to afford the 6- chloro-N-(4-(chloromethyl)-2-fluorobenzyl)pyridazin-4-amine (600 mg, yield: 93%). ESI-MS [M +H]+:286.1.
Synthesis of N-((6-cyclopropylimidazo[l ,2-b]pyridazin-2-yl)methyl)-2,2,2-trifhioroethan-l- amine
Figure imgf000273_0001
[0637] Synthesis of 6-cyclopropyliniidazo[l,2-b]pyridazine-2-carbaldehyde. To a solution of (6-cy cl opropylimidazo[l,2-b]pyridazin-2-yl)m ethanol (650 mg, 3.44 mmol) in DCM (20 mL) was added Mn02 (4.46 g, 51.3 mmol) at room temperature. After the mixture was stirred at room temperature for 6 h, the mixture was filtered and filer cake was washed with DCM/MeOH (10/1, 100 mL). The filtrate was concentrated and purified by silica gel column chromatography (DCM/MeOH = 10:1) to afford 6-cyclopropylimidazo[l,2-b]pyridazine-2-carbaldehyde (400 mg, yield: 62%) as a yellow solid. ESI-MS [M + H ]+: 188.2.
[0638] Synthesis of N-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-2,2,2- trifluoroethan-l-amine. A mixture of 6-cyclopropylimidazo[l,2-b]pyridazine-2-carbaldehyde (200 mg, 1.07 mmol), 2,2,2-trifluoroethan-l -amine (127 mg, 1.28 mmol) and Ti(EtO)4 (1.09 g, 4.77 mmol) in MeOH (10 mL) and DCM (3 mL) was stirred at 60 °C for 4 h. Then the reaction mixture was cooled to 0 °C, NaBHi (122 mg, 3.21 mmol) was added thereto and stirred at room temperature for another 1 h. The reaction mixture was concentrated and purified by silica gel column chromatography (DCM/MeOH = 20: 1) to afford N-((6-cyclopropylimidazo[l,2- b]pyridazin-2-yl)methyl)-2,2,2-trifluoroethan-l -amine (220 mg, yield: 76%) as a white solid.
ESLMS [M + H]+: 271.1.
Synthesis of (6-cyclopropyl-8-(pyrrolidin-l-ylmethyl)imidazo[l,2-b]pyridazin-2-yl)methanol
Figure imgf000274_0001
[0639] Synthesis of 8-bronio-2-(bromomethyl)-6-chloroimidazo[l,2-b]pyridazine. A mixture of 4-bromo-6-chloropyridazin-3 -amine (6.0 g, 28.98 mmol) and 1,3 -dibrom opropan-2- one (15.65 g, 72.46 mmol) in DME (120 mL) was stirred at 90 °C for 16 h under N2. The mixture was cooled to room temperature and concentrated. The residue was washed with NaHCCh (sat. aq., 100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (PE/EtOAc=2/l) to give the crude 8-bromo-2-(bromomethyl)-6-chloroimidazo[l,2-b]pyridazine as a brown solid (7.85 g, yield: 83%) as a yellow solid. ESLMS [M +H]+: 325.9.
[0640] Synthesis of (8-bromo-6-chloroimidazo[l,2-b]pyridazin-2-yl)methanoL A mixture of 8-bromo-2-(bromomethyl)-6-chloroimidazo[l,2-b]pyridazine (7.85 g, 24.08 mmol) and Na2CO3 (12.76 g, 120 mmol) in THF/H2O (60 mL / 60 mL) was stirred at 80 °C for 16 h. After cooled to room temperature, the reaction mixture was concentrated and the aqueous layer was diluted with water (50 mL) and extracted with EtOAc/MeOH (10/1, 100 mL x 3). The combined organic layers were concentrated and purified by silica gel column chromatography (DCM / MeOH = 30: 1) to give (8-bromo-6-chloroimidazo[l,2-b]pyridazin-2-yl)methanol (2.1 g, yield: 35%) as a yellow solid. ESI-MS [M +H]+: 262.1.
[0641] Synthesis of 8-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloroimidazo[l,2- bfpyridazine. A mixture of (8-bromo-6-chloroimidazo[l,2-b]pyridazin-2-yl)methanol (2.1 g, 8.05 mmol), IH-imidazole (1.09 g, 16.09 mmol) and TBSC1 (1.81 g, 12.07 mmol) in DCM (70 mL) was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography (DCM : MeOH = 40 : 1) to give 8-bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)-6-chloroimidazo[l,2-b]pyridazine (2.4 g, yield: 80%) as a light yellow solid. ESI-MS [M +H]+: 376.2.
[0642] Synthesis of ethyl 2-(((tert-butyldiniethylsilyl)oxy)niethyl)-6-chloroimidazo[l,2- b]pyridazine-8-carboxylate. To a solution of 8-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)- 6-chloroimidazo[l,2-b]pyridazine (400 mg, 1.07 mmol) in EtOH (20 mL) was added Pd(dppf)Ch (87 mg, 0.11 mmol) and TEA (325 mg, 3.21 mmol). The reaction mixture was stirred at 80 °C for 14 h under CO. After cooled to room temperature, the reaction mixture was concentrated and purified by Prep-TLC (PE/EtOAc = 5/1) to give ethyl 2-(((tert- butyldimethylsilyl)oxy)methyl)-6-chloroimidazo[l,2-b]pyridazine-8-carboxylate as a light yellow oil (110 mg, yield : 28%). ESI-MS [M +H]+: 370.1.
[0643] Synthesis of ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-6- cyclopropylimidazo[l,2-b]pyridazine-8-carboxylate. A mixture of ethyl 2-(((tert- butyldimethylsilyl)oxy)methyl)-6-chloroimidazo[l,2-b]pyridazine-8-carboxylate (110 mg, 0.29 mmol), cyclopropylboronic acid (50 mg, 0.58 mmol), Pd(OAc)2 (6.5 mg, 0.029 mmol), Xantphos (16 mg, 0.029 mmol) and K3PO4 (185 mg, 0.87 mmol) in Toluene / H2O (10 mL / 1 mL) was stirred at 85 °C for 16 h under N2. The mixture was cooled to room temperature and concentrated, the residue was purified by Prep - TLC (DCM / MeOH = 20 : 1) to give ethyl 2- (((tert-butyldimethylsilyl)oxy)methyl)-6-cyclopropylimidazo[l,2-b]pyridazine-8-carboxylate as light yellow oil (90 mg, yield: 82%). ESI-MS [M +H]+: 376.1.
[0644] Synthesis of (2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyclopropylimidazo[l,2- b]pyridazin-8-yl)methanol. To a solution of ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-6- cyclopropylimidazo[l,2-b]pyridazine-8-carboxylate (90 mg, 0.24 mmol) in THF (5 mL) was added DIBAL-H (IM in THF, 1.5 mL, 1.5 mmol) drop-wise at 0 °C under N2 and the mixture was stirred at 0°C for 0.5 h. The reaction mixture was quenched with H2O (0.5 mL), NaOH (aq) (0.5 mL) and H2O (1 mL), then the mixture was stirred at room temperature for 15 min. The mixture was filtered, and the filter cake was washed with DCM/MeOH (10: 1, 30 mL). The filtrate was concentrated to give (2-(((tert-butyldimethylsilyl)oxy)methyl)-6- cy cl opropylimidazo[l,2-b]pyridazin-8-yl)m ethanol as a yellow solid (90 mg, crude), which was used into next step without further purification. ESI-MS [M +H]+: 334.2.
[0645] Synthesis of (2-(((tert-butyIdimethylsilyI)oxy)methyl)-6-cycIopropylimidazo[l,2- b]pyridazin-8-yl)methyl niethanesulfonate. To a solution of (2-(((tert- butyldimethylsilyl)oxy)methyl)-6-cyclopropylimidazo[l,2-b]pyridazin-8-yl)methanol (90 mg, crude) in DCM (5 mL) was added TEA (88 mg, 0.87 mmol) and MsCl (50 mg, 0.44 mmol) at 0 °C. After the mixture was stirred at room temperature for 1 h, the mixture was concentrated to give (2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyclopropylimidazo[l,2-b]pyridazin-8- yl)methyl methanesulfonate (100 mg, crude), which was used into next step without purification.
ESI-MS [M +H]+: 412.2.
[0646] Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyclopropyl-8-(pyrrolidin-l- ylmethyl)inndazo[l,2-b]py ridazine.
[0647] To a solution of (2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyclopropylimidazo[l,2- b]pyridazin-8-yl)methyl methanesulfonate (100 mg, crude) in ACN (5 mL) was added K2CO3 (120 mg, 0.87 mmol), pyrrolidine (31 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 16 h. Water (20 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by Prep-TLC (EtOAc) to give 2-(((tert- butyldimethylsilyl)oxy)methyl)-6-cy clopropyl-8-(pyrrolidin- 1 -ylmethyl)imidazo[ 1 ,2- b]pyridazine as a light yellow oil (30 mg, yield : 32% over 3 steps). ESI-MS [M +H]+: 387.3.
[0648] Synthesis of (6-cyclopropyl-8-(pyrrolidin-l-ylmethyl)imidazo[l,2-b]pyridazin-2- yl)methanol. A mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyclopropyl-8-(pyrrolidin- l-ylmethyl)imidazo[l,2-b]pyridazine (30 mg, 0.077 mmol) in HC1 (4M in 1,4-dioxane, 2 mL) was stirred at room temperature for 1 h. The mixture was concentrated to give the (6- cyclopropyl-8-(pyrrolidin-l-ylmethyl)imidazo[l,2-b]pyridazin-2-yl)methanol as a yellow solid (20 mg, crude), which was used into next step without purification. ESLMS [M +H]+: 273.2. Synthesis of (5-cyclopropylbenzo[b]thiophen-2-yl)methanol
Figure imgf000277_0001
[0649] Synthesis of methyl 5-cyclopropylbenzo[b]thiophene-2-carboxylate. A mixture of methyl 5-bromobenzo[b]thiophene-2-carboxylate (600 mg, 2.21 mmol), cyclopropylboronic acid (380 mg, 4.43 mmol), Pd(OAc)2 (50 mg, 0.221 mmol), S-Phos (91 mg, 0.221 mmol) and K3PO4 (1.41 g, 6.63 mmol) in toluene (15 mb) and water (3 mL) was stirred at 90 °C for 16 h. After cooled to room temperature, the reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaiSO-i, concentrated and purified by silica gel chromatography (EtOAc/PE=l/5) to give methyl 5-cyclopropylbenzo[b]thiophene-2-carboxylate (430 mg, yield: 84%) as a yellow solid. ESLMS [M +H]+: 233.1.
[0650] Synthesis of (5-cyclopropylbenzo[b]thiophen-2-yl)methanoL To a stirred solution of methyl 5-cyclopropylbenzo[b]thiophene-2-carboxylate (430 mg, 1.85 mmol) in THF (15 mL) was added dropwise Li AlHi (3.7 mL, 3.7 mmol, 1 M in THF) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with Na SCh’lO H2O (3 g), diluted in THF (30 mL) and filtered. The filtrate was concentrated and purified by silica gel chromatography (EtOAc/PE = 1/3) to give (5-cyclopropylbenzo[b]thiophen-2-yl)methanol (310 mg, yield: 74%) as a yellow solid. ESLMS [M +Na]+: 227.1.
Synthesis of ethyl 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropanoate.
Figure imgf000278_0001
[0651] Synthesis of 7-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridine. To a stirred solution of (7-bromo-5- cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methanol (2.7 g, 10 mmol) and imidazole (2.1 g, 31 mmol) in DCM (30 mL) was added TBSC1 (1.9 g, 13 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. Water (50 mL) was added and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, concentrated to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc/PE = 1/3) to give 7-bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridine (3.1 g, yield: 81%) as a white solid. ESI-MS [M + H]+: 381.0.
[0652] Synthesis of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridine-7-carboxylate. A mixture of 7-bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridine (2.8 g, 7.3 mmol), Pd(dppf)C12 (0.54 g, 0.73 mmol) and EtsN (3.7 g, 37 mmol) in MeOH (40 mL) was stirred at reflux for 16 h under CO (balloon). After cooled to room temperature, the reaction mixture was diluted in DCM/MeOH (50 mL, 10/1), filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc/PE = 1/20) to give methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridine-7- carboxylate (1.1 g, yield: 41%) as a colorless syrup. ESLMS [M + H]+: 361.2. [0653] Synthesis of (2-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l ,5- a]pyridin-7-yl)methanol. To a stirred solution of methyl 2-(((tert- butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridine-7-carboxylate (1.08 g, 3.0 mmol) in THF (30 mL) and EtOH (6 mL) was added LiBEU (196 mg, 9.0 mmol) in portions at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with NH4Q (sat. aq., 40 mL) and extracted with EtOAc (40 mL x 2). The combined organics were washed with brine (80 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EtOAc /PE = 1/5) to give (2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)methanol (760 mg, yield: 76%) as a colorless syrup. ESLMS [M + H]+: 333.2.
[0654] Synthesis of (2-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5- a]pyridin-7-yl)methyl methanesulfonate. To a mixture of (2-(((tert- butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)methanol (760 mg, 2.29 mmol) and EtsN (694 mg, 6.87 mmol) in DCM (20 mL) was added a solution of MsCl (393 mg, 3.44 mmol) in DCM (5 mL) at 0°C and stirred at room temperature for 3 h. The reaction was diluted with water (30 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated to give the crude product (2-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7- yl)methyl methanesulfonate (840 mg, crude) as a yellow syrup. ESLMS [M + H]+: 411.1.
[0655] Synthesis of ethyl 3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoate. To a stirred solution of ethyl isobutyrate (714 mg, 6.15 mmol) in THF (20 mL) was added LDA (3.08 mL, 6.15 mmol) at -40 °C under N2. After stirred at - 40 °C for 1 h, a solution of (2-(((tert- butyldimethylsilyl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)methyl methanesulfonate (840 mg, crude) in THF (5 mL) was added dropwise at -70 °C over 20 min. The resulting mixture was stirred for 1.5 h at -70 °C. The reaction mixture was quenched with NH4Q (sat. aq., 30 mL), extracted with EtOAc (40 mL x 3). The combined organics were washed with brine (80 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EtOAc/PE = 1/10) to give ethyl 3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoate (260 mg, yield: 26% over 2 steps) as a colorless syrup. ESLMS [M + H]+: 431.2. [0656] Synthesis of ethyl 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l ,5-a]pyridin-7-yl)~
2,2-dimethylpropanoate. To a solution of ethyl 3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoate (260 mg, 0.60 mmol) in THF (6 mL) was added TBAF (1 M in THF, 1 mL, 1 mmol) and stirred at room temperature for 1 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EtOAc/PE = 1/2) to give ethyl 3-(5-cyclopropyl-2- (hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoate (160 mg, yield: 84%) as a yellow syrup. ESLMS [M + H]+: 317.2.
Synthesis of 6-cyclopropyl-2-(hydroxymethyl)imidazo[l,2-c]pyrimidin-5(6H)-one
Figure imgf000280_0001
[0657] A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (500 mg, 2.2 mmol) and Na2CO3 (742 mg, 7 mmol) in THF/ZH2O (25 mL / 25 mL) was stirred at 90 °C for 16 h. After cooled to room temperature, the reaction was diluted with H2O (30 mL), extracted with EtOAc (30mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography (DCM/MeOH=10/l) to give 6-cyclopropyl-2- (hydroxymethyl)imidazo[l,2-c]pyrimidin-5(6H)-one (175 mg, 38%) as yellow oil. ESLMS [M +H]+: 206.1.
Synthesis of 3-chloro-6-(hydroxymethyl)quinoline-8-carbonitrile.
Figure imgf000280_0002
[0658] Synthesis of methyl 3-chloroquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (6 g, 32 mmol) and NCS (4.7 g, 35 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCOs (sat. aq., 100 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (80 mL), dried over NaiSCL, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3-chloroquinoline-6-carboxylate (5 g, 70%) as a yellow solid. ESLMS [M +H]+:
222.2.
[0659] Synthesis of3-chloro-6-(methoxycarbonyl)quinoline l-oxide. To a solution of methyl 3-chloroquinoline-6-carboxylate (5 g, 22.5 mmol) in DCM (70 mL) was added m-CPBA (4.6 g, 27 mmol) as 0 °C. The resulting reaction was stirred at room temperature for 2 h. The reaction was quenched with NaHCOi (sat. aq., 70 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-25% EtOAc in PE to give 3-chloro-6-(methoxycarbonyl)quinoline l-oxide (3.5 g, 65%) as a yellow solid. ESLMS [M +H]+: 238.1.
[0660] Synthesis of 3-chloro-8-iodo-6-(methoxycarbonyl)quinoline l-oxide. A mixture of 3-chloro-6-(methoxycarbonyl)quinoline l-oxide (3.5 g, 14.7 mmol), NIS (8.1 g, 36 mmol), [RhCp*Ch]2 (908 mg, 1.47 mmol) and AgNTf2 (1.1 g, 2.94 mmol) in DCE (75 mL) was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was diluted with NaHCOs (sat. aq., 80 mL), extracted with EtOAc (60 mL x 3). The combined organic layers washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-35% EtOAc in PE to 3-chloro-8- iodo-6-(methoxycarbonyl)quinoline l-oxide (1.7 g, 32%) as a yellow solid. ESLMS [M +H]+:
364.2.
[0661] Synthesis of (3-chIoro-8-iodoquinolin-6-yl)methanol. To a solution of 3-chloro-8- iodo-6-(methoxycarbonyl)quinoline l-oxide (1.7 g, 4.7 mmol) in THF (35 mL) was added LiAlH(t-BuO)3 (23.5 mL, 23.5 mmol, 1 M solution in THF). The resulting reaction was stirred at 50 °C for 12 h. The reaction was cooled to 0 °C, quenched with NH4CI (sat. aq., 50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to give (3-chloro-8- iodoquinolin-6-yl)methanol (120 mg, 8%) as a yellow solid. ESI-MS [M +H]+: 320.1.
[0662] Synthesis of 3-chloro-6-(hydroxymethyl)quinoline-8-carbonitrile. A mixture of (3- chloro-8-iodoquinolin-6-yl)methanol (120 mg, 0.38 mmol), Zn(CN)i (133 mg, 1.14 mmol) and Pd(PPh3)4 (44 mg, 0.038 mmol) in DMF (5 mL) was stirred at 65 °C for 15 h. After cooled to room temperature, the reaction was diluted with FLO (20 mL), extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: PE/EtOAc = 1/1) to give 3-chloro-6-(hydroxymethyl)quinoline-8-carbonitrile (75 mg, 90%) as a yellow solid. ESI-MS [M +H]+: 219.2.
Synthesis of 8-butyl-3-chloro-6-(hydroxymethyl)quinoline 1-oxide
Figure imgf000282_0001
of 3-chloro-8-iodo-6-(methoxycarbonyl)quinoline 1-oxide (1 g, 2.75 mmol) in THF (60 mL) was added n-BuLi (1.1 mL, 3 mmol, 2.7 M solution in heptane) dropwise at -78°C. The reaction was stirred at -78 °C for 10 min, a solution of oxetan-3-one (594 mg, 8.25 mmol) in THF (10 mL) was added thereto. The resulting reaction was stirred at -78 °C for 3 h. The reaction was quenched with NH4CI (sat. aq., 50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-40% EtOAc in PE to give 8-butyl-3-chloro-6-(methoxycarbonyl)quinoline 1-oxide (120 mg, 15%) as a yellow solid. ESI-MS [M +H]+: 294.2.
[0664] Synthesis of 8-butyl-3-chloro-6-(hydroxymethyl)quinoline 1-oxide. To a solution of 8-butyl-3-chloro-6-(methoxycarbonyl)quinoline 1-oxide (120 mg, 0.41 mmol) in THF (10 mL) was added DIBAL-H (0.81 mL, 0.81 mmol, 1 M solution in toluene) at -78 °C. The reaction was stirred at -78 °C for 4 h. The reaction was quenched with NH4CI (sat. aq., 20 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-40% EtOAc in PE to give 8-butyl-3-chloro-6- (hydroxymethyl)quinoline 1-oxide (60 mg, 55%) as a yellow solid. ESI-MS [M +H]+: 266.2.
Synthesis of 3 -chloro- 6-((( 6-chloropyridazin-4-yl) oxy) methyl) quinoline
Figure imgf000283_0001
[0665] (3-chloroquinolin-6-yl)methanol (100 mg, 0.52 mmol) in DMF (1.0 mL) was added dropwise to a stirred suspension of NaH (60% in mineral oil, 25 mg, 0.62 mmol) in DMF (1.0 mL) at 0 °C. The reaction was stirred at 0 °C for 30 min then 3,5-dichloropyridazine (131 mg, 0.88 mmol) in DMF (1.0 mL) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSO4 then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0 - 5% MeOH in DCM to give the title compound (129 mg, 81%). ’H NMR (400 MHz, CDCh) 8 8.96 (d, J=2.5 Hz, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.19 - 8.16 (m, 2H), 7.80 (s, 1H), 7.73 (dd, J=2.0, 8.8 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 5.36 (s, 2H).
[0666] The intermediate compounds in Table 8 were synthesised following a similar procedure to 3-chloro-6-(((6-chloropyridazin-4-yl)oxy)methyl)quinoline from 3,5- dichloropyridazine and an appropriate coupling partner.
Table 8
Figure imgf000283_0002
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0002
Synthesis of 5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)-3-chloropyridazine
Figure imgf000286_0001
[0667] A stirred solution of L(4-((l//-pyrazol-l-yl)methyl)phenyl)ethan-l-ol (1.2 g, 5.9 mmol) in DMF (10 mL) was cooled to 0 °C under a N2 atmosphere and NaH (60% in mineral oil, 0.29 g, 7.1 mmol) was added portion-wise. The reaction mixture was stirred at 0 °C for 10 min and 3,5-dichloropyridazine (0.97 g, 6.5 mmol) was added and the reaction mixture was stirred at 0 °C for a further 15 min. The reaction mixture was then stirred at room temperature for 24 h. The reaction mixture was poured into a mixture of water (25 mL) and brine (25 mL) at 0 °C and extracted with EtOAc (3 x 50 mL). The combined organics were dried over MgSCL and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 20-80% EtOAc in DCM to give the title compound (1.2 g, 65%) as a cream solid. ESI-MS (M+H)+: 315.1. 'H NMR (400 MHz, DMSO) 8 9.00 (d, J=2.5 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.46 - 7.41 (m, 4H), 7.21 (d, J=8.3 Hz, 2H), 6.27 (dd, J=2.0, 2.0 Hz, 1H), 5.85 (q, J=6.4 Hz, 1H), 5.33 (s, 2H), 1.59 (d, J=6.4 Hz, 3H).
[0668] Using a similar procedure to that used for 5-(l-(4-((l//-pyrazol-l- yl)methyl)phenyl)ethoxy)-3-chloropyridazine, the intermediate compounds in Table 9 were prepared from 3,5-dichloropyridazine and an appropriate coupling partner.
Table 9
Figure imgf000287_0001
Figure imgf000288_0002
Synthesis of l-(4-((( 6-chloropyridazin-4-yl) oxy) methyl) benzyl)piperidin-2-one
Figure imgf000288_0001
[0669] A solution of l-(4-(hydroxymethyl)benzyl)piperidin-2-one (250 mg, 1.1 mmol) in DMF (5.0 mL) was added dropwise to a stirring solution of NaH (60% in mineral oil, 55 mg, 1.4 mmol) in DMF (6.0 mL) cooled to 0 °C. The reaction mixture was stirred at room temperature for 90 min and 3,5-dichloropyridazine (260 mg, 1.7 mmol) was added. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with water (3 x 20 mL), brine (40 mL), dried over MgSCh and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-2% MeOH in DCM to give the title compound (220 mg, 52%) as a white solid. ESI-MS (M+H)+: 332.0. 'H NMR (400 MHz, DMSO) 5 9.06 (d, J=2.6 Hz, 1H), 7.66 (d, J=2.5 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 5.29 (s, 2H), 4.52 (s, 2H), 3.18 (s, 2H), 2.34 - 2.28 (m, 2H), 1.75 - 1.70 (m, 4H). [0670] Using a similar procedure to that used for l-(4-(((6-chloropyridazin-4- yl)oxy)methyl)benzyl)piperidin-2-one, the intermediate compounds in Table 10 were prepared from 3,5-dichloropyridazine and an appropriate coupling partner.
Table 10
Figure imgf000289_0001
Figure imgf000290_0003
Synthesis of 5-((6-((lH-pyrazol-l-yl)methyl)pyridin-3-yl)methoxy)-3-chloropyridazine
Figure imgf000290_0001
[0671] A stirred solution of (6-((l /-pyrazol- 1 -yl)methyl)pyri din-3 -yl)methanol (150 mg, 0.78 mmol) in THF (8.0 mL) was placed under N2, cooled to 0 °C then NaH (60% in mineral oil, 34 mg, 0.85 mmol) was added portionwise. The reaction mixture stirred for 10 min. The reaction mixture was then stirred at room temperature for 15 min, re-cooled to 0 °C and a solution of 3,5-dichloropyridazine (120 mg, 0.78 mmol) in THF (2.0 mL) and DMF (2.0 mL) was added dropwise over 20 min. The resulting reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 1 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (20 mL) and washed with water (2 x 15 mL) and brine (2 x 20 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-5% MeOH in DCM to give the title compound (109 mg, 46%) as a yellow oil. ESI-MS (M+H)+: 302.0.
Synthesis of 5-((5-((l H-pyrazol-l-yl)methyl)pyridin-2-yl)methoxy)-3-chloropyridazine
Figure imgf000290_0002
[0672] Using a similar procedure to that used for 5-((6-((17/-pyrazol-l-yl)methyl)pyridin-3- yl)methoxy)-3-chloropyridazine, the title compound was prepared from (5-((l/7-pyrazol-l- yl)methyl)pyridin-2-yl)methanol and 3,5-dichloropyridazine (43 mg, 67%). ESI-MS (M+H)+: 302, 'H NMR (400 MHz, CDCh) 8 8.91 (d, J=2.0 Hz, 1H), 8.51 (s, 1H), 7.61 - 7.54 (m, 2H), 7.47 - 7.39 (m, 2H), 7.05 (d, J=2.3 Hz, 1H), 6.33 - 6.28 (m, 1H), 5.37 (s, 2H), 5.27 (s, 2H). Synthesis of 3-(4-(((6-chloropyridazin-4-yl)oxy)methyl)henzyl)-l-methylpyridin-2(IH)-one
Figure imgf000291_0001
[0673] A stirred solution of 3-(4-(hydroxymethyl)benzyl)-l-methylpyridin-2(l//)-one (100 mg, 0.44 mmol) and 3,5-dichloropyridazine (71 mg, 0.48 mmol) in DMF (1.5 mL) was placed under N2 and cooled to 0 °C. NaH (60% in mineral oil, 18 mg, 0.46 mmol) was added portionwise and the reaction mixture stirred at 0 °C for 30 min. The reaction mixture was diluted with water (2 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 1-10% MeOH in DCM to give the title compound (70 mg, 47%) as a yellow solid. ESI-MS (M+H)+: 342.0. 1 H NMR (400 MHz, DMSO) 5 9.04 (d, J=2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.58 (dd, J=2.1, 6.7 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.24 (dd, J=1.9, 6.7 Hz, 1H), 6.18 - 6.14 (m, 1H), 5.26 (s, 2H), 3.76 (s, 2H), 3.43 (s, 3H).
Example 1
Synthesis ofN-((l-aniino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methylisoquinolin-3- yl)methyl)-lH-pyrazole-4-carboxamide (1-1 )
Figure imgf000291_0002
[0674] Synthesis of 3-(chloromethyl)-6-methylisoquinoline. To a solution of (6- methylisoquinolin-3-yl)methanol (20 mg, 0.12 mmol) in dry DCM (4 mL) was added SOCh (0.5 mL) slowly at 0 °C, and the resulting reaction mixture was stirred at room temperature for 2 h.
Then the mixture was concentrated in vacuo to give the crude (20 mg, crude), which was used in the next step without further purification. ESI-MS [M +H]+: 192.1.
[0675] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6- methylisoquinolin-3-yl)niethyl)-lH-pyrazole-4-c(irboxamide. A mixture of 3-(chloromethyl)-6- methylisoquinoline (20 mg, crude), N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (44 mg, 0.15 mmol), and CsiCCh (82 mg, 0.25 mmol) in DMF (2 mL) was stirred at 45 °C for 4 h. Water (10 mL) was added, and the reaction was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over NaiSCL, and concentrated in vacuo to give the residue, which was purified by Prep-TLC (DCM:MeOH=10:l) to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6- methylisoquinolin-3-yl)methyl)-lH-pyrazole-4-carboxamide (13 mg, 24% over 2 steps) as a white solid. ESLMS [M +H]+: 451.3. 1H NMR (400 MHz, DMSO) S9.19 (s, 1H), 8.34 (s, 1H), 8.13 (t, J=4.4, 1H), 8.00 (d, J=8.4, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.74 (d, J=6.2, 1H), 7.70 (s, 1H), 7.51 (m, 2H), 7.01 (d, J=6.2, 1H), 6.79 (s, 2H), 5.52 (s, 2H), 4.59 (d, J=4.5, 2H), 3.30 (s, 3H), 2.52 (s, 6H).
[0676] Using a similar procedure to that used for synthesis ofN-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-((6-methylisoquinolin-3-yl)methyl)-lH-pyrazole-4- carboxamide, the compounds in Table 11 were prepared using an appropriate coupling alcohol.
Table 11
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0002
Example 128
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N-methyl-l-((6- methylinudazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxanude (1-128).
Figure imgf000323_0001
[0677] Synthesis of di-tert-butyl (5, 7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2- yl)niethyl)-lH-pyrazole-4-carboxamido)methyl)isoquinolin-l-yl)iminodicarbonate. A mixture of N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (100 mg, 0.23 mmol), BOC2O (149 mg, 0.69 mmol), TEA (232 mg, 2.3 mmol), and DMAP (3 mg, 0.023 mmol) in DMF (5 mL) was stirred at room temperature for 12 h. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SOr, and concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 20/1) to give di-tert-butyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamido)methyl)isoquinolin-l-yl)iminodicarbonate (50 mg, 34%) as a yellow solid. ESLMS [M +H]+: 640.1
[0678] Synthesis of di-tert-butyl (5, 7-dimethyl-6-((N-methyl-l-((6-methylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamido)niethyl)isoquinolin-l-yl)inunodicarbonate. To a solution of di-tert-butyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-4-carboxamido)methyl)isoquinolin-l-yl)iminodicarbonate (50 mg, 0.078 mmol) in THF (4 mL) was added NaH (6.4 mg, 0.16 mmol, 60% dispersion in mineral oil) at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. Then a solution of Mel (42 mg, 0.3 mmol) in THF (1 mL) was added thereto, and the reaction was stirred at room temperature for 3 h. The reaction was quenched with NH4CI (sat. aq., 15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 25 / 1) to give di-tert-butyl (5,7-dimethyl-6-((N-methyl-l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-4-carboxamido)methyl)isoquinolin-l-yl)iminodicarbonate (23 mg, 45%) as a yellow solid. ESI-MS [M +H]+: 654.3
[0679] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)-N-methyl-l-((6- methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide. To a solution of di- tert-butyl (5,7-dimethyl-6-((N-methyl-l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH- pyrazole-4-carboxamido)methyl)isoquinolin-l-yl)iminodicarbonate (23 mg, 0.035 mmol) in 1,4- di oxane (2 mL) was added HC1 (0.5 mL, 4 M solution in 1,4-dioxane). The reaction mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo to give the crude, which was purified with Prep-HPLC to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)- N-methyl-l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (8 mg, 50%) as a white solid. ESI-MS [M +H]+: 454.2. 1H NMR (400 MHz, DMSO) 8 8.32 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.80 - 7.75 (m, 3H), 7.41 (d, J = 9.2 Hz, 1H), 7.10 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 6.1 Hz, 1H), 6.88 (s, 2H), 5.43 (s, 2H), 4.92 (s, 2H), 2.47 (s, 6H), 2.41 (s, 3H), 2.25 (s, 3H).
Example 129
Synthesis of 2-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-
Figure imgf000324_0001
[0680] To a solution of methyl 2-(4-(((l -amino-5,7-dimethylisoquinolin-6- yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2-(6-methylimidazo[l,2-a]pyridin-2-yl)acetate (20 mg, 0.04 mmol) in THF/H2O (3 mL/lmL) was added LiOH-H2O( 5 mg , 0.12 mmol). The mixture was stirred at room temperature for 2 h. Water (10 mL) was added, and pH of the reaction mixture was adjusted to 6 by adding HC1 (IM aq.). The reaction was then extracted with DCM/MeOH (10: 1, 3 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to the residue, which was purified by Prep-TLC (DCM/MeOH=10/l) to give 2-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2-(6- methylimidazo[l,2-a]pyridin-2-yl)acetic acid (5 mg, yield: 26%) as a white solid . ESI-MS [M +H]+: 484.1. 1H NMR (400 MHz, DMSO-d6) 8 13.43 (s, 1H), 9.05 (s, 2H), 8.50 (s, 1H), 8.33 (m, 3H), 8.15 (s, 1H), 7.94 (s, 1H), 7.63 (dd, J = 25.1, 7.9 Hz, 2H), 7.34 (m, 2H), 6.65 (s, 1H), 4.62 (d, J = 4.2 Hz, 2H), 2.58 (s, 3H), 2.54 (s, 3H), 2.31 (s, 3H).
Example 130
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(2-hydroxy-l-(6-
Figure imgf000325_0001
[0681] To a solution of methyl 2-(4-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)carbamoyl)- IH-pyrazol- 1 -yl)-2-(6-methylimidazo[ 1 ,2-a]pyridin-2-yl)acetate (25 mg, 0.05 mmol) in MeOH (3 mL) was added NaBHi (6 mg , 0.15 mmol). The mixture was stirred at room temperature for 2 h. Water (10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to afford the residue, which was purified by Prep-TLC (DCM/MeOH=10/l) to give N- ((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(2-hydroxy-l-(6-methylimidazo[l,2- a]pyridin-2-yl)ethyl)-lH-pyrazole-4-carboxamide(17 mg, yield: 72%) as white solid . ESI-MS [M +H]+: 470.2. 1HNMR (400 MHz, DMSO) 8 8.34 (s, 1H), 8.28 (s, 1H), 8.08 (t, J = 4.5 Hz, 1H), 7. 90 (s, 1H), 7. 88 (s, 1H),7.76 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.08 (m, 1H), 6.99 (d, J = 6.2 Hz, 1H), 6.63 (s, 2H), 5.53 (m, 1H), 5.15 (s, 1H), 4.58 (d, J = 4.5 Hz, 2H), 4.09 (m, 2H), 2.49 (s, 6H), 2.23 (s, 3H). Example 131
Synthesis of 2-(4-((4-(((l-anuno-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-
1-y I) methyl)phenyl) acetic acid (1-131)
Figure imgf000326_0001
[0682] To a solution of methyl 2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)phenyl)acetate (15 mg, 0.03 mmol) in MeOH (1 mL) was added LiOH-HiO (6.3 mg, 0.15 mmol), and the mixture was stirred at room temperature for 5 h. pH of the reaction was adjusted to 5 with IM HC1, then concentrated and purified by Prep-TLC (DCM/MeOH=10/l) to give 2-(4-((4-(((l-amino-5,7-dimethylisoquinolin- 6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)phenyl)acetic acid (10 mg, yield: 75%) as a white solid. ESI-MS [M +H]+: 444.2. 1H NMR (400 MHz, DMSO) 5 13.15 (s, 1H), 8.48 (s,58 2H), 8.25 (s, 1H), 8.22 - 8.20 (m, 2H), 7.87 (s, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.20 (q, J = 8.2 Hz, 4H), 5.29 (s, 2H), 4.61 (d, J = 4.7 Hz, 2H), 3.53 (s, 2H), 2.58 (s, 3H), 2.55 (s, 3H).
Example 132
Synthesis of ethyl (6-((l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamido)niethyl)-
5, 7-dimethylisoquinolin-l-yl)carbamate (1-132)
Figure imgf000326_0002
[0683] To a solution of N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (250 mg, 0.53 mmol) in NaHCCh (sat. aq., 5 mL)/THF (5 mL) was added ethyl chlorofomate (173 mg, 1.6 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with H2O (25 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give ethyl (6-((l-((3-chloroquinolin-6- yl)methyl)-lH-pyrazole-4-carboxamido)methyl)-5,7-dimethylisoquinolin-l-yl)carbamate (35 mg, 12%) as a white solid. ESI-MS [M +H]+: 543.2. 1H NMR (400 MHz, MeOD) S 8.72 (d, J = 2.0 Hz, 1H), 8.29 - 8.28 (m, 2H), 8.00 - 7.95 (m, 3H), 7.83 (s, 1H), 7.73 (s, 1H), 7.64-7.62 (m, 2H), 5.54 (s, 2H), 4.77 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.65 (s, 3H), 2.55 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
Example 133
Synthesis ofN-((l-acetamido-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6- yl)methyl)-lH-pyrazole-4-carboxamide (1-133)
Figure imgf000327_0001
[0684] A mixture of N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (50 mg, 0.11 mmol) and AC2O (22 mg, 0.22 mmol) in pyridine (2 mL) was stirred at room temperature for 5h. The reaction was concentrated in vacuo to give the crude, which was purified with Prep-HPLC to give N-((l- acetamido-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (15 mg, 27%) as a white solid. ESI-MS [M +H]+: 513.2. 1H NMR (400 MHz, MeOD) 5 8.77 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 7.7 Hz, 2H), 7.98 (d, J = 10.1 Hz, 2H), 7.85 (d, J = 6.1 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.64 (dd, J = 8.7, 1.8 Hz, 1H), 5.54 (s, 2H), 4.79 (s, 2H), 2.70 (s, 3H), 2.60 (s, 3H), 2.28 (s, 3H).
Example 134
Synthesis of l-((6-cyclopropylinudazo[l,2-a]pyridin-2-yl)methyl)-N-((5, 7-dimethyl-l- (methylanuno)isoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-134).
Figure imgf000328_0001
[0685] Synthesis of (Z)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-N-((l-
(((dimethylamino)methylene)amino)-5, 7-dimethyUsoquinolin-6-yl)methyl)-lH-pyrazole-4- carboxamide. A mixture of N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (108 mg, 0.23 mmol) and 1,1 -dimethoxy -N,N-dimethylmethanamine (214 mg, 1.8 mmol) in DMF (3 mL) was stirred at 50 °C for 2 h. The mixture was cooled to room temperature and used in next step without purification.
[0686] Synthesis of l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-N-((5, 7-dimethyl- l-(methylamino)isoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide. NaBHi (43.7 mg, 1.15 mmol) was added to the above solution. After stirring at 50 °C for 3h, the mixture was cooled to room temperature and diluted with H2O (20 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated in vacuo to give the residue, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to afford l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-N-((5,7-dimethyl-l-(methylamino)isoquinolin-6- yl)methyl)-lH-pyrazole-4-carboxamide (7 mg, 6% over 2 steps) as a white solid. ESI-MS [M +H]+: 480.2. 1H NMR (400 MHz, DMSO) 5 8.32 (s, 1H), 8.23 (s, 1H), 8.11 - 8.09 (m, 1H), 7.87 - 7.83 (m, 3H), 7.72 (s, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 4.1 Hz, 1H), 6.99 - 6.94 (m, 2H), 5.36 (s, 2H), 4.56 (d, J = 3.8 Hz, 2H), 2.93 (d, J = 3.7 Hz, 3H), 2.48 (s, 6H), 1.92 - 1.88 (m, 1H), 0.91 - 0.89 (m, 2H), 0.66 - 0.64 (m, 2H).
Example 135
Synthesis ofN-((l-aniino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-7- methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-135)
Figure imgf000329_0001
[0687] Synthesis of 6-bromo-2-(chloromethyl)-7-methylimidazo[l,2-a]pyridine. A mixture of 5-bromo-4-methylpyridin-2-amine (1.0 g, 5.4 mmol) and l,3-dichloropropan-2-one (1.36 g, 10.8 mmol) in EtOH (30 mL) was stirred at 95 °C for 14 h. After cooled to room temperature, NaHCOr (sat. aq., 50 mL) was added, the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over sodium sulfate, fdtered and concentrated to give the crude, which was purified by silica gel chromatography (PE/EtOAc = 1/1) to give the 6-bromo- 2-(chloromethyl)-7-methylimidazo[l,2-a]pyridine (500 mg, yield: 36%) as a yellow oil. ESLMS [M +H]+: 259.2.
[0688] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo- 7- methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide. To a solution of 6- bromo-2-(chloromethyl)-7-methylimidazo[l,2-a]pyridine (103 mg, 0.4 mmol) in DMF (10 mL) was added N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (177 mg, 0.6 mmol) and CS2CO3 (391 mg, 1.2 mmol). The mixture was stirred at 40°C for 8 h. Water (50 mL) was added to the reaction and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by silica gel chromatography (DCM/MeOH = 10/1) to give the N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-7-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH- pyrazole-4-carboxamide (35 mg, yield: 17%) as a white solid. ESLMS [M +H]+: 518.1. 1H NMR (400 MHz, DMSO) 5 8.88 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.11-8.08 (m, 1H), 7.89-7.87 (m, 2H), 7.80 - 7.64 (m, 2H), 7.49 (s, 1H), 6.98 (d, J = 6.1 Hz, 1H), 6.62 (s, 2H), 5.39 (s, 2H), 4.57 (d, J = 4.4 Hz, 2H), 2.48 (s, 6H), 2.35 (s, 3H).
[0689] Using a similar procedure to that used for synthesis of N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-7-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH- pyrazole-4-carboxamide, the compounds in Table 12 were prepared using an appropriate intermediate. Table 12
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0002
Example 150
Synthesis of l-((l,5-naphthyridin-2-yl)methyl)-N-((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)-lH-pyrazole-4-carboxamide (1-150)
Figure imgf000333_0001
[0690] Synthesis of 2-(chloromethyl)-l,5-naphthyridine. A mixture of 2-methyLl,5- naphthyridine (406 mg, 2.82 mmol), NBS (602 mg, 3.38 mmol), BPO (68 mg, 0.28 mmol) in CCh(10 mL) was stirred at 100 °C for 16 h. After cooled to room temperature, water (20 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (PE/EtOAc=4/l) to give the 2-(chloromethyl)-l,5-naphthyridine (400 mg, yield: 80%) as a yellow oil. ESLMS [M +H] +: 179.2.
[0691] Synthesis of l-((l,5-naphthyridin-2-yl)methyl)-N-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-c(irboxamide. A mixture of 2-(chloromethyl)- 1,5-naphthyridine (21 mg, 0.12 mmol), N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (35 mg, 0.12 mmol) and CS2CO3 (78 mg, 0.24 mmol) in DMF (3 mL) was stirred at 45 °C for 4 h. Then water (20 mL) was added and extracted by EtOAc (20 mL x 3), the combined organic layers were washed with brine, dried over Na2SO-i and concentrated to give the residue, which was purified by Prep-TLC (DCM: MeOH=10:l) to give l-((l,5-naphthyridin- 2-yl)methyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (15 mg, 29%) as a white solid. ESLMS [M +H]+: 438.2. 1H NMR (400 MHz, DMSO) 5 8.99 (dd, J = 4.1, 1.6 Hz, 1H), 8.43 - 8.37 (m, 3H), 8.16 (t, J = 4.6 Hz, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.79 (dd, J = 8.5, 4.1 Hz, 1H), 7.75 (d, J = 6.2 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 6.3 Hz, 1H), 6.81 (s, 2H), 5.68 (s, 2H), 4.60 (d, J = 4.6 Hz, 2H), 2.53 (s, 6H).
[0692] Using a similar procedure to that used for synthesis of l-((l,5-naphthyridin-2- yl)methyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide, the compounds in Table 13 were prepared using an appropriate intermediate.
Table 13
Figure imgf000334_0001
Figure imgf000335_0002
Example 154
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(2-oxo-2- (phenylamino)ethyl)-lH-pyrazole-4-carboxamide (1-154)
Figure imgf000335_0001
[0693] Synthesis of 2-bromo-N-phenylacetamide. To a solution of aniline (500 mg, 5.37 mmol) in DCM (20 mL) was added to 2-bromoacetyl bromide (1.07 g, 5.37 mmol) and TEA (1.08 g, 10.7 mmol). Then the mixture was stirred at room temperature for 16 h. Water (50 mL) was added, extracted with DCM (30 mL x 3). The combined organic layers were dried with NaiSOi, concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 20-50% EtOAc in PE to give the 2-bromo-N-phenylacetamide (700 mg, 61%) as a yellow solid. ESI-MS [M +H]+: 214.2.
[0694] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(2-oxo-2-
(phenylamino)ethyl)-lH-pyrazole-4-carboxamide. A mixture of 2-bromo-N-phenylacetamide (85 mg, 0.4 mmol), N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4- carboxamide (177 mg, 0.6 mmol) and CS2CO3 (391 mg, 1.2 mmol) in DMF (5 mL) was stirred at room temperature for 12 h. Water (30 mL) was added, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel (DCM/MeOH=10/l) to give the N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(2-oxo-2-(phenylamino)ethyl)- lH-pyrazole-4-carboxamide (45 mg, yield: 26%) as a white solid. ESI-MS [M +H]+: 429.2. 1H NMR (400 MHz, DMSO) 5 10.32 (s, 1H), 8.23 (s, 1H), 8.15 (t, J = 4.6 Hz, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.73 (d, J = 6.3 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.05 (t, J = 7.3 Hz, 2H), 6.97 (s, 2H), 5.01 (s, 2H), 4.60 (d, J = 4.6 Hz, 2H), 2.53 (s, 3H), 2.50 (s, 3H).
[0695] Using a similar procedure to that used for synthesis of N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-(2-oxo-2-(phenylamino)ethyl)-lH-pyrazole-4-carboxamide, the compounds in Table 14 were prepared using an appropriate intermediate.
Table 14
Figure imgf000336_0001
Example 156
Synthesis ofN-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((7-bromoquinolin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-156)
Figure imgf000337_0001
[0696] Synthesis of 7-bromo-2-(chloromethyl)quinolone. A mixture of 7-bromo-2- methylquinoline (100 mg, 0.45 mmol), TBAI (166 mg, 0.45 mmol), Urea (27 mg, 0.45 mmol) in 1,2-di chloroethane (3 mL) was stirred at 110°C for 30 min under microwave irradiation. The reaction was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 0-10% EtOAc/PE to afford 7-bromo-2-(chloromethyl)quinoline (70 mg, yield 61%) as a white solid. ESI-MS [M +H]+: 256.2.
[0697] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)-l-((7- bromoquinolin-2-yl)niethyl)-lH-pyrazole-4-carboxamide. CS2CO3 (263 mg, 0.81 mmol) was added to a mixture of 7-bromo-2-(chloromethyl)quinoline (70 mg, 0.27 mmol) and N-((l-amino- 5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (95 mg, 0.32 mmol) in DMF (4 mL). The mixture was stirred at room temperature for 12 h. Water (20 mL) was added, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 12/1) to afford N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((7- bromoquinolin-2-yl)methyl)-lH-pyrazole-4-carboxamide (13.6 mg, yield: 10%) as a white solid. ESLMS [M +H]+: 515.1. 1H NMR (400 MHz, DMSO) 5 8.40 - 8.38 (m, 2H), 8.20 - 8.13 (m, 2H), 7.96 - 7.86 (m, 3H), 7.76 - 7.66 (m, 2H), 7.26 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 6.1 Hz, 1H), 6.74 (s, 2H), 5.63 (s, 2H), 4.60 (d, J = 4.3 Hz, 2H), 2.53 (s, 6H).
[0698] Using a similar procedure to that used for synthesis ofN-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-((7-bromoquinolin-2-yl)methyl)-lH-pyrazole-4- carboxamide, the compounds in Table 15 were prepared using an appropriate intermediate. Table 15
Figure imgf000338_0001
Example 160
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4- carboxamide (1-160)
Figure imgf000339_0001
[0699] DIPEA (0.62 mmol, 0.11 mL) was added to a mixture of l-benzyl-lH-pyrazole-4- carboxylic acid (0.25 mmol, 0.050 g), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (0.25 mmol, 0.050 g) and HATU (0.26 mmol, 0.099 g) in DMF (2.0 mL). The mixture was stirred at room temperature for 18h then concentrated in vacuo. The residue was dissolved in a mixture of water (10 mL) and NaHCCh (sat. aq., 10 mL). The mixture was extracted with EtOAc ( 2 x 20 mL) and then DCM (20 mL). The combined organics were dried over MgSCU, fdtered then concentrated in vacuo. The residue was purified by reversed-phase preparative HPLC to give the title compound as a cream solid (34 mg, 36%). ESLMS (M+H)+: 386.2, 'H NMR (400 MHz, MeOD) 8 8.43 (s, 1H), 8.12 (s, 1H), 8.06 (s, 0.75H), 7.92 (d, J=0.7 Hz, 1H), 7.58 (d, J=7.1 Hz, 1H), 7.37 - 7.28 (m, 4H), 7.27 - 7.23 (m, 2H), 5.33 (s, 2H), 4.78 (s, 2H), 2.66 (s, 3H), 2.63 (s, 3H). Exchangable protons not observed.
[0700] The compounds in Table 16 were prepared in a similar manner to N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l -benzyl- lH-pyrazole-4-carboxamide from 6-(aminomethyl)- 5,7-dimethylisoquinolin-l -amine or 6-(aminomethyl)-5,7,8-trimethylisoquinolin-l-amine and the indicated coupling partner.
Table 16
Figure imgf000339_0002
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0002
Example 171
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4-
Figure imgf000343_0001
[0701] Synthesis of l-benzyl-lH-pyrazole-4-carboxylic acid To a solution of ethyl 1- benzyl-lH-pyrazole-4-carboxylate (160 mg, 0.69 mmol) in MeOH (3 mL), THF (3 mL) and water (3 mL) was added LiOH-FLO (1 15 mg, 2.8 mmol). The mixture was stirred at 40 °C for 2 h. The solvent was removed, and the residue was diluted with water (15 mL), the pH of the solution was adjusted to ~4-5 by HC1 (1 M aq.) and extracted by EtOAc (30 mL x 3). The combined organic layers were dried over NaiSCL, concentrated to give 1 -benzyl- lH-pyrazole-4- carboxylic acid (130 mg, crude) as a white solid. ESLMS [M +H]+: 203.1.
[0702] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-benzyl-lH- pyrazole-4-carboxamide. A mixture of 1 -benzyl- lH-pyrazole-4-carboxylic acid (40 mg, crude), HATU (95 mg, 0.25 mmol) and DIPEA (81 mg, 0.63 mmol) in DMF (4 mL) was stirred at room temperature for 10 min. 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (20 mg, 0.10 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine (40 mL x 3), dried over Na2SO-i, concentrated to give the crude product, which was purified by Prep-TLC (DCM/MeOH = 10/1) to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l- benzyl-lH-pyrazole-4-carboxamide (13 mg, yield: 15% over 2 steps) as a yellow solid. ESLMS [M +H]+: 386.2. 1H NMR (400 MHz, DMSO) S 8.27 (d, J = 0.5 Hz, 1H), 8.09 (t, J = 4.6 Hz, 1H), 7.93 - 7.87 (m, 2H), 7.76 (d, J = 6.1 Hz, 1H), 7.39 - 7.26 (m, 3H), 7.26 - 7.21 (m, 2H), 6.98 (d, J = 6.1 Hz, 1H), 6.60 (s, 2H), 5.31 (s, 2H), 4.57 (d, J = 4.7 Hz, 2H), 2.49 (s, 3H), 2.48 (s, 3H).
[0703] Using a similar procedure to that used for the synthesis of N-((l-amino-7-ethyl-5- methylisoquinolin-6-yl)methyl)-l -benzyl- lH-pyrazole-4-carboxamide, the compounds in Table 17 were prepared using an appropriate intermediate.
Table 17
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0002
Example 204
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2- ((cyclopropylmethyl)(methyl)amino)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-204).
Figure imgf000354_0001
[0704] Synthesis of benzyl lH-pyrazole-4-carboxylate. To a solution of lH-pyrazole-4- carboxylic acid (2 g, 17.9 mmol) in DMF (800 mL) was added (bromomethyl)benzene (4.6 g, 26.9 mmol) and Cs2CO3 (17.5 g, 53.7 mmol) at room temperature. The resulting reaction was stirred at RT for 6 h. The solution was quenched with H2O (250 ml) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 50% EtOAc in PE to give the benzyl lH-pyrazole-4- carboxylate (1.2 g, yield :33%) as a light yellow solid. ESLMS [M +H]+: 203.2.
[0705] Synthesis of benzyl l-(4-(2-ethoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylate.
To a solution of benzyl lH-pyrazole-4-carboxylate (606 mg, 3.0 mmol) in THF (30 mL) was added ethyl 2-(4-(hydroxymethyl)phenyl)acetate (873 mg, 4.5 mmol) and PPh; (1.18 g, 4.5 mmol) and DEAD (783 mg, 4.5 mmol) at 0°C under nitrogen. The resulting reaction was stirred at room temperature for 8 h. Water (100 mL) was added to the reaction, extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (PE/EtOAc = 5/1) to give benzyl l-(4-(2-ethoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylate (600 mg, yield: 53%) as a white solid. ESI-MS [M +H]+: 379.2.
[0706] Synthesis of l-(4-(2-ethoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylic acid. To a solution of benzyl l-(4-(2-ethoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylate (455 mg, 1.2 mmol) in MeOH (20 mL) was added Pd/C(60 mg ) at room temperature under H2(g) . The resulting reaction was stirred at RT for 6 h. The solution was filtered through celite, the filter cake was washed with MeOH (20 mL) and the filtrate was concentrated in vacuo to give l-(4-(2- ethoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylic acid (460 mg, crude) as a light yellow solid. ESI-MS [M +H]+: 289.2.
[0707] Synthesis of ethyl 2-(4-((4-(((l-amino-5, 7-dimethylisoquinolin-6- yl)niethyl)carbamoyl)-lH-pyrazol-l-yl)methyl)phenyl)acetate. To a solution of l-(4-(2-ethoxy- 2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylic acid (460 mg, crude) in DMF (15 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine(361 mg, 1.8 mmol), HATU (684 mg, 1.8 mmol) and DIPEA (464 mg, 3.6 mmol). Then the mixture was stirred at room temperature for 12 h. H2O (50 mL) was added to the reaction, extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (DMC/MeOH = 10/1) to give ethyl 2-(4-((4-(((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)phenyl)acetate (300 mg, yield: 53 % over 2 steps) as a white solid. ESI-MS [M +H]+: 472.2.
[0708] Synthesis of 2-(4-((4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)- lH-pyrazol-l-yl)methyl)phenyl)acetic acid To a solution of ethyl 2-(4-((4-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)phenyl)acetate (283 mg, 0.6 mmol) in THF (10 mL) and water (10 mL) was added LiOH-H2O (123 mg, 3.0 mmol). The mixture was stirred at room temperature for 6 hours. THF was concentrated and pH of the aqueous layer was adjusted to 3 by 1 N HC1 and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 2- (4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetic acid (250 mg, crude). ESI-MS [M +H]+: 444.2. [0709] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-
((cyclopropyhnethyl)(methyl)amino)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide. A mixture of 2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetic acid (250 mg, crude), 1-cyclopropyl-N-methylmethanamine (77 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol) and DIPEA (232 mg, 1.8 mmol) in DMF (10 mL) was stirred at room temperature for 8 h. Water (40 mL) was added to the reaction, extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (DCM/MeOH = 10/1) to give N- ((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((cyclopropylmethyl)(methyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (120 mg, yield: 39 % over 2 steps) as a white solid. ESI-MS [M +H]+: 511.3. 1H NMR (400 MHz, DMSO) 5 8.25 (d, J = 5.8 Hz, 1H), 8.12 (d, J = 17.3 Hz, 1H), 7.90 (d, J = 19.6 Hz, 2H), 7.74 (d, J = 6.2 Hz, 1H), 7.16 (d, J = 8.9 Hz, 4H), 7.01 (d, J = 6.3 Hz, 1H), 6.81 (s, 2H), 5.28 (s, 2H), 4.57 (d, J = 4.5 Hz, 2H), 3.65 (d, J = 3.0 Hz, 2H), 3.21 - 3.07 (m, 2H), 2.98 (d, J = 12.9 Hz, 2H), 2.82 (d, J = 19.5 Hz, 1H), 2.50 (t, J = 4.0 Hz, 6H), 0.88 (dd, J = 12.7, 7.1 Hz, 1H), 0.41 (td, J = 13.9, 5.6 Hz, 2H), 0.17 (d, J = 4.7 Hz, 2H). [0710] Using a similar procedure to that used for the synthesis of N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((cyclopropylmethyl)(methyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide, the compounds in Table 18 were prepared using the appropriate reagent.
Table 18
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000364_0001
Example 233
Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(naphthalen-2- ylmethyl)pyrimidine-4, 6-diamine (1-233).
Figure imgf000365_0001
[0711] Synthesis of 6-chloro-N-(naphthalen-2-ylmethyl)pyrimidin-4-amine. A mixture of
4,6-dichloropyrimidine (200 mg, 1.35 mmol), naphthalen-2-ylmethanamine (212 mg, 1.35 mmol) and DIPEA (348 mg, 2.7 mmol) in /-PrOH (10 mL) was stirred at 100 °C for 16 h. The mixture was cooled to room temperature and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give 6-chloro-N-(naphthalen-2- ylmethyl)pyrimidin-4-amine (100 mg, yield: 27%) as a white solid. ESI-MS [M +H]+: 270.2. [0712] Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(naphthalen-2- ylmethyl)pyrimidine-4,6-dian ne. A mixture of 6-chloro-N-(naphthalen-2-ylmethyl)pyrimidin- 4-amine (73 mg, 0.27 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (54 mg, 0.27 mmol), Pd-PEPPSI-IPent'cl o-picoline (25 mg, 0.03 mmol) and CS2CO3 (264 mg, 0.81 mmol) in DMF (5 mL) was stirred at 80 °C for 3 h under N2. The reaction mixture was cooled to room temperature. The mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 30 mL). The filtrate was concentrated to give the crude, which was purified by Prep-HPLC to give N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(naphthalen-2- ylmethyl)pyrimidine-4, 6-diamine (15 mg, yield: 13%) as a white solid. ESI-MS [M +H]+: 435.3. 1H NMR (400 MHz, DMSO) 8 8.11 (s, 1H), 8.00 - 7.92 (m, 4H), 7.84 (d, J - 6.2 Hz, 2H), 7.60 - 7.53 (m, 3H), 7.35 (d, J = 6.1 Hz, 1H), 7.06 (d, J = 6.1 Hz, 1H), 6.79 - 6.69 (m, 3H), 5.59 (s, 1H), 4.62 (s, 4H), 2.57 (s, 3H), 2.53 (s, 3H). [0713] Using a similar procedure to that used for the synthesis of N4-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-N6-(naphthalen-2-ylmethyl)pyrimidine-4,6-diamine, the compounds in Table 19 were prepared using an appropriate intermediate.
Table 19
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001
Figure imgf000369_0001
Figure imgf000370_0002
Example 247
Synthesis of N- ( 6, 8-dimethyl- 7-(((6-((4-( (2-oxopyridin-l (2H)~ yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-l-yl)acetanude (1-247).
Figure imgf000370_0001
[0714] To a solution of l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzyl)pyridin-2(lH)-one (50 mg, 0.1 mmol) in pyridine (2 mL) was added acetic anhydride (21 mg, 0.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h under N2. The reaction was diluted with H2O (20 mL) and extracted with DCM/MeOH (10/1, 20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SOr, and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH=10/l) to give N-(6,8-dimethyL7-(((6-((4-((2- oxopyridin-l(2H)-yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-l- yl)acetamide (9.3 mg, yield: 17%) as a white solid. ESLMS [M +H]+: 534.3. 1H NMR (400 MHz, DMSO) 8 10.33 (s, 1H), 8.26 (d, J = 5.8 Hz, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.79-7.71 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 7.23-7.20 (m, 4H), 7.13 (s, 1H), 6.73 (s, 1H), 6.39 (d, J = 9.2 Hz, 1H), 6.21 (t, J = 6.6 Hz, 1H), 5.43 (s, 1H), 5.04 (s, 2H), 4.58 (s, 2H), 4.32 (s, 2H), 2.61 (s, 3H), 2.51 (s, 3H), 2.17 (s, 3H). Example 248
Synthesis of benzyl (6,8-dimethyl- 7-(((6-((4-((2-oxopyridin-l (2H)~ yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-l-yl)carbamate (1-248).
Figure imgf000371_0001
[0715] To a mixture of l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzyl)pyridin-2(lH)-one (60 mg, 0.12 mmol) in DMF (3 mL) was added DIPEA (46 mg, 0.36 mmol), then CbzCI (18.8 mg, 0.11 mmol) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h under N2. The reaction was diluted with H2O (20 mL) and extracted with DCM/MeOH (10/1, 20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH=10/l) to give benzyl (6,8-dimethyl-7-(((6-((4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-l-yl)carbamate (4 mg, yield: 5%) as a yellow solid. ESLMS [M +H]+: 626.2. 1H NMR (400 MHz, DMSO) 8 10.07 (s, 1H), 8.25 (d, J = 5.9 Hz, 1H), 8.00 (s, 1H), 7.77-7.74 (m, 3H), 7.46-7.35 (m, 1H), 7.25-7.20 (m, 4H), 7.12 (t, J = 6.0 Hz, 1H), 6.71 (s, 1H), 6.39 (d, J = 9.2 Hz, 1H), 6.21 (t, J = 6.7 Hz, 1H), 5.42 (s, 1H), 5.17 (d, J = 6.3 Hz, 2H), 5.04 (s, 2H), 4.58 (s, 2H), 4.33 (s, 2H), 2.61 (s, 3H), 2.47 (s, 3H).
Example 249
Synthesis of ethyl (5,7-dimethyl-6-(((6-((4-((2-oxopyridin-l(2H)~
Figure imgf000371_0002
[0716] To a mixture of l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzyl)pyridin-2(lH)-one (70 mg, 0.14 mmol) in DMF (1 mL) and THF (2 mL) was added TEA (43 mg, 0.43 mmol), followed by ethyl chloroformate (15 mg, 0.14 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h under N2. The reaction was diluted with H2O (20 mL) and extracted with DCM/MeOH (10/1, 20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give the crude, which was purified by Prep- TLC (eluent: DCM/MeOH=10/l) to give ethyl (5,7-dimethyl-6-(((6-((4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-l-yl)carbamate (18.8 mg, yield: 24%) as a yellow solid. ESLMS [M +H]+: 564.2. 1H NMR (400 MHz, DMSO) 5 9.89 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.76 - 7.72 (m, 3H), 7.40 (t, J = 7.6 Hz, 1H), 7.23-7.21 (m, 4H), 7.16 (s, 1H), 6.75 (s, 1H), 6.39 (d, J = 9.3 Hz, 1H), 6.21 (t, J = 6.7 Hz, 1H), 5.43 (s, 1H), 5.04 (s, 2H), 4.58 (s, 2H), 4.33 (s, 2H), 4.13 (m, 2H), 2.61 (s, 3H), 2.52 (s, 3H), 1.24 (s, 3H).
Example 250
Synthesis of 3-(2-(((6-(((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)amino)pyrinudin-4- yl)oxy)methyl)-6-cyclopropylimidazo[I,2-a]pyridin-8-yl)oxetan-3-ol (1-250).
Figure imgf000372_0001
[0717] Synthesis of 3-(2-(((6-chloropyriniidin-4-yI)oxy)niethyl)-6-cyclopropylimidazo[l, 2- a]pyridin-8-yl)oxetan-3-ol. To a solution of 3-(6-cyclopropyl-2-(hydroxymethyl)imidazo[l,2- a]pyridin-8-yl)oxetan-3-ol (25 mg, 0.096 mmol) in DMF (3 mL) was added 4,6- dichloropyrimidine (16 mg, 0.11 mmol) and Cs2CO3(94 mg, 0.29 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. H2O (30 mL) was added to the reaction, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH = 10/1) to give the 3-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)- 6-cyclopropylimidazo[l,2-a]pyridin-8-yl)oxetan-3-ol (20 mg, yield: 56%) as a yellow solid. ESIMS [M +H]+: 373.2.
[0718] Synthesis of 3-(2-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[l,2-a]pyridin-8-yl)oxetan- 3-o1. CS2CO3 (39 mg, 0. 12 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (10 mg, 0.05mmol) and Pd-PEPSI-IPENTcl-o-picoline(4 mg, 0.005 mmol) were added to a solution of 3- (2-(((6-chloropyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[l,2-a]pyridin-8-yl)oxetan-3-ol (20 mg, 0.054 mmol) in DMF (5 mL) at room temperature under nitrogen. The mixture was stirred at 85 °C for 16 h. After cooled to room temperature, the reaction mixture was diluted with H2O (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH = 10/1) to give 3-(2-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[l,2- a]pyridin-8-yl)oxetan-3-ol (5 mg, yield: 17%) as a white solid. ESLMS [M +H]+: 538.2. 1H NMR (400 MHz, DMSO) 8 8.33-8.29 (m, 2H), 7.91 (s, 1H), 7.85 (s, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.23 (t, J = 4.3 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.99 (d, J = 6.4 Hz, 1H), 6.62 (s, 2H), 6.46 (s, 1H), 5.89-5.86 (m, 1H), 5.39-5.34 (m , 2H), 5.24 (d, J = 6.5 Hz, 2H), 4.71 - 4.54 (m, 4H), 2.48-2.42 (m, 6H), 1.97 - 1.91 (m, 1H), 0.96 - 0.89 (m, 2H), 0.71 - 0.65 (m, 2H).
[0719] Using a similar procedure to that used for the synthesis of 3-(2-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[l,2- a]pyridin-8-yl)oxetan-3-ol, the compounds in Table 20 were prepared using an appropriate intermediate.
Table 20
Figure imgf000373_0001
Figure imgf000374_0001
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0001
Example 272
Synthesis of 6-(((6-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)iniidazo[l,2-a]pyridin-2-
Figure imgf000381_0001
[0720] DAST (60 mg, 0.37 mmol) was added to a mixture of 3-(2-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[l,2- a]pyridin-8-yl)oxetan-3-ol (40 mg, 0.074 mmol) in DCM ( 5 mL ) at -40°C under nitrogen. The mixture was stirred at -40°C for 3 h. H2O (10 mL) was added to the reaction, extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO-i, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH = 10/1) to give the 6-(((6-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[l,2- a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (10 mg, yield: 25%) as a white solid. ESLMS [M +H]+: 540.2 'H NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 8.29 (s, 1H), 7.94-7.86 (m, 2H), 7.76 (d, J = 6.2 Hz, 1H), 7.24 (t, J = 4.4 Hz, 1H), 7.15 (s, 1H), 7.00 (d, J = 6.2 Hz, 1H), 6.69 (s, 2H), 5.89 (s, 1H), 5.40 - 5.27 (m, 4H), 5.00 (d, J = 9.1 Hz, 1H), 4.94 (d, J = 9.1 Hz, 1H), 4.68-4.58 (m, 2H), 2.47 (s, 6H), 2.00 - 1.94 (m, 1H), 0.98 - 0.90 (m, 2H), 0.76 - 0.70 (m, 2H).
Example 273
Synthesis of 3-(2-(((6-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l, 5-a]pyridin- 7-yl)propanoic acid (1-273).
Figure imgf000381_0002
[0721] To solution of ethyl 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyri din-7- yl)propanoate (20 mg, 0.035 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH H2O (7 mg, 0.17 mmol). The reaction was stirred at room temperature for 2 h. Water (10 mL) was added and extracted with EtOAc (20 mL x 2). The aqueous layer was collected, and the pH was adjusted with HC1 (0.5 M/L) to 5, then extracted with EtOAc (20 mL x 4). The combined organic layers were washed with saturated brine (30 ml), dried with Na2SO4, concentrated and purified by silica gel column chromatography (DCM/MeOH = 8/1) to give 3-(2-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5- a]pyridin-7-yl)propanoic acid (5 mg, yield: 26.6%) as a white solid. ESLMS [M +H]+: 538.3. 1H NMR (400 MHz, DMSO) 8 8.29 (s, 1H), 7.91 (s, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.25 (d, J = 7.4 Hz, 2H), 6.99 (d, J = 6.1 Hz, 1H), 6.63 (s, 2H), 6.48 (d, J = 3.7 Hz, 2H), 5.89 (s, 1H), 5.44 (s, 2H), 4.61 (s, 2H), 3.33-3.22 (m, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H), 2.47 (s, 3H), 1.97- 1.94 (m, 1H), 0.99-0.98 (m, 2H), 0.76-0.74 (m, 1H).
Example 274
Synthesis of ethyl 3-(4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrinudin-2-yl)propanoate (1-274).
Figure imgf000382_0001
[0722] Synthesis of ethyl 3-(4-chloro-6-((6-cyclopropyliniidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidin-2-yl)propanoate. To a solution of (6-cyclopropylimidazo[l,2-a]pyridin- 2-yl)methanol (750 mg, 4.0 mmol) in dry THF (40 mL) was added NaH (192 mg, 4.8 mmol, 60% dispersion in mineral oil) slowly at 0°C. The resulting mixture was stirred at room temperature for 20 min. Then the reaction was cooled to 0 °C, a solution of ethyl 3-(4,6- dichloropyrimidin-2-yl)propanoate (1.2 g, 4.8 mmol) in THF (5 mL) was added to the mixture, and the mixture was stirred at room temperature for another 2 h. H2O (50 mL) was added and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over NaiSOi, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give the ethyl 3- (4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (350 mg, yield: 22%) as a yellow solid. ESI-MS [M +H]+: 401.2
[0723] Synthesis of ethyl 3-(4-(((l-aniino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6- ((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate. To a solution of ethyl 3-(4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimi din-2- yl)propanoate (130 mg, 0.33 mmol) in DMF (10 mL) was added 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (80 mg, 0.40 mmol), Pd-PEPPSI-IPENT-Cl (o-picoline) (14 mg, 0.02 mmol) and CS2CO3 (323 mg, 0.99 mmol). The mixture was stirred at 110 °C for 2 h under N2. The reaction was cooled to room temperature. Water (40 mL) was added and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO-i, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with DCM/MeOH (10/1) to give ethyl 3-(4-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidin-2-yl)propanoate (50 mg, 27% yield) as a white solid. ESI-MS [M +H]+: 566.3. 1H NMR OO MHz, DMSO) 8 8.33 (s, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.14-7.12 (m, 1H), 7.01-6.98 (m, 2H), 6.72 (s, 2H), 5.68 (s, 1H), 5.32 (s, 2H), 4.61 (s, 2H), 4.07-4.02 (m, 2H), 2.95-2.93 (m, 2H), 2.78 - 2.72 (m, 2H), 2.47 (s, 6H), 1.95-1.91 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H), 0.93-0.91 (m, 2H), 0.68-0.66 (m, 2H).
[0724] Using a similar procedure to that used for the synthesis of ethyl 3-(4-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methoxy)pyrimidin-2-yl)propanoate, the compounds in Table 21 were prepared using an appropriate intermediate. Table 21
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0002
Examples 276-277
Figure imgf000390_0001
[0725] The mixture was separated using chiral column separation [CHIRALPAK OZ, 5.0 cm I.D x 25 cm L Hexane/EtOH/DEA=55/45/0.1(V/V/V), 60 mL/min, 35°C) to give two enantiomers: (R)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine and (S)-6-(((5-(l-(4-((lH-pyrazol-l- yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine [0726] (S*)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-277), first eluting isomer: ESI-MS [M +H]+: 480.2. 1H NMR (400 MHz, MeOD) 8 8.20 (d, J = 2.5 Hz, 1H), 7.88 (s, 1H), 7.69 (d, J = 6.5 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.20- 7.15 (m, 3H), 6.30 (t, J = 2.1 Hz, 1H), 6.15 (d, J = 2.5 Hz, 1H), 5.41 (q, J = 6.3 Hz, 1H), 5.31 (s, 2H), 4.65 (s, 2H), 2.56 (s, 3H), 2.51 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). RT = 7.523 min, 100.0% e.e.
[0727] (R*)-6-(((5-( 1 -(4-(( IH-pyrazol- 1 -yl)methyl)phenyl)ethoxy)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-276), second eluting isomer: ESI-MS [M +H]+: 480.2. 1H NMR (400 MHz, MeOD) 8 8.19 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J = 6.5 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.19- 7.14 (m, 3H), 6.29 (t, J = 2.1 Hz, 1H), 6.14 (d, J = 2.5 Hz, 1H), 5.40 (q, J = 6.3 Hz, 1H), 5.30 (s, 2H), 4.63 (s, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H).RT = 9.835 min, 98.04% e.e.
Example 293
Synthesis of 3-(4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-
Figure imgf000391_0001
[0728] To a solution of ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)- 6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (40 mg, 0.07 mmol) in THF/EtOH/TLO (2 mL/2 mL/1 mL) was added LiOH H2O (12 mg, 0.30 mmol). The mixture was stirred at 50 °C for 3h. The resulting mixture was concentrated to give the crude, which was purified with Prep-HPLC to give 3-(4-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2- yl)propanoic acid (15 mg, yield: 40%) as a white solid. ESI-MS [M +H]+: 538.2. 1H NMR (400 MHz, DMSO) 8 12.34-11.92 (m, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.75 (d, J = 6.2 Hz, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.14-7.09 (m, 1H), 7.03-6.99 (m, 2H), 6.78-6.72 (m, 2H), 5.68 (s, 1H), 5.33 (s, 2H), 4.62 (s, 2H), 2.92-2.89 (m, 2H), 2.72-2.67 (m, 2H), 2.47 (s, 6H), 1.97 - 1.86 (m, 1H), 0.96 - 0.85 (m, 2H), 0.72 - 0.63 (m, 2H). Example 294
Synthesis of 3-(4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropyUmidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-294).
Figure imgf000392_0001
[0729] A mixture of ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6- ((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoate (56 mg, 0.1 mmol) and L1OH-H2O (12.5 mg, 0.3 mmol) in EtOH/THF/tbO (2 mL/2 mL/1 mL) was stirred at 50 °C for 3h. After the mixture was cooled to room temperature, pH of the reaction was adjusted to 6 by adding HC1 (1 M aq ). The reaction was concentrated in vacuo to give the crude, which was purified with Prep-HPLC to give 3-(4-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidin-2- yl)propanoic acid (20 mg, 37%) as a white solid. ESI-MS [M +H]+: 539.3. 1H NMR (400 MHz, DMSO) 5 8.69 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 7.77 - 7.75 (m, 2H), 7.14 (s, 1H), 6.99 (d, J = 6.2 Hz, 1H), 6.66 (s, 2H), 5.70 (s, 1H), 5.38 (s, 2H), 4.62 (s, 2H), 3.00 - 2.81 (m, 2H), 2.79 - 2.62 (m, 2H), 2.47 (s, 6H), 2.07 - 1.89 (m, 1H), 1.10 - 0.97 (m, 2H), 0.76 (d, J = 4.1 Hz, 2H).
Example 295
Synthesis of 3-(4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl- [l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-295).
Figure imgf000392_0002
[0730] A mixture of ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6- ((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (20 mg, 0.035 mmol) and LiOH-H2O (6 mg, 0.14 mmol) in EtOH/THF/H2O (2 mL/2 mL/1 mL) was stirred at room temperature for 4h. pH of the reaction was adjusted to 6 by HC1 (IM aq.) and the reaction was concentrated in vacuo to give the crude, which was purified with Prep-HPLC to give 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl- [l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (10 mg, 53%) as a white solid. ESI-MS [M +H]+: 539.2. 1H NMR (400 MHz, DMSO) 8 8.75 (s, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.17 (s, 1H), 6.99 (d, J = 5.7 Hz, 1H), 6.68 (s, 2H), 5.73 (s, 1H), 5.46 (s, 2H), 4.63 (s, 2H), 2.87 (s, 2H), 2.70 - 2.66 (m, 2H), 2.51 - 2.30 (m, 6H), 2.20 - 2.07 (m, 1H), 0.98 (d, J = 7.0 Hz, 2H), 0.88 - 0.71 (m, 2H).
Example 296
Synthesis of l-(4-(((6-(((l-amino-5f7-dimethylisoquinolin-6-yl)niethyl)aniino)pyrimidin-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-296).
Figure imgf000393_0001
[0731] Synthesis of l-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(lH)-one. A solution of l-(4-(hydroxymethyl)phenyl)pyridin-2(l 7)-one (90 mg, 0.45 mmol) in DMF (1.0 mL) at 0 °C was treated with NaH (60% in mineral oil, 21 mg, 0.49 mmol). After stirring for 15 min, 4,6-dichloropyrimidine (73 mg, 0.49 mmol) was added and the mixture stirred at room temperature for 24 h. Water was added and the mixture was extracted with EtOAc. The combined organics were dried over MgSCh and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 1-5% MeOH in DCM to give the desired product (57 mg, 40%). ESI-MS (M+H)+: 314, >H NMR (400 MHz, DMSO) 8 8.74 (d, J=0.9 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.62 - 7.59 (m, 2H), 7.55 - 7.50 (m, 1H), 7.46 - 7.43 (m, 2H), 7.31 (d, J=0.9 Hz, 1H), 6.50 - 6.48 (m, 1H), 6.35 - 6.31 (m, 1H), 5.54 (s, 2H).
[0732] Synthesis of l-(4-(((6-(((l-annno-5, 7-dimethylisoquinolin-6- yl)niethyl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(lH)-one. A mixture of l-(4-(((6- chloropyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(177)-one (55 mg, 0.18 mmol), 6- (aminomethyl)-5,7-dimethylisoquinolin-l-amine (53 mg, 0.26 mmol), Pd-PEPP SLIP ent (o- picoline) (15 mg, 0.02 mmol) and CS2CO3 (171 mg, 0.53 mmol) in DMF (2 mL) was degassed with nitrogen for 15 min, then heated at 130 °C for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of 1-15% of (7N NH3 in MeOH) in DCM followed by preparative HPLC to give the desired product as a yellow solid (13 mg, 16%). ESLMS (M+H):+ 479.3, ‘H NMR (400 MHz, DMSO) 5 8.28 (s, 1H), 8.18 (s, 0.8H), 7.91 (s, 1H), 7.77 (d, J=6.1 Hz, 1H), 7.65 - 7.62 (m, 1H), 7.55 - 7.48 (m, 3H), 7.41 - 7.38 (m, 2H), 7.26 (t, J=4.4 Hz, 1H), 6.99 (dd, J=0.6, 6.1 Hz, 1H), 6.63 (s, 2H), 6.48 - 6.46 (m, 1H), 6.31 (dt, J=1.3, 6.7 Hz, 1H), 5.92 (s, 1H), 5.38 (s, 2H), 4.61 (s, 2H), 2.47 (s, 3H). One CH3 not visible as obscured by DMSO signal at 2.5 ppm.
[0733] The compounds in Table 22 were synthesized in a similar manner to 1 -(4-(((6-((( 1 - amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)pyridin- 2(177)-one from 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine and an appropriate coupling partner.
Table 22
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0002
Example 304
Synthesis of 6-(((6-((6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4- yl)amino)niethyl)-5, 7-dimethylisoquinolin-l-amine (1-304).
Figure imgf000398_0001
[0734] Synthesis of 6-chloro-2-(((6-chioropyrimidin-4-yi)oxy)methyl)-5- methylimidazo[l,2-a]pyridine. (6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methanol (86 mg, 0.44 mmol) in DMF (1.0 mL) was added dropwise to a stirred suspension of NaH (60% in mineral oil, 21 mg, 0.53 mmol) in DMF (1.0 mL) at 0 °C, the reaction was stirred at 0 °C for 30 min. 4,6-dichloropyrimidine (72 mg, 0.48 mmol) in DMF (1.0 mL) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSCU then concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 0 - 5% MeOH in DCM to give the title compound (117 mg, 86%). ESLMS (M+H)+: 309/311, >HNMR (400 MHz, CDCh) 8 8.63 (s, 1H), 7.58 (s, 1H), 7.47 (d, J=9.6 Hz, 1H), 7.23 (s, 1H), 6.86 (s, 1H), 5.64 (s, 2H), 2.69 (s, 3H).
[0735] Synthesis of 6-(((6-((6-chloro-5-methylimidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidin-4-yl)anuno)methyl)-5, 7-dimethylisoquinolin-l -amine. 6-chloro-2-(((6- chloropyrimidin-4-yl)oxy)methyl)-5-methylimidazo[l,2-a]pyridine (62 mg, 0.20 mmol), 6- (aminomethyl)-5,7-dimethylisoquinolin-l -amine (52 mg, 0.26 mmol), BHT (132 mg, 0.60 mmol), CS2CO3 (195 mg, 0.6 mmol) and Pd-PEPPSI-IPENTcl(o-picoline) (13 mg, 0.015 mmol) were suspended in DMF (1.5 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under a N2 environment for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCh then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-( ( ( 6-( 6-chloro-5-methylimidazo[ 1, 2-a]pyridin-2-yl)niethoxy)pyrimidin-4-yl)amino)methyl)- 5, 7-dimethylisoqumolin-l-amine. (22.2 mg, 23%). ESI-MS (M+H)+: 474.3, 'H NMR (400 MHz, DMSO) 8 8.31 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.78 (d, J=6.1 Hz, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.36 (d, J=9.7 Hz, 1H), 7.25 (dd, J=4.5, 4.5 Hz, 1H), 7.01 (d, J=6.5 Hz, 1H), 6.66 (s, 2H), 5.90 (s, 1H), 5.42 (s, 2H), 4.63 - 4.60 (m, 2H), 2.70 (s, 3H), 2.49 (s, 3H). One CH3 signal obscured by DMSO signal.
Example 305
Synthesis of 6-(((6-(( 6-cyclopropylimidazo[l,2-a]pyridin-2-yl) methoxy)pyrimidin-4-
Figure imgf000399_0001
[0736] 6-(((6-(( 6-cyclopropylimidazo[ 1, 2 -a ]pyridin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine was synthesized in a similar manner to 6- (((6-((6-chloro-5-methylimidazo[l,2-tf]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine from 6-(aminomethyl)-5, 7-dimethylisoquinolin-l-amine and 2- (((6-chloropyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[l,2-a]pyridine (53.8 mg, 27%). ESLMS (M+H)+: 466.4, ’H NMR (400 MHz, DMSO) 8 8.34 (s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.24 (dd, J=4.5, 4.5 Hz, 1H), 7.02 - 6.99 (m, 2H), 6.62 (s, 2H), 5.89 (s, 1H), 5.37 (s, 2H), 4.67 - 4.59 (m, 2H), 1.98 - 1.90 (m, 1H), 0.96 - 0.91 (m, 2H), 0.71 - 0.66 (m, 2H). Example 306
Synthesis of N4-((l-amino-5, 7-diniethylisoquinolin-6-yl)methyl)-N6-(quinolin-2- ylmethyl)pyrimidine-4, 6-diamine (1-306).
Figure imgf000400_0001
[0737] 6 -chloro-A-(quinolin-2-ylmethyl)pyrimidin-4-amine (47 mg, 0.174 mmol), 6-
(aminomethyl)-5,7-dimethylisoquinolin-l -amine (46 mg, 0.226 mmol), BHT (115 mg, 0.522 mmol), CS2CO3 (170 mg, 0.522 mmol) and Pd-PEPPSI-IPENTcl(3-chloropyridine) (8 mg, 0.009 mmol) were suspended in DMF (1.0 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under a N2 environment for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCU then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound as a formic acid salt (17.7 mg, 22%). ESI-MS (M+H)+: 436.5, >H NMR (400 MHz, DMSO) 5 8.30 (d, J=8.5 Hz, 1H), 8.21 (s, 1H), 8.02 - 7.87 (m, 4H), 7.76 - 7.71 (m, 2H), 7.58 - 7.53 (m, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.32 (t, J=5.8 Hz, 1H), 6.97 (d, J=6.0 Hz, 1H), 6.71 (t, J=4.3 Hz, 1H), 6.65 (s, 2H), 5.54 (s, 1H), 4.64 (d, J=5.5 Hz, 2H), 4.53 (d, J=3.8 Hz, 2H), 2.48 (s, 3H), 2.44 (s, 3H).
Example 536
Synthesis of l-(4-(((6-(((l-amino-5-methylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)amino) methyl)benzyl)pyridin-2(lH)-one (1-536).
Figure imgf000400_0002
[0738] 6-(Aminomethyl)-5-methylisoquinol-l-amine (101 mg, 0.54 mmol), l-(4-(((6- chloropyridazin-4-yl)amino)methyl)benzyl)pyridine-2(lH)-one (132 mg, 0.40 mmol), Pd- PEPPSI2Me-IPentcl (see Notes for structure, 18.0 mg, 0.02 mmol) and cesium carbonate (418 mg, 1.28 mmol) were placed in a vial and suspended in anhydrous dimethylformamide (1 mL) in a dry microwave vial. Nitrogen was bubbled through the mixture for 2 min. The vial was sealed and the mixture was heated at 90 °C for 3 h. The mixture was cooled to room temperature. The mixture was suspended in 20:1 dichloromethane:methanol + 1% acetic acid (1 mL) and passed through a silica gel plug, eluting with 5-20% methanol in dichloromethane + 1% acetic acid. The fractions were concentrated under reduced pressure and the solid residue was purified by reversed phase column chromatography (Biotage Isolera, 30 g Ultra Cis SNAP cartridge), eluting with 30-65% acetonitrile in water containing 0.1% ammonia over 18 column volumes. l-(4- (((6-(((l-amino-5-methylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)amino) methyl)benzyl)pyridin-2(lH)-one (37 mg, 19%) was isolated as an off white solid. ESI-MS [M + H]+478, 'H NMR (400 MHz, CD3SOCD3, ppm) 5 7.99 (s, 1H), 7.94 (d, J 8.8 Hz, 1H), 7.80 (d, J 6 Hz, 1H), 7.75 (d, J 5.6 Hz, 1H), 7.40 (m, 1H), 7.33 (d, J 8.8 Hz, 1H), 7.28-7.21 (m, 5H), 7.06- 7.01 (m, 2H), 6.66 (s, 2H), 6.39 (d, J 9.2 Hz, 1H), 6.22 (t, J 6.4 Hz, 1H), 5.64 (s, 1H), 5.04 (s, 2H), 4.56 (d, J 5.6 Hz, 2H), 4.18 (d, J 5.6 Hz, 2H), 2.46 (s, 3H).
Example 537
Synthesis of l-(4-(((5-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3- yl)amino) methyl)benzyl)pyridin-2(l H)-one (1-537).
Figure imgf000401_0001
[0739] A mixture of l-(4-(((5-chloropyridazin-3-yl)amino)methyl)benzyl)pyridin-2(lH)-one (61 mg, 0.19 mmol) and 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (49 mg, 0.24 mmol), cesium carbonate (182 mg, 0.56 mmol) and Pd-PEPPSI™-IPent catalyst (dichloro[l,3-bis(2,6- di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium (II) (14.8 mg, 0.019 mmol) in anhydrous DMF (0.5 mL) was degassed and then heated at 130 °C for 1 h. The mixture was cooled to room temperature and fdtered through a short pad of silica gel (2 g), eluting with di chloromethane: methanol: 7 M ammonia in methanol = 90:10:4 (30 mL). The eluent was concentrated under reduced pressure and the residue was dissolved in acetonitrile:water = 2: 1 (2 mL) and purified by reversed phase flash chromatography (Biotage Cis cartridge, 30 g) eluting with 30-70% acetonitrile in 0.1% aqueous ammonia). j_-(4-(((5-(((l-Amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3-yl)amino)methyl)benzyl)pyridin-2(lH)-one (11.9 mg, 13% yield) was isolated as a colourless solid. ESI-MS [M + H]+: 492. ’H NMR (400 MHz, (CD3)2SO, ppm) 5 8.00 (d, J 1.6 Hz, 1H), 7.93 (s, 1H), 7.77 (m, 2H), 7.40 (m, 1H), 7.32 (d, J 7.9 Hz, 2H), 7.25 (d, J 7.9 Hz, 2H), 7.00 (d, J 6.1 Hz, 1H), 6.79 (t, J 5.9 Hz, 1H), 6.65 (s, 2H), 6.53 (s, 1H), 6.40 (d, J 9.1 Hz, 1H), 6.22 (t, J 6.4 Hz, 1H), 5.86 (d, J 1.6 Hz, 1H), 5.06 (s, 2H), 4.47 (d, J 5.9 Hz, 2H), 4.21 (d, J 3.5 Hz, 2H), 2.47 (s, 3H), 2.42 (s, 3H).
Example 307
Figure imgf000402_0001
[0740] Synthesis of N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6- methoxyquinolin-2-yl)methyl)pyrimidine-4,6-diamine was synthesised (as a formic acid salt) following a similar procedure for the synthesis of A^-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)-2V6-(quinolin-2-ylmethyl)pyrimidine-4,6-diamine from 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine and 6-chloro-JV-((6-methoxyquinolin-2-yl)methyl)pyrimidin-4- amine (4.1mg, 11%). ESI-MS (M+H)+: 466.5, ’H NMR (400 MHz, DMSO) 8 8.26 (s, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.02 (s, 1H), 7.89 - 7.84 (m, 2H), 7.75 (d, J=6.1 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.36 (dd, J=2.9, 9.3 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.27 (t, J=5.9 Hz, 1H), 6.97 (d, J=6.1 Hz, 1H), 6.70 (t, J=4.4 Hz, 1H), 6.60 (s, 2H), 5.53 (s, 1H), 4.59 (d, J=5.5 Hz, 2H), 4.53 (d, J=4.0 Hz, 2H), 3.88 (s, 3H), 2.48 (s, 3H), 2.44 (s, 3H).
Example 308
Figure imgf000402_0002
[0741] 6 -chloro-N-methyl-N-(quinolin-6-ylmethyl)pyrimidin-4-amine (93 mg, 0.33 mmol),
6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (85 mg, 0.43 mmol), BHT (218 mg, 0.99 mmol), CS2CO3 (323 mg, 0.99 mmol) and Pd-PEPPSI-IPENTcl(o-picoline) (14 mg, 0.016 mmol) were suspended in DMF (1.5 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under a N2 environment for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCL then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-methyl-N6-(quinolin-6- ylmethyl)pyrimidine-4,6-diamine as a formic acid salt (24.1 mg, 16%). ESI-MS (M+H)+: 450.5, ’H NMR (400 MHz, DMSO) 5 8.85 (dd, J=1.6, 4.2 Hz, 1H), 8.32 (dd, J=1.0, 8.3 Hz, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.75 (d, J=6.2 Hz, 1H), 7.73 (s, 1H), 7.66 (dd, J=1.8, 8.8 Hz, 1H), 7.50 (dd, J=4.3, 8.0 Hz, 1H), 6.98 (d, J=6.1 Hz, 1H), 6.79 (t, J=4.0 Hz, 1H), 6.66 (s, 2H), 5.64 (s, 1H), 4.93 (s, 2H), 4.59 (d, J=3.5 Hz, 2H), 3.03 (s, 3H), 2.46 (s, 3H). One methyl peak is obscured by the DMSO signal.
[0742] The compounds in Table 23 were synthesised following a similar procedure for the synthesis of A4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-?/6-methyl-?/6-(quinolin-6- ylmethyl)pyrimidine-4,6-diamine from 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine and an appropriate coupling partner.
Table 23
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Example 315
Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(isoquinolin-3- ylmethyl)pyrimidine-4, 6-diamine (1-315).
Figure imgf000406_0001
[0743] Synthesis of 6-(((6-chloropyrimidin-4-yl)amino)methyl)-5, 7-dimethylisoquinolin-l- amine. A mixture of 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (1.7 g, 8.4 mmol), 4,6- dichloropyrimidine (1.3 g, 8.4 mmol) and NEt3 (2.8 mL, 10 mmol) in zPrOH (25 mL) was stirred at 60 °C for 3 h. The reaction was allowed to cool to room temperature, diluted with water (40 mL) and filtered. The filtrate was washed with water and dried in vacuo. On standing, further product precipitated from the mother liquor which was isolated in the same manner to the first crop. Product batches were combined to give 6-(((6-chloropyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (2.43 g, 92%) which was used without further purification. 'H NMR (400 MHz, DMSO) 8 8.38 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=6.1 Hz, 2H), 7.00 (d, J=6.3 Hz, 1H), 6.62 (s, 2H), 6.56 - 6.54 (m, 1H), 4.64 (s, 2H), 2.52 (s, 3H), 2.46 (s, 3H).
[0744] Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yI)methyl)-N6-(isoquinolin-3- ylmethyl)pyrimidine-4, 6-diamine. Isoquinolin-3-ylmethanamine (66 mg, 0.42 mmol), 6-(((6- chloropyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine (100 mg, 0.32 mmol), BHT (210 mg, 0.96 mmol), CS2CO3 (310 mg, 0.96 mmol) and Pd-PEPPSI-IPENT-Cl (o- picoline) (14 mg, 0.02 mmol) were suspended in anhydrous DMF (1.8 mL) and degassed with N2 for 10 min. The reaction mixture was heated to 75 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with DCM (3x30 mL).
The combined organics were washed with water (20 mL), dried over MgSCU and concentrated in vacuo. The residue was triturated with Et2O and dried in vacuo. The residue was purified by reverse phase preparative HPLC to give N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6- (isoquinolin-3-ylmethyl)pyrimidine-4, 6-diamine (26 mg, 19%). ESLMS (M+H)+: 436.3, ’H NMR (400 MHz, DMSO) 8 9.27 (s, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.87 (s, 1H), 7.77 - 7.70 (m, 2H), 7.65 - 7.59 (m, 2H), 7.26 (t, J=6.1 Hz, 1H), 6.96 (d, J=6.3 Hz, 1H), 6.67 (t, J=4.5 Hz, 1H), 6.58 (s, 2H), 5.57 - 5.52 (m, 1H), 4.62 (d, J=5.3 Hz, 2H), 4.53 (d, J=3.9 Hz, 2H), 2.48 (s, 3H), 2.44 (s, 3H).
[0745] The compounds in Table 24 were synthesised following a similar procedure for the synthesis of #4-((l-amino-5,7-dimethylisoquinolin-6-yl )methyl)-M’-(isoquinolin-3- ylmethyl)pyrimidine-4,6-diamine from 6-(((6-chloropyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine and an appropriate coupling partner.
Table 24
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0002
Example 338
Synthesis of N4-((l-amino-5, 7-dimethylisoquinoIin-6-yl)methyI)-N6-(4-(pyrazin-2- ylmethyl)benzyl)pyrimidine-4, 6-diamine (1-338).
Figure imgf000414_0001
[0746] A mixture of 6-chloro-A-(4-(pyrazin-2-ylmethyl)benzyl)pyrimidin-4-amine (75 mg, 0.24 mmol) and 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (63 mg, 0.31 mmol) in DIPEA (1.0 mL) was stirred at 140 °C for 18 h. The reaction mixture was cooled to room temperature. A precipitate formed which was collected by fdtration, washed with Et20 (30 mL) then purified by reversed phase preparative HPLC to give N4-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyrazin-2-ylmethyl)benzyl)pyrimidine-4, 6-diamine (18 mg, 14%). ESI-MS (M+H)+: 477.4, ‘H NMR (400 MHz, DMSO) 5 8.60 (d, >1.5 Hz, 1H), 8.53 (dd, >1.6, 2.5 Hz, 1H), 8.46 (d, J=2.6 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.75 (d, >6.1 Hz, 1H), 7.21 - 7.20 (m, 4H), 7.08 (t, >6.1 Hz, 1H), 6.98 (dd, >0.5, 6.2 Hz, 1H), 6.64 - 6.60 (m, 3H), 5.43 (s, 1H), 4.51 (d, >4.1 Hz, 2H), 4.31 (d, J=5.6 Hz, 2H), 4.09 (s, 2H), 2.48 (s, 3H), 2.44 (s, 3H).
Example 339
Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-
Figure imgf000415_0001
[0747] A mixture of 6-chloro-7V-(4-cyclopropylbenzyl)pyrimidin-4-amine (49 mg, 0.19 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (50 mg, 0.25 mmol), CS2CO3 (190 mg, 0.57 mmol) and Pd-PEPPSI-IPENT-Cl (o-picoline) (12 mg, 0.01 mmol) in DMF (1.0 mL) was degassed with N2 for 10 min then stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and stirred for 10 min. The resulting precipitate was collected by filtration, washed with water (25 mL) and Et2O (25 mL) then dried in vacuo. The residue was purified by reverse phase preparative HPLC to give N4-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-N6-(4-cyclopropylbenzyl)pyrimidine-4, 6-diamine (1.2 mg, 2%). ESLMS (M+H)+: 425.2, ’H NMR (400 MHz, DMSO) 8 8.18 (s, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.77 (d, J 6. I Hz, 1H), 7.16 (d, 8.2 Hz, 2H), 7.08 (dd, >6.2, 6.2 Hz, 1H), 7.03 - 6.98 (m, 3H), 6.65 (s, 3H), 5.45 (s, 1H), 4.54 (d, >4.0 Hz, 2H), 4.30 (d, >4.9 Hz, 2H), 2.46 (s, 3H), 1.91 - 1.83 (m, 1H), 0.91 (ddd, >4.2, 6.3, 8.4 Hz, 2H), 0.64 - 0.60 (m, 2H). one CH3 signal obscured by DMSO. Example 340
Synthesis ofN4-(4-((lH-pyra7,ol-l-yl)nuithyl)henzyl)-N6-((l-anuno-5, 7-dinuithylisoquinolin-6- yl)methyl)pyrimidine-4, 6-diamine (1-340).
Figure imgf000416_0001
[0748] A mixture of A-(4-((l//-pyrazol-l-yl)methyl)benzyl)-6-chloropyrimidin-4-amine (100 mg, 0.33 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (100 mg, 0.50 mmol), CS2CO3 (330 mg, 1.0 mmol) and Pd-PEPPSI-IPENT-Cl (o-picoline) (28 mg, 0.03 mmol) was placed under a N2 atmosphere, DMF (0.5 mL) was added and the reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0- 10% (7N NH3 in MeOH) in DCM then reversed phase preparative HPLC. The product was loaded onto a SCX cartridge which was washed with MeOH then eluted with (7N NH3 in MeOH) in DCM. The eluent was concentrated in vacuo to give N4-(4-((lH-pyrazol-l- yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4, 6-diamine (22 mg, 14%) as a white solid. ESI-MS (M+H)+: 465.4, >H NMR (400 MHz, DMSO) 8 8.00 (s, 1H), 7.90 (s, 1H), 7.79 - 7.76 (m, 2H), 7.44 (d, J=1.7 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 7.12 (t, J=6.2 Hz, 1H), 6.99 (d, J=6.1 Hz, 1H), 6.68 - 6.63 (m, 3H), 6.25 (d, J=4.1 Hz, 1H), 5.44 (s, 1H), 5.29 (s, 2H), 4.54 (d, J=5.2 Hz, 2H), 4.35 (d, J=3.5 Hz, 2H), 2.45 (s, 3H). one CH3 obscured by DMSO signal.
Example 341
Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-ben7ylpyrimidine-4, 6- diamine (1-341).
Figure imgf000416_0002
[0749] N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-benzylpyrimidine-4,6- diamine was prepared using a similar procedure to that used forA4-(4-((lH-pyrazol-l- yl)methyl)benzyl)-A6-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4, 6-diamine from A-benzyl-6-chloropyrimidin-4-amine and 6-(aminomethyl)-5,7-dimethylisoquinolin-l- amine (57.4 mg, 31%). ESI-MS (M+H)+: 385.4, ’H NMR (400 MHz, DMSO) 8 8.00 (s, 1H), 7.88 (s, 1H), 7.75 (d, J=6.1 Hz, 1H), 7.29 (d, J=6.3 Hz, 3H), 7.23 - 7.18 (m, 1H), 7.13 (dd, J=6.1, 6.1 Hz, 1H), 6.97 (d, J=6.1 Hz, 1H), 6.65 (dd, J=4.4, 4.4 Hz, 1H), 6.58 (s, 2H), 5.46 (s, 1H), 4.53 (d, J=4.0 Hz, 2H), 4.37 - 4.32 (m, 2H), 2.45 (s, 3H), one CH3 hidden under DMSO peak.
Example 342
Synthesis of N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((l-methyl-l H-l ,2,4- triazol-5-yl)methyl)benzyl)pyrimidine-4,6-diamine (1-342).
Figure imgf000417_0001
[0750] A suspension of 6-chloro-A-(4-((l -methyl- 1H-1, 2, 4-triazol-5- yl)methyl)benzyl)pyrimidin-4-amine (57 mg, 0.18 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (36 mg, 0.18 mmol), CS2CO3 (180 mg, 0.54 mmol) and Pd- PEPPSI-IPENT-C1 (o-picoline) (7.6 mg, 0.01 mmol) and BHT (60 mg, 0.27 mmol) in DMF (1.5 mL) was degassed for 5 min and the reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over MgSOi and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5-10% (7N NH3 in MeOH) in DCM. The residue was purified by reverse phase preparative HPLC to give the title compound (11 mg, 13%). ESI-MS (M+H)+: 480.5, ’H NMR (400 MHz, DMSO) 8 8.15 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.75 (d, J=6.3 Hz, 1H), 7.25 - 7.12 (m, 3H), 7.09 (dd, J=6.3, 6.3 Hz, 1H), 6.98 (d, J=6.3 Hz, 1H), 6.63 (s, 2H), 5.46 - 5.42 (m, 1H), 4.55 - 4.47 (m, 2H), 4.35 - 4.29 (m, 2H), 4.12 (s, 2H), 3.74 (s, 3H), 2.44 (s, 3H), one CH3 hidden under DMSO peak.
[0751] Losing a similar procedure to that used for /v4-((l -amino-5,7-dimethylisoquinolin-6- yl)methyl)-A6-(4-((l-methyl-lH-l,2,4-triazol-5-yl)methyl)benzyl)pyrimidine-4,6-diamine, the compounds in Table 25 were prepared from 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine and an appropriate coupling partner. Table 25
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0002
Example 358
Synthesis ofN4-(4-((lH-pyrazol-3-yl)methyl)benzyl)-N6-((l-aniino-5,7-(limethylisoquinolin-6- yl)methyl)pyrimidine-4, 6-diamine (1-358).
Figure imgf000423_0001
[0752] Synthesis of methyl 4-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)aniino)pyrimidin-4-yl)amino)niethyl)benzoate. Methyl 4-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzoate was synthesized in a similar manner to /c 7-butyl (6-(((5-((4-((17/-pyrazol-l-yl)methyl)benzyl)amino)-6- (trifluoromethyl)pyridazin-3-yl)(te/7-butoxycarbonyl)amino)methyl)-5,7-dimethylisoquinolin-l- yl)(/erZ-butoxycarbonyl)carbamate starting from 6-(((6-chloropyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine and methyl 4-(aminomethyl)benzoate. ESI-MS (M+H)+: 443, 'H NMR (400 MHz, DMSO) 8 8.02 (s, 1H), 7.93 - 7.89 (m, 3H), 7.77 (d, J=6.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.24 (dd, J=6.0, 6.0 Hz, 1H), 6.99 (d, J=6.1 Hz, 1H), 6.68 (dd, J=4.5, 4.5 Hz, 1H), 6.60 (s, 2H), 5.48 (s, 1H), 4.54 (d, J=3.9 Hz, 2H), 4.47 (d, J=5.6 Hz, 2H), 3.85 (s, 3H), 2.46 (s, 3H), one CH3 hidden under DMSO peak.
[0753] Synthesis of (4-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)methanol. LiAlHi (IM in THF, 1.9 mL, 1.9 mmol) was added over 20 min to a solution of methyl 4-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzoate (0.42 g, 0.95 mmol) in THF (15 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 90 min then cooled to 0 °C and further LiAlHi (IM in THF, 0.95 mL, 0.95 mmol) was added. After stirring at room temperature for 1 h, the reaction was quenched by careful addition of water to the ice-cooled mixture. The mixture was passed through an SCX column, loading in 1 : 1 DCMMeOH and eluting the product with 7 N NH3 in MeOH in DCM. Fractions containing product were concentrated in vacuo and the residue re-suspended in a mixture of EtOAc and DCM. The resulting suspension was filtered to give the crude product as a yellow solid (0.41 g) that was used without further purification. ESI-MS (M+H)+: 415, 'H NMR (400 MHz, DMSO) 8 8.00 (s, 1H), 7.93 - 7.87 (m, 1H), 7.76 (d, >6.1 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.23 (s, 3H), 7.10 (dd, J=5.7, 5.7 Hz, 1H), 6.98 (d, J=6.1 Hz, 1H), 6.66 - 6.57 (m, 3H), 5.44 (s, 1H), 4.56 - 4.46 (m, 2H), 4.45 (s, 2H), 4.34 (d, J=4.5 Hz, 2H), 2.45 (s, 3H), one CH3 hidden under DMSO peak.
[0754] Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-
(bromomethyl)benzyl)pyrimidine-4,6-diamine hydrobromide. HBr (33% w/w in acetic acid, 0.21 mL, 1.21 mmol) was added to a solution of (4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)methanol (0.10 g, 0.24 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 90 min, then further HBr (33% w/w in acetic acid, 0.21 mL, 1.21 mmol) was added. After stirring at room temperature for 30 min, the solvents were removed in vacuo to give the crude product as an orange solid (0.18 g) that was used without further purification. ESI-MS (M+H)+: 477, 479. [0755] Synthesis of N4-(4-((lH-pyrazol-3-yl)methyl)henzyl)-N6-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrinudine-4,6-diamine. A mixture of A'4-(( l -amino-5,7- dimethylisoquinolin-6-yl)methyl)-A6-(4-(bromomethyl)benzyl)pyrimidine-4,6-diamine (110 mg, 0.197 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (57 mg, 0.30 mmol) and Na2COs (100 mg, 0.98 mmol) in MeOH (5 mL) was degassed with N2 for 5 min, then Pd(PPh3)4 (46 mg, 0.039 mmol) was added. The mixture was heated at 115 °C for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and diluted with DCM, then passed through an SCX column, eluting the product with 7N NH3 in MeOH in DCM. Fractions containing product were concentrated in vacuo and the residue purified by preparative HPLC to give the desired product (12 mg, 13%). ’H NMR (400 MHz, DMSO) 5 12.56 - 12.39 (m, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.68 (d, J=6.3 Hz, 1H), 7.47 - 7.28 (m, 1H), 7.14 - 7.06 (m, 4H), 7.01 (t, J=6.1 Hz, 1H), 6.93 (d, J=6.1 Hz, 1H), 6.64 (s, 2H), 6.57 (t, J=4.4 Hz, 1H), 5.90 (d, J=1.9 Hz, 1H), 5.36 (s, 1H), 4.46 (d, J=4.0 Hz, 2H), 4.24 (d, J=5.0 Hz, 2H), 3.81 (s, 2H), 2.38 (s, 3H). One CH3 signal obscured by DMSO signal. ESI-MS (M+H)+: 465.5.
Example 359
Synthesis of 2-(4-(((6-(((l-aniino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrinudin-4- yl)amino)niethyl)-2,6-dimethylphenyl)-l-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-l-one (1-359).
Figure imgf000425_0001
[0756] Synthesis of tert-butyl 2-(4-cyano-2>6-dimethylphenyl)acetate. TMSC1 (95 pL, 0.76 mmol) was added to a stirred suspension of Zn powder (0.50 g, 7.6 mmol) in THF (20 mL). The mixture was heated under reflux for 30 min, the temperature adjusted to 55 °C, and /c/7-butyl bromoacetate (1.44 g, 7.40 mmol) was added dropwise over 30 min. The mixture was heated under reflux for 4 h, then cooled to room temperature and Pd(PPh3)4 (0.10 g, 0.114 mmol), QPhos (0.081 g, 0.114 mmol), and 4-bromo-3,5-dimethylbenzonitrile (1.20 g, 5.7 mmol) were added. The mixture was heated at reflux for 16 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography to give tert-butyl 2-(4-cyano-2,6-dimethylphenyl)acetate as a colourless solid (0.94 g, 67%). ’H NMR (400 MHz, CDCh) 8 7.32 (s, 2H), 3.63 (s, 2H), 2.34 (s, 6H), 1.42 (s, 9H).
[0757] Synthesis of tert-butyl 2-(4-(aminomethyl)-2,6-dimethylphenyl) acetate.
COCI2 6H2O (178 mg, 0.75 mmol) was added to a solution of tert-butyl 2-(4-cyano-2,6- dimethylphenyl)acetate (123 mg, 0.50 mmol) in MeOH (5 mL) at 0 °C. After 10 min, NaBHi (0.095 g, 2.50 mmol) was added portion-wise and the mixture was stirred with cooling for 2 h. AcOH was added to quench the reaction and the mixture was allowed to warm to room temperature, then the mixture was passed through an SCX column, eluting the product with 7 N NH3 in MeOH in DCM. Fractions containing product were concentrated to give tert-butyl 2-(4- (aminomethyl)-2,6-dimethylphenyl)acetate as a colourless oil (110 mg, 88%) that was used in the next reaction without further purification. 'H NMR (400 MHz, CDCI3) 8 6.98 (s, 2H), 3.77 (s, 2H), 3.57 (s, 2H), 2.31 (s, 6H), 1.42 (s, 9H), NH2 missing.
[0758] Synthesis of tert-butyl 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)-2,6- dimethylphenyl) acetate. A solution of Zc/V-butyl 2-(4-(aminomethyl)-2,6- dimethylphenyl)acetate (110 mg, 0.44 mmol), 4,6-dichloropyrimidine (66 mg, 0.44 mmol) and DIPEA (0.23 mL, 1.85 mmol) in MeCN (2 mL) was heated at 60 °C for 2 h. The solvents were removed in vacuo, the residue was dissolved in DCM and the solution washed with K2CO3 (10% aq.), dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 10-50% EtOAc in isohexane to give tert-butyl 2-(4- (((6-chloropyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)acetate as a colourless oil (67 mg, 42%). ESI-MS (M+H)+: 362, *H NMR (400 MHz, CDCh) 8 8.36 (s, 1H), 6.96 (s, 2H), 6.34 (s, 1H), 4.41 - 4.41 (m, 2H), 3.59 (s, 2H), 2.31 (s, 6H), 1.43 (s, 9H).
[0759] Synthesis of tert-butyl 2-(4-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)aniino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)acetate. A mixture of tert- butyl 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)acetate (65 mg, 0.18 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (47 mg, 0.23 mmol), Pd-PEPPSI- IPent (o-picoline) (7.6 mg, 0.009 mmol), BHT (119 mg, 0.54 mmol) and CS2CO3 (176 mg, 0.54 mmol) in DMF (2 mL) was degassed with N2 for 15 min, then heated at 80 °C for 2 h. The mixture was treated with water and the resulting suspension fdtered. The filter cake was washed with water, then dissolved in DCM. The solution was dried over MgSCh and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 1-10% of 7N NH3 in MeOH in DCM to give tert-butyl 2-(4-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6- dimethylphenyl)acetate (57 mg, 60%). ESI-MS (M+H)+: 527, 'H NMR (400 MHz, CDCI3) 8 8.14 (s, 1H), 7.90 (d, J=6.1 Hz, 1H), 7.49 (s, 1H), 7.14 (d, 1=6.3 Hz, 1H), 6.99 (s, 2H), 5.37 (s, 1H), 5.16 - 5.08 (m, 3H), 4.63 - 4.51 (m, 3H), 4.35 (d, J=5.6 Hz, 2H), 3.58 (s, 2H), 2.59 (s, 3H), 2.52 (s, 3H), 2.30 (s, 6H), 1.43 (s, 9H).
[0760] Synthesis of 2-(4-(((6-(((l-annno-5, 7-dimethylisoquinolin-6- yl)niethyI)aniino)pyrimidin-4-yl)amino)niethyl)-2,6-diniethylphenyl)acetic acid. TFA (0.1 mL) was added to a solution of Ze/7-butyl 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)acetate (49 mg, 0.104 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 24 h, then the solvents were removed in vacuo to give 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)acetic acid as a pale brown solid (47 mg, 100%) that was used in the next reaction without further purification. ESI-MS (M+H)+: 471, ‘HNMR (400 MHz, DMSO) 8 13.23 (s, 1H), 8.99 (s, 2H), 8.37 (s, 2H), 8.31 (s, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.28 - 7.14 (m, 2H), 6.97 (s, 2H), 4.68 (s, 2H), 4.38 (s, 2H), 3.17 (s, 2H), 2.57 (s, 3H), 2.52 (s, 3H), 2.23 (s, 6H).
[0761] Synthesis of 2-(4-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)-l-(3- azabicyclo[3.1.0]hexan-3-yl)ethan-l-one. HATU (43 mg, 0.112 mmol) was added to a solution of 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)-2,6-dimethylphenyl)acetic acid (44 mg, 0.0935 mmol) and the mixture stirred at room temperature for 5 min. 3-Azabicyclo[3.1.0]hexane hydrochloride (12 mg, 0.14 mmol) and DIPEA (49 pL, 0.281 mmol) were added and the solution was stirred for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over MgSCh, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)-l-(3- azabicyclo[3.1.0]hexan-3-yl)ethan-l-one as a colourless solid (18.5 mg, 37%). ESI-MS (M+H)+: 536.5, ’H NMR (400 MHz, DMSO) 5 7.92 (s, 1H), 7.79 (s, 1H), 7.67 (d, J=6.1 Hz, 1H), 6.94 (dd, J=6.1, 6.1 Hz, 1H), 6.89 (d, J=6.1 Hz, 1H), 6.79 (s, 2H), 6.55 (dd, J=4.1, 4.1 Hz, 1H), 6.49 (s, 2H), 5.36 (s, 1H), 4.45 (d, J=4.3 Hz, 2H), 4.17 (d, J=4.9 Hz, 2H), 3.68 (d, J=10.2 Hz, 1H), 3.58 - 3.43 (m, 3H), 3.38 (s, 1H), 3.18 (dd, J=4.4, 11.5 Hz, 1H), 2.36 (3, 3H), 2.02 (s, 6H), 1.59 - 1.41 (m, 2H), 0.67 - 0.61 (m, 1H).
[0762] The compound in Table 26 was synthesised in a similar manner to 2-(4-(((6-(((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6- dimethylphenyl)- l-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-l -one.
Table 26
Figure imgf000428_0001
Example 361
Synthesis of N4-((l-amino-5, 7-diniethylisoquinolin-6-yl)methyl)-N6-(4-(pyridin-2- yloxy)benzyl)pyrimidine-4, 6-diamine (1-361 ).
[0763] 6-(((6-Chloropyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine (110 mg, 0.35 mmol), (4-(pyridin-2-yloxy)phenyl)methanamine (91 mg, 0.46 mmol), BHT (230 mg, 1.1 mmol), CS2CO3 (340 mg, 1.1 mmol) and Pd-PEPPSI-IPENTcl(o-picoline) (15 mg, 0.018 mmol) were suspended in DMF (2.0 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under N2 for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organic layers were dried (MgSCU) then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give N4- ((1 -amino-5 , 7-dimethyli soquinolin-6-yl)methyl)-N6-(4-(pyridin-2-y loxy)benzyl)pyrimidine-4, 6- diamine (14 mg, 8%). ESI-MS (M+H)+: 478.4, *H NMR (400 MHz, DMSO) 5 8.12 (dd, J=1.7, 4.9 Hz, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.85 - 7.80 (m, 1H), 7.75 (d, J=6.1 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.15 (dd, J=6.2, 6.2 Hz, 1H), 7.12 - 7.08 (m, 2H), 7.06 - 7.03 (m, 2H), 7.01 - 6.96 (m, 2H), 6.66 (dd, J=4.2, 4.2 Hz, 1H), 6.58 (s, 2H), 5.49 (s, 1H), 4.54 (d, J=4.0 Hz, 2H), 4.38 (d, J=5.4 Hz, 2H), 2.46 (s, 3H). One CH? signal obscured by DMSO signal.
[0764] The compounds in Table 27 were synthesised in a similar manner to ^-((l-amino- 5, 7-dimethylisoquinolin-6-yl)methyl)-JV6-(4-(pyridin-2-yloxy)benzyl)pyrimidine-4, 6-diamine from 6-(((6-Chloropyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine and an appropriate coupling partner.
Table 27
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0002
Example 370
Synthesis of l-(3-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrinndin-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-370).
Figure imgf000432_0001
[0765] Synthesis of methyl 3-(2-oxopyridin-l (2H)-yl)benzoate. \R,2R)-Nl , 7V2- dimethylcyclohexane-l,2-diamine (0.24 mL, 1.5 mmol) was added to a stirred solution of methyl 3 -iodobenzoate (2.0 g, 7.6 mmol), pyridin-2(l//)-one (0.796 g, 8.40 mmol), Cui (0.15 g, 0.76 mmol) and K3PO4 (3.2 g, 7.6 mmol) in 1,4-dioxane (25 mL) and degassed with N2 for 5 min. The reaction was heated at 105 °C under a N2 environment for 24 h. The reaction mixture was filtered with EtOAc and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 33-80% EtOAc in DCMto give methyl 3-(2- oxopyridin-l(2H)-yl)benzoate (1.23 g, 70%) as a yellow oil. ESI-MS (M+H)+: 230.0, ’HNMR (400 MHz, DMSO) 5 8.07 - 8.04 (m, 1H), 7.98 - 7.96 (m, 1H), 7.77 - 7.68 (m, 3H), 7.59 - 7.54 (m, 1H), 6.55 - 6.52 (m, 1H), 6.39 - 6.35 (m, 1H), 3.91 (s, 3H).
[0766] Synthesis of 3-(2-oxopyridin-l(2H)-yl)benzoic acid. NaOH (2.0 M aq., 2.7 g, 5.4 mmol) was added to a stirred solution of methyl 3-(2-oxopyridin-l(2//)-yl) benzoate (1.2 g, 5.4 mmol) in THF (20 mL). After 6 h the pH was adjusted to 2 with HC1 (2.0 M aq.) and water (50 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSO , filtered and concentrated in vacuo to give 3-(2-oxopyridin-l(2H)- yl)benzoic acid (1.00 g, 86%) as a cream solid. ESLMS (M+H)+: 216.0.
[0767] Synthesis of l-(3-(hydroxymethyl)phenyl)pyridin-2(lH)-one. Isobutyl chloroformate (0. 66 mL, 5.1 mmol) was added to a stirred solution of 3-(2-oxopyridin-l(277)- yl)benzoic acid (1.0 g, 4.5 mmol) and NEt3 (0.96 mL, 6.9 mmol) in THF (40 mL) at 0 °C The mixture was stirred at 0 °C for 1 h then filtered and washed with THF (3.0 mL). The filtrate was cooled to 0 °C and NaBH4 (0.35 g, 9.3 mmol) was added followed by water (5.8 mL, 0.3 mmol) slowly over 1 h. After 30 min the reaction was warmed to room temperature. After a further 30 min HC1 (1.0 M aq., 2.0 mL) was added followed by NaOH (2.0 M aq., 2.0 mL) and the mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give l-(3-(hydroxymethyl)phenyl)pyridin-2(lH)-one (694 mg, 75%). ESI-MS (M+H)+: 202.
[0768] Synthesis of l-(3-(((6-chloropyrimidin-4-yl)oxy)methy!)phenyl)pyridin-2(lH)-one. NaH (60% in mineral oil, 0.43 g, 1.07 mmol) was added to a stirred solution of l-(3- (hydroxymethyl)phenyl)pyridin-2(H/)-one (0.18 g, 0.89 mmol) in DMF (2.0 mL) at 0 °C. After 15 min 4,6-dichloropyrimidine (0.15 g, 0.98 mmol) was added and after a further 15 min the reaction was warmed to room temperature. After 5 h water (1.0 mL) then MeOH (2.0 mL) was added and the reaction was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 1-10% MeOH in DCM, then by further column chromatography on silica gel, eluting with 30-90% EtOAc in DCM to give l-(3-(((6- chloropyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(lH)-one (130 mg, 61%) as a yellow oil. ESIMS (M+H)+: 315.8.
[0769] Synthesis of l-(3-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)niethyl)anuno)pyrimidin-4-yl)oxy)niethyl)phenyl)pyridin-2(lH)-one. 1 -(3 -(((6- Chloropyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(l/7)-one (130 mg, 0.40 mmol), 6- (aminomethyl)-5,7-dimethylisoquinolin-l-amine (120 mg, 0.60 mmol), Pd-PEPPSI-IPent C1(o- picoline) (34 mg, 0.040 mmol) and CS2CO3 (390 mg, 1.2 mmol) were stirred in DMF (2.0 mL) and degassed with N2 for 5 min. The reaction was heated at 120 °C under aNi environment for 2 h. MeOH (2.0 ml) was added and the reaction was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 1-10% (7N NH3 in MeOH) in DCM followed by reverse phase preparative HPLC to give l-(3-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(lH)-one (44 mg, 23%) (yellow solid) as a formic acid salt. ESI-MS (M+H):+ 479.3, 'H NMR (400 MHz, DMSO) 5 8.27 (s, 0.75H), 8.16 (s, 1H), 7.91 (s, 1H), 7.78 - 7.75 (m, 1H), 7.64 - 7.62 (m, 1H), 7.55 - 7.47 (m, 3H), 7.45 - 7.43 (m, 1H), 7.37 - 7.33 (m, 1H), 7.25 (dd, J=4.4, 4.4 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.64 (s, 2H), 6.49 - 6.46 (m, 1H), 6.33 - 6.29 (m, 1H), 5.90 (s, 1H), 5.36 (s, 2H), 4.61 - 4.57 (m, 2H). One CH3 group obscured by DMSO signal.
Example 371
Synthesis of 5, 7-dimethyl-6-(((6-((2-methylquinolin-6-yl)methoxy)pyrimidin-4- yl)amino)methyl)isoquinolin-l-amine (1-371 ).
Figure imgf000434_0001
[0770] NaH (60% in mineral oil, 0.032 g, 0.81 mmol) was added to a mixture of (2- methylquinolin-6-yl)methanol (0.14 g, 0.61 mmol) in DMF (2.0 mL) at room temperature under a N2 atmosphere and stirred for 30 min. 6-(((6-Chloropyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (0.051 g, 0.16 mmol) was added and the mixture was stirred at 80 °C for 18 h. The mixture was cooled and water was added. The mixture was extracted with EtOAc (3 x) then the combined organic layers were dried over MgSCk, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 5,7-dimethyl-6- (((6-((2-methylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-l-amine (0.016 g, 22%). ESI-MS (M+H):+ 451.2, 'H NMR (400 MHz, DMSO) 6 8.34 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.00 - 7.95 (m, 3H), 7.84 - 7.77 (m, 2H), 7.48 (d, J=8.3 Hz, 1H), 7.31 (t, J=4.4 Hz, 1H), 7.06 - 7.03 (m, 1H), 6.66 (s, 2H), 6.00 - 5.96 (m, 1H), 5.55 - 5.53 (m, 2H), 4.70 - 4.67 (m, 2H), 2.71 (s, 3H), 2.58 - 2.56 (m, 3H), 2.53 (s, 3H).
[0771] The compounds in Table 28 were synthesised in a similar manner to 7-dimethyl-6- (((6-((2-methylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-l -amine.
Table 28
Figure imgf000435_0001
Figure imgf000436_0002
Example 374
Synthesis of 5, 7-dimethyl-6-(((6-(quinolin-6-ylmethoxy)pyrimi(lin-4- yl)amino)methyl)isoquinolin-l-amine (1-374).
Figure imgf000436_0001
[0772] NaH (60% in mineral oil, 0.010 g, 0.025 mmol) was added to a solution of quinolin- 6-ylmethanol (0.040 g, 0.25 mmol) in DMSO (2.5 mL) at room temperature and stirred for 5 min. 6-(((6-Chloropyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine (0.079 g, 0.25 mmol) was added and the mixture was stirred at 65 °C for 72 h then at 80 °C for 5 h. Further NaH (60% in mineral oil, 0.010 g, 0.25 mmol) was added and the mixture was stirred at 80 °C for 18 h. The mixture was cooled and water was added. The mixture was extracted with EtOAc (3 x) and the combined organic layers were concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 5,7-dimethyl-6-(((6-(quinolin-6- ylmethoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-l -amine (1.28 mg, 1%). ESI-MS (M+H):+ 437.4, 1H NMR (400 MHz, DMSO) 8 8.90 (dd, J=1.8, 4.0 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.28 (s, 1H), 8.05 - 7.97 (m, 2H), 7.93 - 7.89 (m, 1H), 7.82 - 7.74 (m, 2H), 7.57 - 7.52 (m, 1H), 7.28 - 7.25 (m, 1H), 7.02 - 6.97 (m, 1H), 6.60 (s, 2H), 5.94 (s, 1H), 5.51 (s, 2H), 4.61 (s, 2H), 2.48 - 2.45 (m, 3H). CH3 signal obscured by DMSO signal.
Example 375
Synthesis of 2-(4-(((6-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrinndin-4- yl)anuno)niethyl)phenyl)-N,N-dimethylacetamide (1-375).
Figure imgf000437_0001
[0773] Synthesis of 2-(4-(hydroxyniethyl)phenyl)-N,N-dimethylacetamide. A mixture of 2- (4-(hydroxymethyl)phenyl)acetic acid (166 mg, 1 mmol), dimethylamine hydrochloride (162 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol) and DIPEA (387 mg, 3 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by silica gel chromatography (EtOAc / PE = 1/1) to get 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide (110 mg, yield: 57%) as a yellow oil. ESLMS [M +H]+: 194.2.
[0774] Synthesis of 2-(4-(chloromethyl)phenyl)-N,N-dimethylacetamide. To a solution of 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide (100 mg, 0.52 mmol) in DCM (5 mL) was added SOC12 (307 mg, 2.6 mmol) slowly at 0 °C. The reaction was stirred at room temperature for 2 h. The mixture was concentrated to afford 2-(4-(chloromethyl)phenyl)-N,N- dimethylacetamide (110 mg, crude) as a yellow oil. ESI-MS [M +H]+:212.1.
[0775] Synthesis of 2-(4-(aminomethyl)phenyl)-N,N-dimethylacetamide. To a solution of 2-(4-(chloromethyl)phenyl)-N,N-dimethylacetamide (110 mg, crude) in MeOH (2 mL) was added NEE (7 M in MeOH, 2 mL). After the reaction was stirred at room temperature for 2 h, the reaction was concentrated to afford 2-(4-(aminomethyl)phenyl)-N,N-dimethylacetamide (110 mg, crude) as a yellow oil. ESLMS [M +H]”: 193.1. [0776] Synthesis of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)-N,N- dimethylacetamide. To a solution of 2-(4-(aminomethyl)phenyl)-N,N-dimethylacetamide(l 10 mg, crude) in i-PrOH (5 mL) was added 4,6-dichloropyrimidine (92 mg, 0.62 mmol) and DIPEA (201 mg, 1.56 mmol). The reaction was stirred at 60 °C for 16 h. After cooled to room temperature, the reaction mixture was concentrated and purified by Prep-TLC (EtOAc/PE=2/l) to afford 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)-N,N-dimethylacetamide (108 mg, yield: 68% over 3 steps) as yellow oil. ESI-MS [M +H]+: 305.3.
[0777] Synthesis of 2-(4-(((6-(((l-annno-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)-N,N-dimethylacetamide. To a solution of 2-(4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)-N,N-dimethylacetamide (48 mg, 0.16 mmol) in i-PrOH(10 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (38 mg, 0.19 mmol) and DIPEA (209 mg, 1.62 mmol). The mixture was stirred at 140 0 C for 4 h under microwave. After the reaction mixture cooled to room temperature, the reaction mixture was concentrated and purified by Prep-TLC (DCM/MeOH=10/l) to afford 2-(4-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)-N,N- dimethylacetamide (14 mg, yield: 18 %) as a pale solid. ESI-MS [M +H]+: 470.3. 1H NMR (400 MHz, DMSO) 5 8.01 (s, 3H), 7.72 (s, 1H), 7.35 - 7.15 (m, 7H), 6.72 (s, 1H), 5.45 (s, 1H), 4.55 (s, 2H), 4.33 (s, 2H), 3.63 (s, 2H), 2.97 (s, 3H), 2.80 (s, 3H), 2.50 (s, 6H).
[0778] The compounds in Table 29 were prepared using a similar procedure to that used for 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenyl)-N,N-dimethylacetamide.
Table 29
Figure imgf000439_0001
Example 379
Synthesis of N4-(4-((lH-pyrazol-l-yl)methyl)-2- luorobenzyl)-ST6-((l-amino-5, 7-
Figure imgf000440_0001
[0779] Synthesis of N-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-N-(6-chloropyrimidin-
4-yl)nitrous amide. To a solution of N-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-6- chloropyrimidin-4-amine (159 mg, 0.5 mmol) in AcOH (5 mL) was added a solution of NaNCh (345 mg, 5 mmol) in H2O (1 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated, and the residue was washed with NaHCCh (sat. aq., 25 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (PE:EtOAc=l:l) to afford N-(4-((lH-pyrazol-l-yl)methyl)-2- fluorobenzyl)-N-(6-chloropyrimidin-4-yl)nitrous amide (100 mg, 57.8%) as a yellow solid. ESIMS [M +H]+:347.1.
[0780] Synthesis of N-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-N-(6-(((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)nitrous amide. To a solution of N-(4- ((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-N-(6-chloropyrimidin-4-yl)nitrous amide (65 mg, 0.19 mmol) in DMF (3 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (24 mg, 0.12 mmol) and DIPEA (39 mg, 0.3 mmol). The reaction mixture was stirred for 4 h at 70 °C. After cooled to room temperature, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude N-(4-((lH-pyrazol-l-yl)methyl)-2- fluorobenzyl)-N-(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)nitrous amide (60 mg, crude). ESLMS [M +H]+:512.3. [0781] Synthesis of N4-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-N6-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrinddine-4,6-diamine. To a solution ofN-(4-((lH-pyrazol- l-yl)methyl)-2-fluorobenzyl)-N-(6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)nitrous amide (60 mg, crude) in EtOH/TbO (8 mL/2 mL) was added iron powder (17 mg, 0.3 mmol) and NH4CI (21 mg, 0.4 mmol). The reaction mixture was stirred at 70 °C for 3 h under N2 atmosphere. After cooled to room temperature, the mixture was filtrated through celite1®, washed by (DCM/MeOH=10/l, 20 mL). The filtrate was concentrated to give the crude, which was purified by Prep-HPLC to give the N4-(4-((lH-pyrazol-l- yl)methyl)-2-fluorobenzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6- diamine (31.6 mg, 54% over two steps) as white solid. ESLMS [M +H]+: 483.3. 1H NMR (4OO MHz, MeOD) 5 8.40 (s, 2H),8.13 (s, 1H), 8.03 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 10.9 Hz, 1H), 6.35 (s, 1H), 5.53 (s, 1H), 5.36 (s, 2H), 4.65 (s, 2H), 4.49 (s, 2H), 2.65 (s, 3H), 2.60 (s, 3H).
[0782] The compounds in Table 30 were prepared using a similar procedure to that used for N4-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine.
Table 30
Figure imgf000441_0001
Figure imgf000442_0002
Example 384
Synthesis of 6-(((6-((6-cyclopropyl-[l,2>4]triazolo[l,5-a]pyrimidin-2-yl)methoxy)pyrimidin-4-
Figure imgf000442_0001
[0783] Synthesis of 2-(((6-chloropyrimidin-4-yl)oxy)methyl)-6-cyclopropyl-
[l,2,4]triazolo[l,5-a]pyrimidine. To a solution of (6-cyclopropyL[l,2,4]triazolo[l,5- a]pyrimidin-2-yl)methanol (30 mg, 0.16 mmol), 4,6-dichloropyrimidine (23 mg, 0.16 mmol) in DMF (3 mL) was added CS2CO3 (156 mg, 0.48 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give the crude, which was purified by Prep-TLC (eluent: EtOAc/PE =1/2) to give 2-(((6-chloropyrimidin-4-yl)oxy)methyl)-6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyrimidine (25 mg, yield: 52%) as a white solid. ESLMS [M +H]+: 303.1.
[0784] Synthesis of 6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyrimidin-2- yl)methoxy)pyrimidin-4-yl)annno)methyl)-5, 7-dimethylisoquinolin-l-aniine. A mixture of 2- (((6-chloropyrimidin-4-yl)oxy)methyl)-6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyrimidine (25 mg, 0.083 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (25 mg, 0.12 mmol) and DIPEA (32 mg, 0.25 mmol) in i-PrOH (2 mL) was stirred in a sealed tube. After degassing with N2 for 1 min, the reaction was irradiated in microwave at 140 °C for 2 h. After cooled to room temperature, the reaction mixture was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH=10/l) to give 6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyrimidin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (19.8 mg, yield: 51%) as a yellow solid. ESLMS [M +H]+: 468.2. 1H NMR (400 MHz, DMSO) 8 9.15 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.24 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.28 (t, J = 4.4 Hz, 1H), 7.00 (d, J = 6.1 Hz, 1H), 6.65 (s, 2H), 5.93 (s, 1H), 5.53 (s, 2H), 4.61 (s, 2H), 2.52 (s, 3H), 2.47 (s, 3H), 2.11-2.08 (m, 1H), 1.04-1.02 (m, 2H), 0.93 D 0.87 (m, 2H).
[0785] The compounds in Table 31 were prepared using a similar procedure to that used for 6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl )-5 , 7 -dimethyli soquinolin- 1 -amine.
Table 31
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Example 401
Synthesis of 6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyriniidin-4-
Figure imgf000449_0001
[0786] A mixture of 6-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3-chloroquinoline-8-carbonitrile (35 mg, 0.07 mmol), K2CO3 (39 mg, 0.28 mmol) and H2O2 (27 mg, 0.28 mmol, 35% aqueous solution) in DMSO (2 mL) was stirred at 50 °C for 3 h. The reaction was diluted with H2O (15 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep- TLC (eluent: DCM/MeOH = 10/1) to give 6-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3-chloroquinoline-8-carboxamide (8 mg, 22%) as a white solid. ESI-MS [M +H]+: 514.2. 1H NMR (400 MHz, DMSO) 8 9.63 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.33 (s, 3H), 8.28 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.31 (s, 1H), 7.00 (d, J = 6.1 Hz, 1H), 6.66 (s, 2H), 5.97 (s, 1H), 5.58 (s, 2H), 4.62 (s, 2H), 2.55 (s, 3H), 2.48 (s, 3H).
Example 402
Synthesis of 6-(((6-((8-butyl-3-chloroquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-
Figure imgf000449_0002
[0787] To a solution of 6-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-8-butyl-3-chloroquinoline 1-oxide (30 mg, 0.055 mmol) in DCM (4 mL) was added DAST (35 mg, 0.22 mmol) at - 40 °C. After the reaction was stirred at - 40 °C for 3 h, the reaction was quenched with NaHCCh (sat. aq., 20 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give 6-(((6-((8-butyl-3-chloroquinolin-6-yl)methoxy)pyrimidin- 4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (10 mg, 34%) as a white solid. ESI-MS [M +H]+: 427.2. 1H NMR (400 MHz, DMSO) 5 8.53 (s, 1H), 8.28 (s, 1H), 7.98 - 7.91 (m, 3H), 7.79 - 7.76 (m, 2H), 7.27 (t, J = 4.4 Hz, 1H), 6.99 (d, J = 6.2 Hz, 1H), 6.62 (s, 2H), 5.93 (s, 1H), 5.50 (s, 2H), 4.61 (s, 2H), 3.12 - 3.00 (m, 2H), 2.47 (s, 6H), 1.80 - 1.72 (m, 2H), 1.42 (dd, J = 14.8, 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).
Example 403
Synthesis of 6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine (1-403).
Figure imgf000450_0001
[0788] Hydrazine hydrate (0.01 mL, 0.16 mmol) was added to a stirred suspension of (6-(((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(6-cyclopropylimidazo[l,2- tz]pyridin-2-yl)methanone (38 mg, 0.088 mmol) and KOH (14 mg, 0.25 mmol) in ethylene glycol (1.0 mL). The reaction was then heated to 100 °C for 18 h. The reaction was cooled to room temperature and loaded onto an SCX column which was then washed with DCM:MeOH (3 : 1, 20 mL) and eluted with DCM:NHj in MeOH (3 : 1, 20 mL) which was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-(((6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (4.2 mg, 11%). ESLMS (M+H)+: 449.4, ’HNMR (400 MHz, DMSO) 5 8.23 - 8.20 (m, 1H), 7.88 - 7.83 (m, 2H), 7.71 - 7.69 (m, 1H), 7.53 - 7.50 (m, 1H), 7.29 - 7.26 (m, 1H), 6.94 - 6.86 (m, 2H), 6.55 - 6.54 (m, 2H), 6.40 - 6.37 (m, 2H), 6.35 - 6.33 (m, 1H), 4.50 - 4.47 (m, 2H), 3.79 - 3.75 (m, 2H), 1.86 - 1.85 (m, 1H), 0.87 - 0.82 (m, 2H), 0.60 - 0.57 (m, 2H). Two CI L signals obscured by DMSO signal. Example 404
Synthesis of 6-(((6-(( 6-cyclopropylimidazo[l, 2-a]pyridin-2-yl) difluoromethyl)pyrimidin-4- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine (1-404).
Figure imgf000451_0001
[0789] Synthesis of (6-chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2- yl) methanone. 6-cyclopropylimidazo[l,2-a]pyridine-2-carbaldehyde (3.1 g, 16.7 mmol), 4,6- dichloropyrimidine (1.9 g, 13 mmol), and l-butyl-3-methylimidazolium tetrafluoroborate (1.0 mL, 5.5 mmol) were dissolved in DCM (200 mL) under N2. Sodium hydride (60 % in mineral oil, 0.67 g, 17 mmol) was added portion-wise and the resulting reaction mixture was heated to 40 °C for 3 h. The reaction mixture was allowed to cool to room temperature and poured into ice- cold water (100 mL) and saturated brine solution (100 mL). The solution was extracted with DCM (100 mL) and the organic layer was dried over MgSCh. The solvent was concentrated in vacuo and the residue purified by silica gel chromatography, eluting with a gradient of cyclohexane -> 100 % EtOAc. The fractions containing the title compound were combined and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10 % (7N NEE in MeOH) in DCM to give (6-chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methanone (900 mg, 23 %) which was used without further purification. ‘H NMR (400 MHz, CDCE) 8 9.20 (1H, d, J = 1.0 Hz), 8.87 (1H, d, J = 0.9 Hz), 8.24 (1H, d, J = 1.0 Hz), 7.95 (1H, ddd, J = 0.9, 0.9, 1.6 Hz), 7.61 (1H, ddd, J = 0.9, 1.0, 9.5 Hz), 7.04 (1H, dd, J = 1.6, 9.5 Hz), 1.96 - 1.88 (1H, m), 1.06 - 1.00 (2H, m), 0.76 - 0.71 (2H, m).
[0790] Synthesis of 2-((6-chloropyrimidin-4-yl)difluoromethyl)-6-cyclopropylimidazo[l,2- ajpyridine. DAST (0.4 mL, 3.02 mmol) was added dropwise to a stirred solution of (6- chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-cz]pyridin-2-yl)methanone (180 mg, 0.60 mmol) in DCM (2.0 mL), the reaction was stirred at room temperature for 18 h. The reaction was poured over ice water (20 mL) and extracted with DCM (3 x 15 mL). The combined organics were dried over MgSCh then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-100 % EtOAc in cyclohexane to give 2-((6-chloropyrimidin-4-yl)difluoromethyl)-6-cyclopropylimidazo[l,2-a]pyridine (100 mg, 52%). ESI-MS (M+H)+: 321, 'H NMR (400 MHz, CDCh) S 9.03 (s, 1H), 7.94 - 7.89 (m, 3H), 7.48 (d, J=9.3 Hz, 1H), 7.00 (dd, J=1.8, 9.6 Hz, 1H), 1.94 - 1.86 (m, 1H), 1.02 - 0.96 (m, 2H), 0.71 - 0.66 (m, 2H).
[0791] Synthesis of 6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)difluoromethyl)pyrimidin-4-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine. DIPEA (0.057 mL, 0.33 mmol) was added to a stirred solution of 2-((6-chloropyrimidin-4- yl)difluoromethyl)-6-cyclopropylimidazo[l,2-a]pyridine (60 mg, 0.13 mmol) and 6- (aminomethyl)-5, 7-dimethylisoquinolin-l-amine (53 mg, 0.26 mmol) in zPrOH (2.0 mL) and stirred at 80 °C for 18 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)difluoromethy l)pyrimidin-4-yl )amino)methyl )-5 , 7 -dimethyli soquinolin- 1 -amine (60 mg, 24%). ESI-MS (M+H)+: 486, 'H NMR (400 MHz, MeOD) 8 8.55 (s, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (d, J=6.3 Hz, 1H), 7.45 (d, J=9.4 Hz, 1H), 7.21 - 7.18 (m, 2H), 6.97 (s, 1H), 4.89 (s, 2H), 4.87 - 4.85 (m, 2H), 2.66 (s, 3H), 2.61 (s, 3H), 2.03 - 1.92 (m, 1H), 1.06 - 1.00 (m, 2H), 0.80 - 0.75 (m, 2H).
Example 405
Synthesis of 6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4- yl) amino) methyl)- 5, 7-dimethylisoquinolin-l-amine (1-405).
Figure imgf000452_0001
[0792] Synthesis of ( 6-chloropyrimidin-4-yl) ( 6-cyclopropylimidazo[ 1 ,2-a]pyridin-2- yl)methanol. NaBH-i (62.4 mg, 1.7 mmol) was added portionwise to a stirred solution of (6- chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanone (450 mg, 1.5 mol) in MeOH (10 mL) at 0 °C and stirred at 0 °C for 5 min. The reaction was then allowed to warm to room temperature and stirred for 30 min. The reaction was quenched with NH4CI (sat. aq., 10 mL) and extracted with EtOAc (3 x 15 mL). The combined organics were dried over MgSCU then concentrated in vacuo to give (6-chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methanol (450 mg) which was carried forward to the next step without further purification. 'H NMR (400 MHz, CDCh) 5 8.89 (d, >1.0 Hz, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.90 (dd, >1.8, 9.3 Hz, 1H), 6.00 (s, 1H), 5.49 - 5.49 (m, 1H), 0.97 - 0.91 (m, 2H), 0.66 - 0.60 (m, 2H).
[0793] Synthesis of 2-((6-chloropyrimidin-4-yl)fluoromethyl)-6-cyclopropylimidazo[l,2- ajpyridine. DAST (290 mg, 1.8 mmol) was added dropwise to a stirred solution of (6- chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol (450 mg, 1.5 mmol) in DCM (5.0 mL), the reaction was stirred at room temperature for 18 h. The reaction was poured over ice water (20 mL) and extracted with DCM (3 x 15 mL). The combined organics were dried over MgSO4 then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-100 % EtOAc in cyclohexane to give 2-((6- chloropyrimidin-4-yl)fluoromethyl)-6-cyclopropylimidazo[l,2-a]pyridine (205 mg, 45%). ESIMS (M+H)+: 303, 'H NMR (400 MHz, CDCh) 5 8.92 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.64 (d, >3.0 Hz, 1H), 7.49 (d, J=9.3 Hz, 1H), 6.96 (dd, >1.8, 9.3 Hz, 1H), 6.61 (d, >47.1 Hz, 1H), 1.57 - 1.49 (m, 1H), 1.00 - 0.94 (m, 2H), 0.69 - 0.64 (m, 2H).
[0794] Synthesis of 6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-5, 7-diniethylisoquinolin-l-amine. DIPEA (0.053 mL, 0.41 mmol) was added to a stirred solution of 2-((6-chloropyrimidin-4- yl)fluoromethyl)-6-cyclopropylimidazo[l,2-rz]pyridine (49 mg, 0.11 mmol) and 6- (aminomethyl)-5,7-dimethylisoquinolin-l-amine (36 mg, 0.18 mmol) in zPrOH (1.0 mL) and stirred at 80°C for 18 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (33 mg, 44%). ESLMS (M+H)+: 303, 'H NMR (400 MHz, DMSO) 8 8.55 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 8.01 (d, >3.0 Hz, 1H), 7.90 (d, >6.3 Hz, 1H), 7.78 (dd, >4.0, 4.0 Hz, 1H), 7.54 (d, >9.3 Hz, 1H), 7.17 - 7.12 (m, 2H), 6.91 (s, 1H), 6.81 (s, 2H), 6.53 (d, J=46.6 Hz, 1H), 4.80 (d, J=2.0 Hz, 2H), 2.68 (s, 3H), 2.10 - 2.01 (m, 1H), 1.08 - 1.02 (m, 2H), 0.83 - 0.77 (m, 2H), 3H hidden under DMSO peak.
Example 406
Synthesis of (6- (((1 -amino-5, 7-dimethylisoquinolin-6-yl) methyl)amino)pyrimidin-4-yl) ( 6- cyclopropylimidazo L, 2-a]pyridin-2-yl) methanol (1-406).
Figure imgf000454_0001
[0795] Synthesis of (6-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)anuno)pyrimidin-4- yl)(6-cyclopropylimidazo[ 1 ,2-a]pyridin-2-yl)methanone. DIPEA (0.072 mL, 0.42 mmol) was added to a stirred solution of (6-chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methanol (50 mg, 0.17 mmol) and 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (33 mg, 0.17 mmol) in zPrOH (2.0 mL) and stirred at 80 °C for 1 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-10 % MeOH in DCM to give the title compound (40 mg, 52%) which was used directly in the next step.
[0796] Synthesis of (6-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)aniino)pyrimidin-4- yl)(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol NaBH (62 mg, 1.7 mmol) was added portion-wise to a stirred solution of (6-chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2- rz]pyridin-2-yl)methanone (450 mg, 1.5 mol) in MeOH (10 mL) at 0°C and stirred at 0°C for 5 min. The reaction was then allowed to warm to room temperature and stirred for 30 min. The reaction was quenched with NH4CI (sat. aq., 10 mL) and extracted with EtOAc (3 x 15 mL). The combined organics were dried over MgSO4 then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (2.5 mg, 6%). ESLMS (M+H)+: 466.2, 'H NMR (400 MHz, DMSO) 8.40 (s, 1H), 8.31 (s, 1H), 7.93 (s, 1H), 7.78 (d, J=6.1 Hz, 1H), 7.65 (s, 1H), 7.47 (br t, J=4.6 Hz, 1H), 7.35 (d, J=9.3 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 6.96 (dd, J=1.8, 9.3 Hz, 1H), 6.74 (s, 1H), 6.64 (s, 2H), 5.83 (d, J=5.0 Hz, 1H), 5.50 (d, J=5.0 Hz, 1H), 4.67 (s, 2H), 1.96 - 1.89 (m, 1H), 0.92 (ddd, J=4.2, 6.2, 8.4 Hz, 2H), 0.69 - 0.64 (m, 2H) (methyl groups obscured by DMSO).
Example 407
Synthesis of 6-(((5-( (3-chloroquinolin- 6-yl) methoxy)pyridazin-3-yl) amino) methyl)- 5, 7- dimethylisoquinolin-1 -amine (1-407).
Figure imgf000455_0001
[0797] 3 -chloro-6-(((6-chloropyridazin-4-yl)oxy)methyl)quinoline (80 mg, 0.26 mmol), 6-
(aminomethyl)-5,7-dimethylisoquinolin-l-amine (68 mg, 0.34 mmol), BHT (172 mg, 0.78 mmol), CS2CO3 (254 mg, 0.78 mmol) and Pd-PEPPSI-IPENTcl(o-picoline) (11 mg, 0.013 mmol) were suspended in DMF (1.5 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under a N2 environment for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSOi then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-(((5-((3-chloroquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine (16.3 mg, 13%). ESLMS (M+H)+: 471.4, 'H NMR (400 MHz, DMSO) 8 8.91 (d, J=2.5 Hz, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.38 (d, J=2.7 Hz, 1H), 8.36 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.85 (dd, J=2.0, 8.8 Hz, 1H), 7.79 (d, J=6.1 Hz, 1H), 7.01 (d, J=6.4 Hz, 1H), 6.77 (t, J=4.4 Hz, 1H), 6.63 (s, 2H), 6.41 (d, J=2.7 Hz, 1H), 5.35 (s, 2H), 4.68 (d, J=5.4 Hz, 2H), 2.54 (s, 3H).
[0798] The compounds in Table 32 were synthesised following a similar procedure to the synthesis of 6-(((5-((3-chloroquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-l-amine from 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine and an appropriate coupling partner. Table 32
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Example 427
[0799] Synthesis of 3-(4-(((6-(((l-anino-5, 7-diniethylisoquinolin-6- yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenoxy)-l -methylpyridin-2(l H)-one (1-427)
Figure imgf000463_0001
[0800] Synthesis of methyl 4-((2-chloropyridin-3-yl)oxy)benzoate. A mixture of 2-chloro-
3 -fluoropyridine (10.57 g, 80.30 mmol), methyl 4-hydroxy benzoate (8.16 g, 53.60 mmol) and cesium carbonate (44.88 g, 137.8 mmol) in anhydrous A,A-dimethylformamide (80 mL) was stirred at 100 °C under nitrogen for 91.5 h. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and water (150 mL). The aqueous phase was extracted with ethyl acetate (2 x 200 mL) and the combined organic extracts were dried (MgSCL), filtered and concentrated under reduced pressure to give an oil. The crude product was purified by flash chromatography eluting with 10-25% ethyl acetate in heptane. The isolated material was purified further by flash chromatography eluting with 100% di chloromethane to give two batches of methyl 4-((2-chloropyridin-3-yl)oxy)benzoate (5.019 g and 1.927 g) both as a colourless solids. The combined yield was 6.946 g (49 %). It was observed that both batches contained an impurity that was inseparable at this stage. ESLMS [M + H]+ 264. LH NMR (400 MHz, CDCh, ppm) 5 8.23 (d, J 4 Hz, 1H), 8.00 (d, J 8.8 Hz, 2H), 7.36 (d, J 7.6 Hz, 1H), 7.24 (dd, J 8, 3.6 Hz, 1H), 6.39 (d, J 8.8 Hz, 2H), 3.86 (s, 3H).
[0801] Synthesis of 2-chloro-3-(4-(methoxycarbonyl)phenoxy)-l-methylpyridin-l-ium- trifluoromethane-sulfonate. Methyl trifluoromethanesulfonate (3.00 mL, 26.5 mmol) was added to a solution of methyl 4-((2-chloropyridin-3-yl)oxy)benzoate (4.98 g, 18.9 mmol) in anhydrous dichloromethane (50 mL) and stirred at room temperature under nitrogen for 2 h. The reaction mixture was concentrated under reduced pressure to give crude 2-chloro-3-(4- (methoxycarbonyl)phenoxy)-l-methylpyridin-l-ium trifluoromethansulfonate as a colourless solid (8.517 g), which was used directly for the next step without purification. ESI-MS [M]+ 278. [0802] Synthesis of sodium 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)oxy)benzoate. A mixture of 2-chl oro-3 -(4-(m ethoxy carbonyl)phenoxy)-l-methylpyri din- 1-ium trifluoromethanesulfonate (8.517 g, as prepared above) was dissolved in a mixture of industrial methylated spirits (50 mL) and aqueous sodium hydroxide (2M, 36 mL). The mixture was stirred at 50 °C for 90 min. The reaction mixture was concentrated under reduced pressure to give crude sodium 4-((l- methyl-2-oxo-l,2-dihydropyridin-3-yl)oxy)benzoate as a white solid (10.30 g), which was used directly for the next step without purification. ESI-MS [M + H]+ 246.
[0803] Synthesis of methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)oxy)benzoate. A mixture of sodium 4-((l-methyl-2-oxo-l,2-dihydropyri din-3 -yl)oxy)benzoate (10.30 g, as prepared above) was suspended in a mixture of 5% concentrated sulfuric acid in methanol (300 mL). The mixture was heated under reflux under nitrogen for 24 h. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (400 mL) and water (250 mL). The organic phase was washed with saturated aqueous sodium hydrogen carbonate (2 x 250 mL) and water (150 mL). The combined aqueous washes were extracted further with ethyl acetate (2 * 300 mL). The combined organic extracts were dried (MgSCL), filtered and concentrated under reduced pressure to give methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3- yl)oxy)benzoate as a colourless solid (3.808 g, 78% over 3 steps). ESI-MS [M + H]+ 260. XH NMR (400 MHz, CDCh, ppm) 5 7.98 (d, J 8.8 Hz, 2H), 7.17 (d, J 6.4 Hz, 1H), 7.08 (d, J 6.4 Hz, 1H), 6.97 (d, J 8.8 Hz, 2H), 6.13 (t, J 6.4 Hz, 1H), 3.87 (s, 3H), 3.59 (s, 3H).
[0804] Synthesis of 3-(4-(hydroxymethyl)phenoxy)-l-methylpyridin-2(lH)-one. Lithium borohydride (1.892 g, 86.90 mmol) was added portion-wise over 5 min to a solution of methyl 4- ((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)oxy)benzoate (4.513 g, 17.40 mmol) in anhydrous tetrahydrofuran (150 mL) under a positive flow of nitrogen. The mixture was stirred at 60 °C under nitrogen for 16 h. Approximately 35% conversion was observed. More lithium borohydride (1.152 g, 52.9 mmol) was added and the temperature was increased to 75 °C. After a further 5 h the mixture was cooled to room temperature and slowly added to saturated aqueous ammonium chloride (250 mL) with cooling in an ice bath and the solution was stirred for 30 min. The solution was then extracted with ethyl acetate (5 x 200 mL) and the combined extracts were dried (MgSCh), filtered and concentrated under reduced pressure to give an oil. The oil was purified by flash chromatography eluting with 1-10% methanol in dichloromethane to give 3-(4- (hydroxymethyl)phenoxy)-l-methylpyridin-2(177)-one as a colourless oil (2.997 g, 74%) which subsequently crystallised. ESI-MS [M + H]+ 232. ’ll NMR (400 MHz, CDCh, ppm) 8 7.33 (d, J 8.4 Hz, 2H), 7.09 (d, J 6.8 Hz, 1H), 6.99 (d, J 8.4 Hz, 2H), 6.87 (d, J 6.8 Hz, 1H), 6.06 (t, J 6.8 Hz, 1H), 4.65 (d, J 5.6 Hz, 2H), 3.61 (s, 3H), 1.66 (t, J 5.6 Hz, 1H).
[0805] Synthesis of 3-(4-(((3-chIoropyridazin-5-yl)oxy)methyl)phenoxy)-l-methylpyridin- 2(lH)-one. 3-(4-(Hydroxymethyl)phenoxy)-l-methylpyridin-2(l/7)-one (204 mg, 0.88 mmol) was suspended in anhydrous tetrahydrofuran (3 mL) and added as a slurry to a suspension of sodium hydride (60% dispersion in oil, 55 mg, 1.38 mmol) in anhydrous tetrahydrofuran (3 mL) under nitrogen in an ice bath. The mixture was stirred for 15 min and then 90 min at room temperature. 3,5-Dichloropyridazine (182 mg, 1.22 mmol) was added portionwise and the reaction mixture was stirred at room temperature under nitrogen for 23 h. No reaction was observed. Anhydrous dimethylformamide (1 mL) was added dropwise and the reaction mixture was stirred at room temperature for a further 17.5 h. The reaction mixture was quenched with aqueous citric acid (0.1 M, 3 mL) to give pH 5 and the solvent was removed under reduced pressure. The residue was partitioned between water (15 mL) and ethyl acetate (3 x 30 mL).
The combined extracts were dried (MgSCh), filtered and concentrated under reduced pressure to give a brown solid. The solid was purified by flash chromatography eluting with 5% methanol in dichloromethane to give 3-(4-(((3-chloropyridazin-5-yl)oxy)methyl)phenoxy)-l- methylpyridin-2(177)-one as a pale brown oil that subsequently crystallised to give a pale brown solid (232 mg, 77%). 'H NMR (400 MHz, CDCh, ppm) 8 8.85 (d, J 2.4 Hz, 1H), 7.73 (d, J 8.4 Hz, 2H), 7.14 (dd, J 6.8, 1.2 Hz, 1H), 7.04-6.97 (m, 4H), 6.11 (t, J 6.8 Hz, 1H), 5.08 (s, 2H), 3.59 (s, 3H). 13C NMR (100 MHz, CDCh, ppm) 8 158.5, 158.1, 157.4, 156.8, 146.1, 143.7, 133.7, 129.7, 128.4, 125.2, 118.1, 110.4, 104.5, 70.6, 37.7.
[0806] Synthesis of 3-(4-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenoxy)-l-methylpyridin-2(lH)-one. 6- (Aminomethyl)-5,7-dimethylisoquinolin-l -amine (100 mg, 0.50 mmol), 3-(4-(((3- chloropyridazin-5-yl)oxy)methyl)phenoxy)-l-methylpyridin-2(17/)-one (142 mg, 0.41 mmol), Pd-PEPPSI2Me-IPentcl (see Notes for structure, 18 mg, 0.02 mmol) and cesium carbonate (418 mg, 1.28 mmol) were suspended in anhydrous A-dimethylformamide (0.8 mL) in a dry microwave vial. Nitrogen was bubbled through the mixture for 2 min. The vial was sealed and the mixture was heated at 75 °C for 3 h. The mixture was cooled to room temperature and suspended in 20: 1 di chloromethane: methanol + 1% acetic acid (1 mL) and passed through a silica gel plug, eluting with 5-20% methanol in dichloromethane + 1% acetic acid. The fractions were concentrated under reduced pressure and the residue treated with concentrated aqueous ammonia until pH 10. The solid was purified by reversed phase flash chromatography (Biotage Isolera, 30 g Cis Ultra SNAP cartridge), eluting with 30-65% acetonitrile in water containing 0.1% ammonia over 18 column volumes. 3-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenoxy)-l-methylpyridin-2(lH)-one was isolated as a pale yellow solid (36 mg, 17%). ESI-MS [M + H]+ 509. ’H NMR (400 MHz, CD3SOCD3, ppm) 5 8.27 (d, J2.4 Hz, 1H), 7.93 (s, 1H), 7.77 (d, J6.2 Hz, 1H), 7.61 (d, J 6.8 Hz, 1H), 7.38 (d, J 8.4 Hz, 2H), 7.22 (d, J 6.8 Hz, 1H), 7.00 (d, J 62 Hz, 1H), 6.89 (d, J 8.4 Hz,2H), 6.75 (br. t, J4 Hz, 1H),6.64 (s, 2H), 6.37 (d, J2.4 Hz, 1H), 6.21 (t, .76,8 Hz, 1H), 5.03 (s, 1H), 4.67 (d, J4 Hz, 2H), 3.47 (s, 3H), 2.54 (s, 3H). A resonance for one of the methyl groups (s, 3H) is presumably hidden under the solvent resonance at 2.50 ppm.
Example 428
Synthesis of N3 -((l-amino-S,7-dimethylisoquinolin-6-yl)methyl)-N5-methyl-N5-(quinolin-6- ylmethyl)pyridazine-3, 5-diamine (1-428).
Figure imgf000466_0001
[0807] Synthesis of 6-chloro-N-methyl-N-(quinolin-6-ylmethyl)pyridazin-4-amine.
DIPEA (0.42 mL, 2.4 mmol) was added to a stirred solution of 3,5-dichloropyridazine (107 mg, 0.72 mmol) and A-m ethyl- l-(quinolin-6-yl)methanamine hydrochloride (125 mg, 0.6 mmol) in NMP (15.0 mL) and stirred at 100 °C for 18 h. The reaction concentrated in vacuo and the residue was diluted with water (25 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was then further extracted with EtOAc (2 x 20 mL). The organics were combined, dried over M SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0 - 5% MeOH in DCM to give 6-chloro- N-methyl-N-(quinolin-6-ylmethyl)pyridazin-4-amine (103 mg, 60%). ESI-MS (M+H)+: 285.0, ’El NMR (400 MHz, CDCh) 8 8.93 (dd, J=1.8, 4.3 Hz, 1H), 8.72 (d, J=2.8 Hz, 1H), 8.15 - 8.09 (m, 2H), 7.54 - 7.51 (m, 2H), 7.44 (dd, J=4.3, 8.3 Hz, 1H), 6.65 (d, J=2.8 Hz, 1H), 4.81 (s, 2H), 3.22 (s, 3H).
[0808] Synthesis of N3-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N5-methyl-N5- (quinolin-6-ylmethyl)pyridazine-3,5-diamine. 6-chloro-/V-methyl-A-(quinolin-6- ylmethyl)pyridazin-4-amine (103 mg, 0.36 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l- amine (94 mg, 0.47 mmol), BHT (237 mg, 1.08 mmol), CS2CO3 (351 mg, 1.08 mmol) and Pd- PEPPSI-IPENTcl(o-picoline) (15 mg, 0.018 mmol) were suspended in DMF (1.5 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under N2 for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCU then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give N3-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)-N5-methyl-N5-(quinolin-6-ylmethyl)pyridazine-3,5-diamine (17.9 mg, 12%). ESIMS (M+H)+: 450.5, ’H NMR (400 MHz, DMSO) 8 8.87 (dd, >1.6, 4.0 Hz, 1H), 8.35 - 8.32 (m, 2H), 8.01 (d, J=8.8 Hz, 1H), 7.90 (s, 1H), 7.78 - 7.74 (m, 2H), 7.62 (dd, J=2.5, 8.4 Hz, 1H), 7.51 (ddd, J=4.3, 4.3, 4.3 Hz, 1H), 6.99 (d, J=6.2 Hz, 1H), 6.60 (s, 2H), 6.26 (t, J=4.3 Hz, 1H), 5.94 (d, J=2.7 Hz, 1H), 4.81 (s, 2H), 4.64 (d, J=4.1 Hz, 2H), 3.10 (s, 3H), 2.49 (s, 3H).
Example 429
Synthesis of 6-(((5-(l-(4-((lH-pyrazol-l-yl)niethyl)phenyl)ethoxy)pyridazin-3-
Figure imgf000467_0001
[0809] 5-(l-(4-((l//-pyrazol-l-yl)methyl)phenyl)ethoxy)-3-chloropyridazine (60 mg, 0.19 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (58 mg, 0.29 mmol), CS2CO3 (190 mg, 0.57 mmol) and Pd-PEPPSI-IPENT-Cl (o-picoline) (16 mg, 0.02 mmol) were suspended in DMF (0.5 mL) and placed under a N2 atmosphere. The reaction mixture was stirred at 130 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with MeOH (5 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-2% (7N NH3 in MeOH) in DCM. The residue was purified by reverse phase preparative HPLC to give 6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (14.2 mg, 16%). ESLMS (M+H)+: 480.4, ’H NMR (400 MHz, MeOD) 8 8.22 (d, J=2.5 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J=6.4 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.21 - 7.16 (m, 3H), 6.33 (t, J=2.1 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 5.44 (q, J=6.5 Hz, 1H), 5.34 (s, 2H), 4.67 (s, 2H), 2.59 (s, 3H), 2.53 (s, 3H), 1.63 (d, J=6.0 Hz, 3H).
Example 430
Synthesis of 5, 7-dimethyl-6-(((5-((2-phenylthiazol-4-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin-l-amine (1-430).
Figure imgf000468_0001
[0810] 5,7 -dimethyl-6-(((5 -((2-phenylthiazol-4-y l)methoxy)pyridazin-3 - yl)amino)methyl)isoquinolin-l -amine (7.7 mg, 4%) was prepared from 4-(((6-chloropyridazin-4- yl)oxy)methyl)-2-phenylthiazole and 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine using a similar procedure to that used for 6-(((5-(l-(4-((l//-pyrazol-l- yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine. ESIMS (M+H)+: 469.3, 'HNMR (400 MHz, MeOD) 8 8.32 (d, >3.1 Hz, 1H), 7.98 - 7.95 (m, 2H), 7.89 (s, 1H), 7.75 (d, J=6.5 Hz, 1H), 7.66 (s, 1H), 7.50 - 7.47 (m, 3H), 7.18 (d, J=6.5 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.29 (s, 2H), 4.77 (s, 2H), 2.65 (s, 3H), 2.60 (s, 3H). 431
Synthesis of 6-(((5-((4-((3-cyclopropyl-lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-3- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine (1-431).
Figure imgf000469_0001
[0811] 3 -Chloro-5-((4-((3-cyclopropyl-l/7-pyrazol-l-yl)methyl)benzyl)oxy)pyridazine (70 mg, 0.21 mmol), 6-(aminomethyl)-5, 7-dimethylisoquinolin-l-amine (85 mg, 0.32 mmol) and Pd- PEPPSI-IPENT-C1 (o-picoline) (17 mg, 0.02 mmol) were dissolved in DMF (2.1 mL). CS2CO3 (210 mg, 0.63 mmol) was added and the reaction mixture was degassed for 10 min. The reaction mixture was then stirred at 120 °C for 2 h, then cooled to room temperature, diluted with MeOH (5 mL) and concentrated in vacuo. The residue was dissolved in DCM (10 mL), filtered through Celite® and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-(((5-((4-((3-cyclopropyl-lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-3- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine (15.6 mg, 15%). ESLMS (M+H)+: 506.3, ’H NMR (400 MHz, DMSO) 8 8.33 (d, J=2.5 Hz, 1H), 7.98 (s, 1H), 7.83 (d, J=6.1 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.05 (d, J=6.3 Hz, 1H), 6.78 (dd, J=4.4, 4.4 Hz, 1H), 6.66 (s, 2H), 6.40 (d, J=2.5 Hz, 1H), 5.98 (d, J=2.0 Hz, 1H), 5.26 (s, 2H), 5.12 (s, 2H), 4.72 (d, J=4.3 Hz, 2H), 2.58 (s, 3H), 2.54 (s, 3H), 1.92 - 1.83 (m, 1H), 0.89 - 0.83 (m, 2H), 0.65 - 0.60 (m, 2H).
[0812] Using a similar procedure to that used for 6-(((5-((4-((3-cyclopropyl-17/-pyrazol-l- yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine, the compounds in Table 33 were prepared from 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine and a suitable coupling partner.
Table 33
Figure imgf000469_0002
Figure imgf000470_0001
Figure imgf000471_0001
Figure imgf000472_0003
Example 438
Synthesis of l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)niethyl)amino)pyridazin-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-438).
Figure imgf000472_0001
[0813] l-(4-(((6-chloropyridazin-4-yl)oxy)methyl)phenyl)pyridin-2(l//)-one (70 mg, 0.22 mmol) 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (67 mg, 0.33 mmol), CS2CO3 (220 mg, 0.67 mmol) and Pd-PEPPSI-IPENT-Cl (o-picoline) (19 mg, 0.02 mmol) were dissolved in DMF (1.0 mL) and the reaction mixture was degassed for 5 min. The reaction mixture was then stirred at 70 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 1-10% (7N NH3 in MeOH) in DCM then by preparative HPLC to give the title compound (6.5 mg, 6%). ESI-MS (M+H)+: 479.2, ’H NMR (400 MHz, DMSO) 8 8.33 (d, J=2.5 Hz, 1H), 7.93 (s, 1H), 7.78 (d, J=6.1 Hz, 1H), 7.65 - 7.63 (m, 1H), 7.58 - 7.55 (m, 2H), 7.53 -
7.48 (m, 1H), 7.44 - 7.41 (m, 2H), 7.02 - 7.00 (m, 1H), 6.77 (dd, J=4.4, 4.4 Hz, 1H), 6.61 (s, 2H),
6.49 - 6.46 (m, 1H), 6.41 (d, J=2.5 Hz, 1H), 6.31 (dt, J=1.3, 6.7 Hz, 1H), 5.17 (s, 2H), 4.68 (d, J=4.4 Hz, 2H), 2.54 (s, 3H). One CH3 group obscured by DMSO signal at 2.5 ppm.
Example 439
Synthesis of 5,7-dimethyl-6-(((5-((4-((l-methyl-lH-pyrazol-3-yl)methyl)benzyl)oxy)pyridazin- 3-yl)amino)methyl)isoquinolin-l-amine (1-439).
Figure imgf000472_0002
[0814] 3 -chloro-5-((4-((l-methyl-17/-pyrazol-3-yl)methyl)benzyl)oxy)pyridazine (120 mg,
0.37 mmol) 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (96 mg, 0.47 mmol), Pd-PEPPSI- IPENT-C1 (o-picoline) (15 mg, 0.02 mmol), CS2CO3 (0.36 g, 1.1 mmol) and BHT (0.24 g, 1.1 mmol) were suspended in DMF (2.0 m ) and the reaction mixture was degassed for 5 min. The reaction mixture was then stirred at 75 °C for 90 min, cooled to room temperature and concentrated /// vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 1-15% (7N NH3 in MeOH) in DCM then by reverse phase preparative HPLC to give 5,7-dimethyl-6-(((5-((4-((l-methyl-lH-pyrazol-3-yl)methyl)benzyl)oxy)pyridazin-3- yl)amino)methyl)isoquinolin-l-amine (53 mg, 30%) as a yellow solid. ESI-MS (M+H)+: 480.3, ’El NMR (400 MHz, DMSO) 5 8.27 (d, J=2.5 Hz, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.77 (d, J=6.3 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.34 - 7.31 (m, 2H), 7.25 - 7.22 (m, 2H), 7.01 (d, J=6.1 Hz, 1H), 6.72 (t, J=4.4 Hz, 1H), 6.67 (s, 2H), 6.35 (d, J=2.5 Hz, 1H), 5.96 (d, J=2.3 Hz, 1H), 5.04 (s, 2H), 4.67 (d, J=4.3 Hz, 2H), 3.84 (s, 2H), 3.75 (s, 3H), 2.53 (s, 3H). One CH3 not visible as obscured by DMSO signal at 2.5 ppm.
[0815] Using a similar procedure to that used for 5,7-dimethyl-6-(((5-((4-((l-methyl-l/7- pyrazol-3-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)isoquinolin-l -amine, the compounds in Table 34 were prepared from 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine and an appropriate coupling partner.
Table 34
Figure imgf000473_0001
Figure imgf000474_0001
Figure imgf000475_0002
Example 445
Synthesis of 6-(((5-((6-((lH-pyrazol-l-yl)methyl)pyridin-3-yl)methoxy)pyridazin-3-
Figure imgf000475_0001
[0816] A mixture of 5-((6-((lZ/-pyrazol-l-yl)methyl)pyridin-3-yl)methoxy)-3- chloropyridazine (80 mg, 0.27 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (71 mg, 0.35 mmol), Pd-PEPPSI-IPENT-Cl (o-picoline) (11 mg, 0.01 mmol), CS2CO3 (260 mg, 0.81 mmol) and BHT (180 mg, 0.81 mmol) in DMF (2.0 mL) was degassed for 10 min. The reaction mixture was then stirred at 75 °C for 1 h, then at 100 °C for 2 h. The reaction mixture was cooled to room temperature and poured into water (2 mL), stirred for 15 min and filtered. The precipitate was washed with water, partially dried and triturated with Et2O. The residue was further purified by preparative HPLC to give the title compound (13 mg, 10%) as a cream solid. ESI-MS (M+H)+: 467.4, ’H NMR (400 MHz, DMSO) 8 8.52 (d, J=1.8 Hz, 1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.76 (d, J=6.1 Hz, 1H), 7.70 (dd, J=2.0, 8.1 Hz, 1H), 7.46 (d, J=1.3 Hz, 1H), 7.10 (dd, J=4.3, 4.3 Hz, 1H), 7.00 - 6.94 (m, 2H), 6.61 (s, 2H), 6.28 (dd, J=2.0, 2.0 Hz, 1H), 5.41 (s, 2H), 5.20 (s, 1H), 4.97 (s, 2H), 4.44 - 4.41 (m, 2H), 2.47 (s, 3H), 2.43 (s, 3H).
Example 446
Synthesis of 6-(((5-((5-((lH-pyrazol-l-yl)methyl)pyridin-2-yl)methoxy)pyridazin-3- yl) amino) methyi)-5, 7-dimethylisoquinolin-l -amine (1-446).
Figure imgf000476_0001
[0817] 6-(((5-((5-((lH-pyrazol-l-yl)methyl)pyridin-2-yl)methoxy)pyridazin-3- yl)amino)methyl)-5, 7-dimethylisoquinolin-l -amine was prepared from 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine and 5-((5-((l//-pyrazol-l-yl)methyl)pyridin-2-yl)methoxy)-3- chloropyridazine (6 mg, 10%) using a similar procedure to that used for 6-(((5-((6-((l/f-pyrazol- l-yl)methyl)pyridin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)-5, 7-dimethylisoquinolin-l- amine. ESI-MS (M+H)+: 467.4, ’H NMR (400 MHz, DMSO) 8 8.47 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H), 7.91 (s, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.77 (d, J=6.1 Hz, 1H), 7.66 (dd, J=2.0, 8.1 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.01 - 6.97 (m, 1H), 6.74 (dd, 4.3, 4.3 Hz, 1H), 6.63 (s, 2H), 6.33 (d, J=2.5 Hz, 1H), 6.27 (dd, J=2.1, 2.1 Hz, 1H), 5.38 (s, 2H), 5.15 (s, 2H), 4.66 (d, J=4.3 Hz, 2H), 2.53 (s, 3H).
Example 447
Synthesis ofN3-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5, 7-dimethylisoquinolin-6- yl) methyl)pyridazine-3, 5-diamine (1-447).
Figure imgf000477_0001
[0818] Synthesis ofN-(4-((lH-pyrazol-l-yl)methyl)benzyl)-6-chloropyridazin-4-amine. A solution of (4-((l/7-pyrazol-l-yl)methyl)phenyl)m ethanamine (90 mg, 0.74 mmol), 3,5- dichloropyridazine (133 mg, 0.89 mmol) and NEt3 (0.26 mL, 1.85 mmol) in /PrOH (20 mL) was heated at 80 °C for a 16 h. Further 3,5-dichloropyridazine (66 mg, 0.44 mmol) was added and heating was continued for 5 h. The solvents were removed in vacuo, the residue re-dissolved in DCM and the solution washed with water, passed through a hydrophobic frit then concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 0- 10% (7N NEE in MeOH) in DCM to give the desired product (92 mg, 41%). ESI-MS (M+H)+: 300, 'H NMR (400 MHz, CDCh) 5 8.46 (d, J=2.8 Hz, 1H), 7.56 - 7.54 (m, 1H), 7.43 - 7.41 (m, 1H), 7.30 - 7.26 (m, 2H), 7.23 - 7.17 (m, 2H), 6.49 (d, J=2.5 Hz, 1H), 6.31 - 6.29 (m, 1H), 5.34 - 5.32 (m, 2H), 5.13 - 5.10 (m, 1H), 4.35 (d, J=5.3 Hz, 2H).
[0819] Synthesis of N3-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyridazine-3, 5-diamine. A mixture of A-(4-((H7-pyrazol-l- yl)methyl)benzyl)-6-chloropyridazin-4-amine (90 mg, 0.30 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (91 mg, 0.45 mmol), Pd-PEPPSI-IPent (o-picoline) (25 mg, 0.03 mmol) and CS2CO3 (293 mg, 0.90 mmol) in DMF (1.5 mL) was degassed with N2 for 15 min, then heated at 120 °C for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of 0-10% (7N NH3 in MeOH) in DCM followed by reverse phase preparative HPLC to give the desired product (57 mg, 41%) as a formic acid salt. ESI-MS (M+H)+: 465.3, >H NMR (400 MHz, DMSO) 8 8.17 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.89 (s, 1H), 7.79 - 7.74 (m, 2H), 7.43 - 7.42 (m, 1H), 7.27 - 7.24 (m, 2H), 7.18 - 7.13 (m, 3H), 7.00 - 6.97 (m, 1H), 6.68 - 6.64 (m, 2H), 6.33 (s, 1H), 6.24 (t, J=2.0 Hz, 1H), 5.68 (d, J=2.3 Hz, 1H), 5.28 (s, 2H), 4.57 (d, J=4.5 Hz, 2H), 4.18 (d, J=5.8 Hz, 2H), 2.45 (s, 3H), one CH3 signal obscured by DMSO signal.
Example 448
Synthesis ofN3-((l-amino-5,7-dimethylisoquinolin-6-yl)niethyl)-N5-benzylpyridazine-3,5- diamine (1-448).
Figure imgf000478_0001
[0820] N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-benzylpyridazine-3,5- diamine was synthesised in a similar manner to Ar5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-jV3-((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)pyridazine-3,5-diamine from benzylamine, 6- (aminomethyl)-5,7-dimethylisoquinolin-l -amine and 3,5-dichloropyridazine. ESI-MS (M+H)+:
385.4, ’H NMR (400 MHz, DMSO) 5 8.06 (d, J=2.5 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J=6.1 Hz, 1H), 7.33 - 7.31 (m, 4H), 7.27 - 7.21 (m, 1H), 7.07 (dd, J=5.9, 5.9 Hz, 1H), 7.00 - 6.98 (m, 1H), 6.60 (s, 2H), 6.21 (t, J=4.5 Hz, 1H), 5.72 (d, J=2.4 Hz, 1H), 4.59 (d, J=4.5 Hz, 2H), 4.22 (d, J=5.9 Hz, 2H), 2.47 (s, 3H), one CH3 signal obscured by DMSO signal.
Example 449
Synthesis of 6-(((6-(benzyloxy)pyrimidin-4-yI)amino)methyl)-5, 7-dimethylisoquinolin-l-anune (1-449).
Figure imgf000478_0002
[0821] Synthesis of 6-(((6-chloropyrimidin-4-yl)amino)methyl)-5, 7-dimethylisoquinolin-l- amine. 6-(((6-chloropyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine was synthesized in a similar manner to A-(4-((17/-pyrazol-l-yl)methyl)benzyl)-6-chloropyridazin-4- amine starting from 4,6-dichloropyrimidine and 6-(aminomethyl)-5,7-dimethylisoquinolin-l- amine, and was carried forward to the next step without further purification (0.46 g, 44%). ESIMS (M+H)+: 314.0
[0822] Synthesis ofN5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyridazine-3,5-diamine. NaH (60% in mineral oil, 9 mg, 0.38 mmol) was suspended in dry DMSO (2.5 mL) and benzyl alcohol (26 pL, 0.25 mmol) was added, followed by 6-(((6-chloropyrimidin-4-yl)amino)methyl)-5, 7-dimethylisoquinolin-l -amine (80 mg, 0.25 mmol). The mixture was heated to 80 °C for 16 h. The solvent was removed in vacuo and the residue treated with water and EtOAc. The organic extract was separated, dried over MgSCh and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the desired product (55 mg, 57%). ’H NMR (400 MHz, DMSO) 8 8.28 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=6.1 Hz, 1H), 7.44 - 7.32 (m, 5H), 7.24 (dd, J=4.5, 4.5 Hz, 1H), 7.00 (d, J=6.1 Hz, 1H), 6.62 (s, 2H), 5.89 (s, 1H), 5.31 (s, 2H), 4.62 - 4.57 (m, 2H), 2.52 (s, 3H). ESI-MS (M+H)+: 386.3.
Example 450
Synthesis of 6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-(trifluoromethyl)pyridazin-3- yl) amino) methyi)-5, 7-dimethylisoquinolin-l -amine (1-450).
Figure imgf000479_0001
[0823] Synthesis of 5, 7-dimethyl-6-(((6-(trifluoromethyl)pyridazin-3- yl)anuno)niethyl)isoquinolin-l-amine. A mixture of 3-chloro-6-(trifluoromethyl)pyridazine (500 mg, 2.75 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (552 mg, 2.75 mmol) and DIPEA (1.44 mL, 8.25 mmol) in 1,4-dioxane (8.0 mL) was heated at 180 °C under microwave irradiation for 45 minutes. Further 3-chloro-6-(trifluoromethyl)pyridazine (250 mg, 1.37 mmol) was added and heating continued at 180 °C for 2 h. The solvents were removed in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of 0- 10% (7N NH3 in MeOH) in DCM to give the desired product as a brown solid (531 mg, 55%). ESI-MS (M+H)+: 348, ’H NMR (400 MHz, DMSO) 8 8.77 - 8.77 (m, 1H), 8.09 (s, 1H), 7.76 - 7.70 (m, 2H), 7.68 (d, J=9.3 Hz, 1H), 7.45 - 7.42 (m, 1H), 7.13 (d, J=6.6 Hz, 1H), 7.01 (d, J=9.3 Hz, 1H), 4.79 (d, J=4.5 Hz, 2H), 2.57 (s, 3H), 2.53 (s, 3H).
[0824] Synthesis of tert-butyl (tert-butoxycarbonyl)(6-(((tert-butoxycarbonyl)(6- (trifluoromethyl)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-l-yl)carbamate.
BOC2O (1.33 g, 6.11 mmol) was added to a solution of 5,7-dimethyl-6-(((6- (trifluoromethyl)pyridazin-3-yl)amino)methyl)isoquinolin-l-amine (0.53 g, 1.53 mmol), DIPEA (1.06 mL, 6.11 mmol) and DMAP (0.24 g, 1.99 mmol) in THF (20 mL). The mixture was stirred at room temperature overnight, then further BociO (0.67 g, 3.05 mmol), DIPEA (0.53 mL, 3.05 mmol) and DMAP (0.19 g, 1.52 mmol) were added. After stirring for 5 h, further BOC2O (0.67 g, 3.05 mmol) and DIPEA (0.53 mL, 3.05 mmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of 0-20% EtOAc in DCM to give tert-butyl (tertbutoxy carbonyl)(6-(((tert-butoxycarbonyl)(6-(trifluoromethyl)pyridazin-3-yl)amino)methyl)-5, 7- dimethylisoquinolin-l-yl)carbamate as a yellow oil (485 mg, 49%). ESI-MS (M+H)+: 648.
[0825] Synthesis of tert-butyl (tert-butoxycarbonyl)(6-(((tert-butoxycarbonyl)(5-iodo-6- (trifluoromethyl)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-l-yl)carbamate. n- BuLi (1.6 M in hexanes; 0.35 mL, 0.56 mmol) was added to an ice-cooled solution of 2, 2, 6, 6- tetramethylpiperidine (0.094 mL, 0.56 mmol) in THF (8.0 mL). The mixture was stirred at room temperature for 30 min, then cooled to -78 °C and a solution of /c/'Z-butyl (tert- butoxycarbonyl)(6-(((ZerZ-butoxycarbonyl)(6-(trifluoromethyl)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-l-yl)carbamate (0.12 g, 0.185 mmol) in dry THF (2.0 mL) was added.
After stirring at -78 °C for 1 h, the reaction was quenched by addition of AcOH (3.0 mL). The mixture was warmed to room temperature, diluted with DCM and washed with NaHCCh (sat. aq.). The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of 0-25% EtOAc in DCM to give tert-butyl (tertbutoxy carbonyl)(6-(((tert-butoxycarbonyl)(5-iodo-6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l-yl)carbamate as a yellow oil (30 mg, 20%). ESIMS (M+H)+: 774, ‘H NMR (400 MHz, CDCh) 5 8.54 (s, 1H), 8.35 (d, J=6.1 Hz, 1H), 7.73 (d, J=6.1 Hz, 1H), 7.53 (s, 1H), 5.65 (s, 2H), 4.12 (q, J=7.1 Hz, 1H), 2.69 (s, 3H), 2.63 (s, 3H), 1.58 (s, 4H), 1.50 (s, 9H), 1.24 (s, 18H).
[0826] Synthesis of tert-butyl (6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-
(trifluoromethyl)pyridazin-3-yl)(tert-butoxycarbonyl)amino)methyl)-5, 7-dimethylisoquinolin- l-yl)(tert-butoxycarbonyl)carbamate. NaH (60% in mineral oil, 7 mg, 0.17 mmol) was suspended in DMF (1.0 mL) at 0 °C and a solution of (4-((lH-pyrazol-l- yl)methyl)phenyl)methanol (38 mg, 0.20 mmol) in DMF (1.0 mL) was added. The solution was allowed to warm to room temperature, stirred for 10 min, and cooled to 0 °C. A solution of tert- butyl (to7-butoxycarbonyl)(6-(((terLbutoxycarbonyl)(5-iodo-6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l-yl)carbamate (78 mg, 0.10 mmol) in DMF (1.0 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h. NH4CI (sat. aq.), water, and DCM were added, the organic phase separated, and the aqueous phase extracted again with DCM. The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo to give the crude product as a yellow oil (106 mg) that was used without further purification.
[0827] Synthesis of 6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-
(trifluoromethyl)pyridazin-3-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine. HC1 (4 M in 1,4-dioxane, 0.5 mL) was added to a solution of crude te/7-butyl (6-(((5-((4-((l//-pyrazol-l- yl)methyl)benzyl)oxy)-6-(trifluoromethyl)pyridazin-3-yl)(terLbutoxycarbonyl)amino)methyl)- 5,7-dimethylisoquinolin-l-yl)(te77-butoxycarbonyl)carbamate (0.1 mmol) in 1,4-dioxane (1.0 mL) and the mixture stirred at room temperature for 3 h. The solvents were removed in vacuo and the crude residue passed through an SCX column, loading in MeOH and eluting the product with (7N NH3 in MeOH) in DCM. The product-containing fractions were concentrated in vacuo and the residue purified by reverse phase preparative HPLC to give the desired compound (6.9 mg, 13%). ESLMS (M+H)+: 534.4, 'H NMR (400 MHz, DMSO) 8 8.23 (s, 1H), 7.95 (s, 1H), 7.83 (dd, J=0.8, 2.2 Hz, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.49 (t, 1=4.3 Hz, 1H), 7.46 (dd, J=0.7, 1.7 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.02 (d, J=6.0 Hz, 1H), 6.66 (s, 2H), 6.54 (s, 1H), 6.27 (t, J=2.1 Hz, 1H), 5.34 (s, 2H), 5.21 (s, 2H), 4.76 (d, J=4.3 Hz, 2H), 2.54 (s, 3H).
Example 451
Synthesis ofN3-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5,7-dimethylisoquinolin-6-
Figure imgf000482_0001
[0828] Synthesis of tert-butyl (6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)amino)-6- (trifluoroniethyl)pyridazin-3-yl)(tert-butoxycarbonyl)amino)methyl)-5,7-dimethylisoquinolin- l-yl)(tert-butoxycarbonyl)carbamate. A mixture of Zc/'Z-butyl (terZ-butoxycarbonyl)(6-(((tert- butoxycarbonyl)(5-iodo-6-(trifluoromethyl)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-l-yl) (65 mg, 0.084 mmol), (4-((l//-pyrazol-l- yl)methyl)phenyl)methanamine (20 mg, 0.11 mmol), Pd-PEPPSI-IPent (o-picoline) (3.5 mg, 0.004 mmol), BHT (56 mg, 0.25 mmol) and CS2CO3 (82 mg, 0.25 mmol) in DMF (1.0 mb) was degassed with N2 for 5 min, then heated at 75 °C for 1.5 h. Water was added and the mixture extracted with DCM. The combined organic extract was passed through a hydrophobic frit and the solvents were removed in vacuo. The crude residue was purified on an SCX column, loading in MeOH and eluting the product with (7N NH3 in MeOH) in DCM. The product-containing fractions were concentrated in vacuo to give the crude product as a brown oil (57 mg) that was used without further purification. ESI-MS (M+H)+: 833.
[0829] Synthesis of N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5, 7- dimethylisoquinolin-6-yl)niethyl)-6-(trifluoroniethyl)pyridazine-3,5-diamine. HC1 (4 M in dioxane, 0.9 mb) was added to a solution of crude /c/7-butyl (6-(((5-((4-((177-pyrazol-l- yl)methyl)benzyl)amino)-6-(trifluoromethyl)pyridazin-3-yl)(ter/-butoxycarbonyl)amino)methyl)- 5,7-dimethylisoquinolin-l-yl)(te/7-butoxycarbonyl)carbamate (32 mg, 0.04 mmol) in 1,4-dioxane (1.0 mL) and the mixture stirred at room temperature for 2 h. The solvents were removed in vacuo and the crude residue purified by reverse phase preparative HPLC to give the desired compound (8.12 mg, 39%). ESI-MS (M+H)+: 531.5, ’H NMR (400 MHz, DMSO) S 8.27 (s, 1H), 7.91 (s, 1H), 7.79 - 7.77 (m, 2H), 7.43 (dd, J=0.7, 1.9 Hz, 1H), 7.24 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 6.99 (d, J=6.1 Hz, 1H), 6.95 - 6.88 (m, 2H), 6.62 (s, 2H), 6.24 (t, J=2.1 Hz, 1H), 5.78 (s, 1H), 5.28 (s, 2H), 4.64 (d, J=4.2 Hz, 2H), 4.32 (d, J=6.0 Hz, 2H), 2.48 (s, 3H), 2.43 (s, 3H).
Example 452
Synthesis of 6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-4-((quinolin-6- ylmethyl)amino)pyridazine-3-carboxaniide (1-452).
Figure imgf000483_0001
[0830] Synthesis of methyl 6-chloro-4-((quinolin-6-ylmethyl)amino)pyridazine-3- carboxylate. A mixture of methyl 4,6-dichloropyridazine-3-carboxylate (0.20 g, 1.3 mmol) and quinolin-6-ylmethanamine (0.26 g, 1.3 mmol) in /PrOH (5.0 mL) was stirred at 80 °C for 2 h. The mixture was cooled and concentrated in vacuo to give methyl 6-chloro-4-((quinolin-6- ylmethyl)amino)pyridazine-3 -carboxylate, which was used directly in the next step without further purification.
[0831] Synthesis of 6-chloro-4-((quinolin-6-ylmethyl)amino)pyridazine-3-carboxamide.
Methyl 6-chloro-4-((quinolin-6-ylmethyl)amino)pyridazine-3-carboxylate (0.20 g, 0.63 mmol) was stirred in NH3 in MeOH (7.0 N, 5.0 mL) at room temperature for 2.5 h then concentrated in vacuo. The residue was suspended in water with a small quantity of MeOH. The solid was isolated by filtration and dried under suction to give 6-chloro-4-((quinolin-6- ylmethyl)amino)pyridazine-3-carboxamide (0.12 g, 59%) as a beige solid. ESI-MS (M+H):+ 314.2.
[0832] Synthesis of 6-(((l-amino-5, 7-dimethylisoquinoUn-6-yl)methyl)amino)-4- ((quinolin-6-ylmethyl)amino)pyridazine-3-carboxanude. A mixture of 6-chloro-4-((quinolin-6- ylmethyl)amino)pyridazine-3-carboxamide (0.050 g, 0.16 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (0.038 g, 0.19 mmol) and KF (0.023 g, 0.40 mmol) in DMSO was stirred at 120 °C in a microwave reactor for 30 min then at 160 °C for 30 min and at 180 °C for 30 min. The mixture was then stirred at 175 ° C under conventional heating for 18 h. The mixture was cooled and poured into water. The precipitate was collected by filtration, washed with water and dried. The residue was purified by column chromatography on silica gel, eluting with 0-10% (7N NHs in MeOH) in DCM and then by reverse phase preparative HPLC to give 6- (((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-4-((quinolin-6- ylmethyl)amino)pyridazine-3 -carboxamide (0.012 g, 16%) as a formic acid salt. ESI-MS (M+H): + 479.5, ‘H NMR (400 MHz, DMSO) 5 9.07 (t, J=5.9 Hz, 1H), 8.92 - 8.89 (m, 1H), 8.39 - 8.35 (m, 1H), 8.28 - 8.21 (m, 2H), 8.07 - 8.03 (m, 1H), 7.91 (d, J=15.9 Hz, 2H), 7.82 - 7.74 (m, 2H), 7.55 (dd, J=4.2, 8.2 Hz, 1H), 7.48 - 7.46 (m, 1H), 7.01 (d, J=6.3 Hz, 1H), 6.83 (t, J=4.2 Hz, 1H), 6.67.
Example 453
[0833] Synthesis of (2-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyridin-4-
Figure imgf000484_0001
[0834] Synthesis of 6-cyclopropylimidazo[l,2-a]pyridine-2-carbaldehyde. A suspension of (6-cy cl opropylimidazo[l,2-rz]pyridin-2-yl)m ethanol (2.0 g, 11 mmol), manganese (IV) oxide (9.2 g, 110 mmol) in chloroform (25 mL) and MeCN (25 mL) was stirred at 50 °C for 1 hour.
The mixture was cooled to room temperature, filtered through Celite® and concentrated in vacuo to give 6-cyclopropylimidazo[l,2-a]pyridine-2-carbaldehyde (1.3 g, 66 %). ESI-MS (M+H)+: 187.2, 'H NMR (400 MHz, CDCh) 5 10.13 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.57 (d, J=9.6 Hz, 1H), 7.03 (dd, 1=1.8, 9.3 Hz, 1H), 1.95 - 1.87 (m, 1H), 1.05 - 0.99 (m, 2H), 0.75 - 0.69 (m, 2H). [0835] Synthesis of (2-chloropyridin-4-yl)(6-cyclopropyliinidazo[l,2-a]pyridin-2- yl)methanol. /PrMgCl (2.0 M in THF, 2.4 mL, 4.7 mmol) was added slowly to a stirred solution of 4-bromo-2-chloropyridine (0.50 mL, 4.5 mmol) in THF (20 mL) at 0 °C under a N2 atmosphere. The mixture was stirred at room temperature for 2 h then a solution of 6- cyclopropylimidazo[l,2-rz]pyridine-2-carbaldehyde (0.80 g, 4.3 mmol) in THF (20 mL) was added at 0 °C. The mixture was stirred at room temperature for 3 h then cooled to 0 °C and NH4CI (sat. aq., 10 mL) was added. The mixture was diluted with NaHCCh (sat. aq., 90 mL) and water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over MgSCU, filtered and concentrated in vacuo. The residue was partially purified by column chromatography on silica gel, eluting with 0-20% MeOH in DCM. Further purification by column chromatography on silica gel, eluting with 40-80% EtOAc in cyclohexane followed by 0-10% MeOH in DCM gave (2-chloropyridin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methanol (0.59 g, 46%) as an orange gum. ESI-MS (M+H)+: 300.2.
[0836] Synthesis of (2-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)anuno)pyridin-4- yl)(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanoL (2-chloropyridin-4-yl)(6- cyclopropylimidazo[l ,2-A|pyridin-2-yl)methanol (150 mg, 0.50 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (130 mg, 0.65 mmol), BHT (330 mg, 1.5 mmol), CS2CO3 (490 mg, 1.50 mmol) and Pd-PEPPSI(2Me)-IPENTcl (42 mg, 0.05 mmol) were suspended in DMF (5.0 mL) and degassed with N2 for 5 min. The reaction was then heated to 80 °C under a nitrogen atmosphere for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCL then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give (2-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyridin-4-yl)(6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methanol (60 mg, 24%). ESLMS (M+H)+: 465.4, *H NMR (400 MHz, DMSO) 8 8.30 - 8.30 (m, 1H), 8.20 (s, 1H), 7.94 (d, J=5.3 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J=6.1 Hz, 1H), 7.63 (s, 1H), 7.33 (d, J=9.3 Hz, 1H), 6.98 (d, J=6.1 Hz, 1H), 6.94 (q, J=3.7 Hz, 1H), 6.64 (br s, 2H), 6.61 (s, 1H), 6.56 (dd, J=1.3, 5.3 Hz, 1H), 6.51 (t, J=4.5 Hz, 1H), 5.56 (s, 1H), 4.56 (d, J=4.5 Hz, 2H), 2.52 (s, 3H), 2.48 (s, 3H), 1.94 - 1.86 (m, 1H), 0.93 - 0.87 (m, 2H), 0.67 - 0.62 (m, 2H). Exchangeable OH not observed.
Example 454
Synthesis of 6-(((4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-2-yl)amino)methyl)-5,7- dimethylisoquinolin-l-amine (1-454).
Figure imgf000486_0001
[0837] Synthesis of 4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-2-chloropyridine.
Diisopropyl azodicarboxylate (460 mg, 2.3 mmol) in THF (5.0 mL) was added dropwise to a stirred solution of PPh3 (510 mg, 1.95 mmol) in THF (10.0 mL) at 0 °C and stirred for 40 min. A solution of (4-((177-pyrazol-l-yl)methyl)phenyl)m ethanol (280 mg, 1.5 mmol) and 2- chloropyridin-4-ol (210 mg, 1.6 mmol) in THF (5.0 mL) was added dropwise to the cooled solution over 20 min. The reaction was stirred at 0 °C for 1 h and then allowed to warm to room temperature and stirred for 48 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 10-60% EtOAc in cyclohexane to give 4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-2-chloropyridine (78 mg, 18%) which was used directly in the next step without further purification.
[0838] Synthesis of 6-(((4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-2- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine. 4-((4-((l /A-Pyrazol- I - yl)methyl)benzyl)oxy)-2-chloropyridine (40 mg, 0.13 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (35 mg, 0.17 mmol), CS2CO3 (130 mg, 0.39 mmol) and Pd- PEPPSLIPENTcl(o-picoline) (11 mg, 0.013 mmol) were suspended in DMF (1.0 mL) and degassed with N2 for 5 min. The reaction was then heated to 120 °C under N2 for 2 h. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCL and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-(((4-((4-((lH-pyrazol-l- yl)methyl)benzyl)oxy)pyridin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (10 mg, 17%). ESLMS (M+H)+: 465.4, 'H NMR (400 MHz, DMSO) 8 7.83 (s, 1H), 7.79 (d, >5.8 Hz, 1H), 7.73 (d, >1.8 Hz, 1H), 7.69 (d, >6.1 Hz, 1H), 7.38 (d, >1.3 Hz, 1H), 7.30 (d, >8.3 Hz, 2H), 7.14 (d, >8.1 Hz, 2H), 6.92 (d, >6.1 Hz, 1H), 6.52 (s, 2H), 6.34 (dd, >4.5, 4.5 Hz, 1H), 6.20 - 6.13 (m, 2H), 6.04 (d, >2.3 Hz, 1H), 5.25 (s, 2H), 4.94 (s, 2H), 4.48 (d, >4.5 Hz, 2H), 2.39 (s, 6H).
Example 455
Synthesis of 6-(((2-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-l-amine (1-455).
Figure imgf000487_0001
[0839] Synthesis of 2-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-4-chloropyridine. K2CO3 (260 mg, 1.9 mmol) was added to a stirred solution of l-(4-(chloromethyl)benzyl)-17/-pyrazole (160 mg, 0.75 mmol) and 4-chloropyridin-2-ol (97 mg, 0.75 mmol) in DMF (2.0 mL) and the reaction was heated at 80 °C for 4 h. The reaction was cooled to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-5% MeOH in DCM to give 2-((4-((lH-pyrazol-l- yl)methyl)benzyl)oxy)-4-chloropyridine (28 mg, 12%). 'HNMR (400 MHz, CDQ3) 8 8.05 (d, >5.6 Hz, 1H), 7.55 (d, >1.5 Hz, 1H), 7.41 (d, 8.1 Hz, 2H), 7.38 (d, >2.3 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 6.89 (dd, J=1.8, 5.6 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 6.28 (t, J=2.1 Hz, 1H), 5.35 (s, 2H), 5.33 (s, 2H).
[0840] Synthesis of 6-(((2-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-4- yl)amino)niethyl)-5,7-diniethylisoquinolin-l-amine. 2-((4-((l/f-Pyrazol-l- yl)methyl)benzyl)oxy)-4-chloropyridine (74 mg, 0.25 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (75 mg, 0.37 mmol), CS2CO3 (240 mg, 0.75 mmol) and Pd- PEPPSI-IPENTcl(o-pi coline) (21 mg, 0.025 mmol) were suspended in DMF (1.0 mL) and degassed with N2 for 5 min. The reaction was then heated to 120 °C under a N2 environment for 2 h. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL), the layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCM and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-(((2-((4-((lH-pyrazol-l- yl)methyl)benzyl)oxy)pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (15 mg, 13%). ESI-MS (M+H)+: 465.4, 'H NMR (400 MHz, DMSO) 5 7.94 (s, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.78 (d, J=6.1 Hz, 1H), 7.67 (d, J=5 8 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.01 (d, J=6.1 Hz, 1H), 6.66 (s, 2H), 6.50 (dd, J=4.1, 4.1 Hz, 1H), 6.35 (dd, J=1.9, 5.8 Hz, 1H), 6.27 (dd, J=2.0, 2.0 Hz, 1H), 6.04 (d, J=1.9 Hz, 1H), 5.34 (s, 2H), 5.26 (s, 2H), 4.30 (d, J=4.1 Hz, 2H), two CH3 signals obscured by DMSO signal.
Example 456
Synthesis of l-(4-(((2-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-5- chloropyridin-4-yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-456).
Figure imgf000488_0001
[0841] Synthesis of l-(4-(((2,5-dichloropyridin-4-yl)oxy)methyl)benzyl)pyridin-2(lH)-one.
K2CO3 (350 mg, 2.5 mmol) was added to a stirred solution of l-(4- (chloromethyl)benzyl)pyridin-2(17/)-one (230 mg, 1.0 mmol) and 2,5-dichloropyridin-4-ol (160 mg, 1.0 mmol) in DMF (3.0 mL) and the reaction was heated at 80 °C for 4 h. The reaction was cooled to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-5% MeOH in DCM to give the title compound (170 mg, 48%). ESLMS (M+H)+: 361, ’H NMR (400 MHz, CDCh) 8 8.25 (s, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.37 - 7.33 (m, 2H), 7.34 - 7.30 (m, 1H), 7.30 - 7.27 (m, 1H), 6.90 (s, 1H), 6.64 - 6.60 (m, 1H), 6.19 - 6.14 (m, 1H), 5.18 - 5.16 (m, 4H).
[0842] Synthesis of l-(4-(((2-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-5- chloropyridin-4-yl)oxy)methyl)benzyl)pyridin-2(lH)-one. l-(4-(((2,5-Dichloropyridin-4- yl)oxy)methyl)benzyl)pyridin-2(17/)-one (83 mg, 0.23 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (69 mg, 0.35 mmol), CS2CO3 (230 mg, 0.69 mmol) and Pd- PEPPSI-IPENTcl(o-pi coline) (19 mg, 0.023 mmol) were suspended in DMF (2.0 mL) and degassed with N2 for 5 min. The reaction was then heated to 120 °C under N2 for 2 h. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give l-(4-(((2-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)-5-chloropyridin-4-yl)oxy)methyl)benzyl)pyridin- 2(lH)-one (6.9 mg, 6%). ESLMS (M+H)+: 526.2, ’H NMR (400 MHz, DMSO) 8 8.27 (s, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.84 - 7.80 (m, 2H), 7.49 - 7.42 (m, 3H), 7.35 (d, J=8.3 Hz, 2H), 7.03 (d, J=6.3 Hz, 1H), 6.72 (dd, J=4.4, 4.4 Hz, 1H), 6.66 (s, 2H), 6.44 (d, J=9.1 Hz, 1H), 6.34 (s, 1H), 6.30 - 6.25 (m, 1H), 5.13 (d, J=5.8 Hz, 4H), 4.58 (d, J=4.5 Hz, 2H).
Example 457
Synthesis of 6-(((5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-5H-pyrrolo[3,2-c]pyridazin-3- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine (1-457).
Figure imgf000490_0001
[0843] Synthesis of 5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-3-chloro-5H-pyrrolo[3,2- c]pyridazine. 3-Chloro-5//-pyrrolo[3,2-c]pyridazine (100 mg, 0.65 mmol) in DMF (2.0 mL) was added dropwise to a stirred suspension of NaH (60% in mineral oil, 78 mg, 2.0 mmol) in DMF (3.0 mL) at 0 °C and the reaction was stirred at 0 °C for 30 min. l-(4-(Chloromethyl)benzyl)-l/7- pyrazole (150 mg, 0.72 mmol) in DMF (0.50 mL) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-5% MeOH in DCM to give 5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-3-chloro-5H- pyrrolo[3,2-c]pyridazine (75 mg, 37%). ESLMS (M+H)+: 324.0, 'H NMR (400 MHz, DMSO) 5 8.13 (d, J=1.0 Hz, 1H), 8.03 (d, J=3.4 Hz, 1H), 7.78 - 7.77 (m, 1H), 7.43 - 7.42 (m, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.96 (dd, J=0.9, 3.5 Hz, 1H), 6.24 (t, J=2.0 Hz, 1H), 5.44 (s, 2H), 5.28 (s, 2H).
[0844] Synthesis of 6-(((5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-5H-pyrrolo[3,2-c]pyridazin- 3-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine. 5-(4-(( 177-Pyrazol- 1 -yl)methyl)benzyl)- 3-chloro-5//-pyrrolo[3,2-c]pyridazine (73 mg, 0.22 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (59 mg, 0.29 mmol), BHT (150 mg, 0.67 mmol), CS2CO3 (220 mg, 0.67 mmol) and Pd-PEPPSI-IPENTcl(o-picoline) (9.4 mg, 0.011 mmol) were suspended in DMF (1.5 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under N2 for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give 6-(((5-(4-((lH-pyrazol-l- yl)methyl)benzyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)amino)methyl)-5, 7-dimethylisoquinolin-l- amine (1.5 mg, 1%). ESI-MS (M+H)+: 489.5, ’HNMR (400 MHz, DMSO) 5 7.90 (s, 1H), 7.78 - 7.75 (m, 2H), 7.60 (d, J=3.5 Hz, 1H), 7.41 (dd, J=0.6, 1.8 Hz, 1H), 7.14 (s, 4H), 6.99 (d, J=6.1 Hz, 1H), 6.66 - 6.65 (m, 1H), 6.62 (dd, J=0.9, 3.5 Hz, 1H), 6.59 (s, 2H), 6.26 (t, J=4.7 Hz, 1H), 6.23 (t, J=2.1 Hz, 1H), 5.27 (s, 2H), 5.21 (s, 2H), 4.67 (d, J=4.6 Hz, 2H), 2.53 (s, 3H), one methyl peak obstructed by DMSO signal.
Examples 458 and 459
Synthesis of 6-(((l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-lH-pyrazolo[4,3-c]pyridin-6- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine (1-458) and 6-(((2-(4-((lH-pyrazol-l- yl)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-l- amine (1-459).
Figure imgf000491_0001
[0845] Synthesis of l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-6-chloro-lH-pyrazolo[4>3- cjpyridine and 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-6-chloro-2H-pyrazolo[4,3-c]pyridine.
K2CO3 (360 mg, 2.6 mmol) was added to a stirred solution of l-(4-(chloromethyl)benzyl)-l//- pyrazole (300 mg, 1.4 mmol) and 6-chloro-l/7-pyrazolo[4,3-c]pyridine (200 mg, 1.3 mmol) in MeCN (4.0 mL) and the reaction was heated at 60 °C for 2 h. The reaction was cooled to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organics were dried over MgSO-i and concentrated in vacuo to give a mixture of Synthesis of 1- (4-((lH-pyrazol-l-yl)methyl)benzyl)-6-chloro-lH-pyrazolo[4,3-c]pyridine and 2-(4-((lH- pyrazol-l-yl)methyl)benzyl)-6-chloro-2H-pyrazolo[4,3-c]pyridine (450 mg) taken forward without further purification. ESI-MS (M+H)+: 324.0
[0846] Synthesis of 6-(((l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-lH-pyrazolo[4,3-c]pyridin- 6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine and 6-(((2-(4-((lH-pyrazol-l- yl)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l- amine. A mixture of l-(4-((l/7-pyrazol-l-yl)methyl)benzyl)-6-chloro-l//-pyrazolo[4,3- c]pyridine and 2-(4-((177-pyrazol-l-yl)methyl)benzyl)-6-chloro-2/7-pyrazolo[4,3-c]pyridine (100 mg, 0.31 mmol), 6-(aminomethyl)-5, 7-dimethylisoquinolin-l-amine (81 mg, 0.40 mmol), BHT (210 mg, 0.93 mmol), CS2CO3 (300 mg, 0.93 mmol) and Pd-PEPPSI-IPENTcl(o-picoline) (13 mg, 0.016 mmol) were suspended in DMF (1.5 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under a N2 environment for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL), the layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCh and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compounds 6-(((l-(4-((177-pyrazol-l-yl)methyl)benzyl)- l/7-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine (6.9 mg, 5%). ESI-MS (M+H)+: 489.5, ’H NMR (400 MHz, DMSO) 8 8.64 (d, >1.0 Hz, 1H), 8.01 (d, J=0.9 Hz, 1H), 7.91 (s, 1H), 7.78 - 7.76 (m, 2H), 7.41 (dd, >0.6, 1.8 Hz, 1H), 7.15 (s, 4H), 6.98 (dd, >0.2, 6.2 Hz, 1H), 6.60 (s, 2H), 6.44 (s, 1H), 6.39 (t, >4.7 Hz, 1H), 6.24 - 6.22 (m, 1H), 5.42 (s, 2H), 5.28 (s, 2H), 4.57 (d, J=4.6 Hz, 2H), 2.52 (s, 3H), 2.47 (s, 3H); and 6-(((2-(4-((12Apyrazol- l-yl)methyl)benzyl)-277-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l- amine (6.9 mg, 5%). ESI-MS (M+H)+: 489.4, ’H NMR (400 MHz, DMSO) 5 8.80 (d, >1.1 Hz, 1H), 8.52 (s, 1H), 7.91 (s, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.76 (d, J=6.1 Hz, 1H), 7.45 (d, >1.4 Hz, 1H), 7.29 (d, >8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 7.00 (d, >6.1 Hz, 1H), 6.60 (s, 2H), 6.35 (s, 1H), 6.25 (t, >2.0 Hz, 1H), 5.90 (t, >4.8 Hz, 1H), 5.52 (s, 2H), 5.32 (s, 2H), 4.47 (d, >4.6 Hz, 2H), 2.54 (s, 3H), one methyl peak obstructed DMSO signal. Example 460
Synthesis of 6-((6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrin din-4-ylamino)methyl)-5, 7- dimethylisoquinolin-l-amine (1-460).
Figure imgf000493_0001
[0847] Synthesis of ethyl 4,4-diethoxy-3-oxobutanoate. To a solution of ethyl acetate (15 g, 170 mmol) in THF (100 mL) was added LDA (90 mL, 180 mmol, 2M in THF) at - 70 °C and the resulting mixture was stirred at -70 °C for 1 h. Then a solution of ethyl 2,2-diethoxyacetate (10.0 g, 56.8 mmol) in THF (40 ml) was added dropwise and the resulting mixture was stirred for another 2 h. The reaction was quenched with NH4Q (sat. aq., 100 mL). The mixture was concentrated and aqueous layer was extracted with Diethyl ether (100 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SC>4, filtered, and concentrated in vacuo to give the crude (12 g, crude) as yellow oil, which was used into the next step without further purification. ESLMS [M +H]+: 219.2.
[0848] Synthesis of 6-(diethoxymethyl)pyrinudin-4(3H)-one. A mixture of ethyl 4,4- di ethoxy-3 -oxobutanoate (12 g, crude), formimidamide acetate (8.04 g, 77.7 mmol) and KOH (5.6 g, 100 mmol) in EtOH (200 mL) was stirred at 80 °C for 6 h under N2. After cooled to room temperature, the reaction mixture was filtered and the filter cake was washed with MeOH (150 mL). The filtrate was concentrated in vacuo to give the crude, which was purified by silica gel column chromatography (PE/EtOAc=5/l) to give 6-(diethoxymethyl)pyrimidin-4(3H)-one (9.5 g, yield: 84% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 199.1.
[0849] Synthesis of 6-hydroxypyrimidine-4-carbaldehyde. A solution of 6-
(diethoxymethyl)pyrimidin-4(3H)-one (9.5 g, 47.9 mmol) in HC1 (3M, aq., 50 mL) was stirred at 50 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product (9.0, crude), which was used in the next step without further purification. ESI-MS [M +H]+: 125.2.
[0850] Synthesis of (E)-6-(4-((lH-pyrazol-l-yl)methyl)styryl)pyrimidin-4(3H)-one. To a solution of sodium methanolate (475 mg, 8.79 mmol) in methanol (50 mL) was added l-(4- ((triphenyl-14-phosphaneyl)methyl)benzyl)-lH-pyrazole bromide salt (1.50 g, 2.93 mmol) and stirred room temperature for 0.5 h. A solution of 6-hydroxypyrimidine-4-carbaldehyde (2.55 g, crude) in MeOH (20 mL) was added thereto, and the reaction mixture was stirred at room temperature for another 4.5 h. The reaction mixture was concentrated in vacuo to give the crude, which was purified by silica gel column chromatography (eluent: PE/EtOAc=2/l) to give (E)-6- (4-((lH-pyrazol-l-yl)methyl)styryl)pyrimidin-4(3H)-one (400 mg, yield: 10% over 2 steps) as a white solid. ESI-MS [M +H]+: 279.1.
[0851] Synthesis of 6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4(3H)-one. To a solution of (E)-6-(4-((lH-pyrazol-l-yl)methyl)styryl)pyrimidin-4(3H)-one (800 mg, 2.87 mmol) in methanol (20 mL) was added Pd/C (80 mg) and HC1 (0.5 mL, IM aq.). After the resulting mixture was stirred at room temperature for 3 h under H2, the reaction mixture was filtered through celite" and washed with MeOH (50 mL). The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc=2/l ) to give 6-(4- ((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4(3H)-one (605 mg, yield: 75%) as a white solid. ESI-MS [M +H]+: 281.1.
[0852] Synthesis of 4-(4-((lH-pyrazol-l-yl)methyl)phenethyl)-6-chloropyrimidine. A solution of 6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4(3H)-one (605 mg, 2.16 mmol) in POC13 (10 mL) was stirred at 1000 C for 3 h. After cooled to room temperature, the reaction mixture was concentrated and the residue was neutralized with NH3 (7M in MeOH, 15 mL). The resulting mixture was concentrated to the crude, which was purified by silica gel column chromatography (eluent: PE / EtOAc = 1 / 1) to give 4-(4-((lH-pyrazol-l-yl)methyl)phenethyl)- 6-chloropyrimidine (483 mg, yield: 75%) as a white solid. ESI-MS [M +H]+: 299.1. [0853] Synthesis of 6-((6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4- ylamino)methyl)-5, 7-dimethylisoquinolin-l-amine. To a mixture of 4-(4-((lH-pyrazol-l- yl)methyl)phenethyl)-6-chloropyrimidine (100 mg, 0.33 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (94 mg, 0.47 mmol) and CS2CO3 (273 mg, 0.84 mmol) in DMF (5 mL) was added Pd-PEPPSI-iPent-Cl (o-picoline) (28 mg, 0.033 mmol, 0.1 equiv.). The reaction mixture was stirred at 90 °C for 6 h under N2. After cooled to room temperature, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over NaiSCh, filtered and concentrated to give the crude, which was purified by silica gel chromatography (DCM/MeOH=10/l) to afford 6-((6-(4- ((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5, 7-dimethylisoquinolin-l- amine (5.3 mg, yield: 4%) as a white solid. ESLMS [M +H]+: 464.2. 1H NMR (400 MHz, DMSO) 5 8.43 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 7.1 Hz, 2H), 7.43 (s, 1H), 7.30 (s, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 6.2 Hz, 1H), 6.76 (s, 2H), 6.32 (s, 1H), 6.24 (d, J = 4.0 Hz, 1H), 5.26 (s, 2H), 4.61 (s, 2H), 2.94 -2.85 (m, 2H), 2.76 - 2.68 (m, 2H).
Example 461
Synthesis of (4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-
Figure imgf000495_0001
[0854] Synthesis of (4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)methanol. A mixture of (4-(aminomethyl)phenyl)methanol (400 mg, 2.9 mmol), 4,6-dichloropyrimidine (515 mg, 3.48 mmol) and DIPEA (1.12 g, 8.7 mmol) in z-PrOH (10 mL) was stirred at 65 °C for 12 h.
After cooled to room temperature, the mixture was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 35/1) to give (4-(((6-chloropyrimidin-4- yl)amino)methyl)phenyl)methanol (500 mg, yield: 69%) as a white solid. ESI-MS [M +H]+: 250.2.
[0855] Synthesis ofN-(4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)-6-chloropyrimidin- 4-amine. To a solution of (4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)methanol (500 mg, 2 mmol) in DMF (10 mL) was added TBSC1 (360 mg, 2.4 mmol) and Imidazole (204 mg, 3 mmol). The mixture was stirred at room temperature for 12 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to give N-(4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)-6-chloropyrimidin-4-amine (400 mg, yield: 55%) as a white solid. ESLMS [M +H]+: 364.2.
[0856] Synthesis of (4-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)niethyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)methanol. A mixture of N-(4-(((tert- butyldimethylsilyl)oxy)methyl)benzyl)-6-chloropyrimidin-4-amine (100 mg, 0.27 mmol), 6- (aminomethyl)-5,7-dimethylisoquinolin-l -amine (54 mg, 0.27 mmol), Pd-PEPPSLIPent-Cl (o- picoline) (25 mg, 0.03 mmol) and CS2CO3 (264 mg, 0.81 mmol) in DMF (5 mL) was stirred at 125 °C for 2 h under N2. After cooled to room temperature, the mixture was filtered through celite® and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated to give the crude, which was purified by Prep-HPLC to give (4-(((6-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)methanol (45 mg, yield: 40%) as a white solid. ESLMS [M +H]+: 415.4. 1H NMR (400 MHz, DMSO) 5 8.04 (d, J = 1.8 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J = 6.1 Hz, 1H), 7.25 (s, 4H), 7.06 (t, J = 5.7 Hz, 1H), 6.97 (d, J = 6.1 Hz, 1H), 6.59 (s, 2H), 6.19 (s, 1H), 5.69 (s, 1H), 5.12 (s, 1H), 4.58 (d, J = 4.0 Hz, 2H), 4.44 (s, 2H), 4.18 (d, J = 5.5 Hz, 2H), 2.50 (s, 3H), 2.46 (s, 3H).
Example 462
Synthesis of 2-(4-(((5-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3- yl) oxy) methyl)phenyl)-N,N-dimethylacetannde (1-462).
Figure imgf000497_0001
[0857] Synthesis of 2-(4-(((5-chloropyridazin-3-yl)oxy)methyl)phenyl)acetic acid. To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (600 mg, 3.6 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). The mixture was stirred at room temperature for 30 min. Then 3,5-dichloropyridazine (532 mg, 3.6 mmol) was added into the mixture and stirred for another 16 h. The reaction mixture was quenched with H2O (50 mL), pH of the mixture was adjusted to 6 by adding HC1 (aq. 1 N) and then extracted with iPrOH/CHCh (1/3, 30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH=10/l) to get 2-(4-(((5- chloropyridazin-3-yl)oxy)methyl)phenyl)acetic acid (300, yield: 30%) and 2-(4-(((6- chloropyridazin-4-yl)oxy)methyl)phenyl)acetic acid (400 mg, yield: 40%) as a yellow oil, which was used into the next step without further purification. ESI-MS [M +H]+: 279.1.
[0858] Synthesis of 2-(4-(((5-chloropyridazin-3-yl)oxy)methyl)phenyl)-N,N- dimethylacetamide. A mixture of 2-(4-(((5-chloropyridazin-3-yl)oxy)methyl)phenyl)acetic acid (278 mg, 1.0 mmol), dimethylamine hydrochloride (162 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol) and DIPEA (464 mg, 3.6 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. Water (50 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by silica gel column chromatography (EtOAc / PE = 1/1) to get 2-(4-(((5-chloropyridazin-3-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (200 mg, yield: 66%) as a yellow oil. ESLMS [M +H]+: 306.2. [0859] Synthesis of 2-(4-(((5-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyridazin-3-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide. To a mixture of 2-(4-(((5-chloropyridazin-3-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (30 mg, 0.1 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (20 mg, 0.1 mmol) and CS2CO3 (82 mg, 0.25 mmol) in DMF (2 mL) was added Pd-PEPPSI-iPent-Cl (o-picoline) (8 mg, 0.01 mmol). The reaction mixture was stirred at 90 °C for 6.0 h. After cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH=10/l) to afford 2-(4-(((5-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3-yl)oxy)methyl)phenyl)-N,N- dimethylacetamide (10 mg, yield: 21 %) as a white solid. ESLMS [M +H]+: 471.2. 1H NMR (400 MHz, MeOD) 8.50 (s, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.95 (s, 1H), 7.64 (d, J = 6.7 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.27 - 7.24 (m, 3H), 6.04 (s, 1H), 5.44 (s, 2H), 4.63 (s,2H), 3.78 (s, 2H), 3.05 (s, 3H), 2.95 (s, 3H), 2.61 (s, 3H), 2.54 (s, 3H).
Example 463
Synthesis of l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl) amino) methyl) benzyl) -3, 5-dichloropyridin-2 (IH)-one (1-463).
Figure imgf000498_0001
[0860] Synthesis of (4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)methanol. To a solution of (4-(aminomethyl)phenyl)methanol (400 mg, 2.9 mmol) in i-PrOH (10 mL) was added 4,6-dichloropyrimidine (644 mg, 4.35 mmol) and DIPEA (1.12 g, 8.7 mmol). The reaction mixture was stirred at 65 °C for 12 h. After cooling to room temperature, water (30 mL) was added and extracted by EtOAc (35 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SOr and concentrated to give the residue, which was purified by Prep-TLC (EtOAc/PE=l/l) to give (4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)methanol (500 mg, 69%) as a white solid. ESI-MS [M +H]+: 250.1.
[0861] Synthesis of 6-chloro-N-(4-(chloromethyl)benzyl)pyrimidin-4-amine. To a solution of (4-(((6-chloropyrimidin-4-yl)amino)methyl)phenyl)methanol (400 mg, 1.6 mmol) in DCM (5 mL) was added SOCh (0.5 mL) slowly at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to give the residue (420 mg, crude), which was used for the next step without further purification. ESI-MS [M +H]+: 268.1.
[0862] Synthesis of 3,5-dichloro-l-(4-(((6-chloropyrimidin-4- yl)amino)niethyl)benzyl)pyridin-2(lH)-one. A mixture of 3-(chloromethyl)-6- methylisoquinoline (420 mg, crude), 3,5-dichloropyridin-2(lH)-one (261 mg, 1.6 mmol) and CS2CO3 (1.56 g, 4.8 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. The reaction was diluted with water (50 mL) and extracted by EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over NazSCU and concentrated to give the residue, which was purified by Prep-TLC (DCM:MeOH=20: 1) to give 3,5-dichloro-l-(4-(((6- chloropyrimidin-4-yl)amino)methyl)benzyl)pyridin-2(lH)-one (450 mg, 71% over 2 steps) as a white solid. ESI-MS [M +H]+: 395.2.
[0863] Synthesis of l-(4-(((6-(((l-anuno-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)annno)methyl)benzyl)-3,5-dichloropyridin-2(lH)-one. A mixture of 3,5-dichloro-l-(4-(((6-chloropyrimidin-4-yl)amino)methyl)benzyl)pyridin-2(lH)-one (100 mg, 0.25 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (50 mg, 0.25 mmol) and DIPEA (97 mg, 0.75 mmol) in dry MeOH (5 mL) was concentrated and the residue was heated to 140 °C for 2 h. After cooled to room temperature, the residue was purified by Prep- TLC (DCM/MeOH=10/l) to afford I-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzyl)-3,5-dichloropyridin-2(IH)-one (35 mg, yield: 25 %) as a pale solid. ESI-MS [M +H]+: 560.1. 1H NMR (400 MHz, DMSO) 8 8.19 (d, J = 2.6 Hz, 1H), 7.99 (s, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 6.1 Hz, 1H), 7.29 - 7.23 (m, 4H), 7.12 (t, J = 6.0 Hz, 1H), 6.97 (d, J = 6.1 Hz, 1H), 6.67 - 6.58 (m, 3H), 5.43 (s, 1H), 5.09 (s, 2H), 4.52 (s, 2H), 4.34 (s, 2H), 2.48 (s, 3H), 2.45 (s, 3H). Example 464
Synthesis ofN-((l-aniino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2,3-dimethylquinoxalin-6- yl)methyl)-lH-pyrazole-4-carboxamide (1-464).
Figure imgf000500_0001
[0864] Synthesis of ethyl 2>3-dimethylquinoxaline-6-carboxylate. To a solution of ethyl
3,4-diaminobenzoate (400 mg, 2.22 mmol) in EtOH (10 mL) was added 2,3 -Butanedione (191 mg, 2.22 mol). The resulting reaction mixture was stirred at 100 °C for 16 h. After cooled to room temperature, the reaction mixture was concentrated to give ethyl 2,3-dimethylquinoxaline- 6-carboxylate (510 mg, crude), which was used into the next step without any further purification. ESLMS: [M + H]+, 231.2.
[0865] Synthesis of (2,3-dimethylquinoxalin-6-yl)methanol. To a solution of ethyl 2,3- dimethylquinoxaline-6-carboxylate (510 mg, crude) in THF (20 mL) was added LiAlH4 (273 mg, 7.19 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with Na2SO-i’10H2O (3 g), the mixture was filtered and the filer cake was washed by MeOH(20 mL), the filtrate was concentrated to afford the crude, which was purified by silica gel column chromatography (eluent: PE/EtOAc = 1/2) to afford (2,3- dimethylquinoxalin-6-yl)methanol (104 mg, yield: 25 % over 2 steps) as a white solid. ESLMS: [M + H]+, 189.2.
[0866] Synthesis of (2,3-dimethylquinoxalin-6-yl)methyl methanesulfonate. To a solution of (2,3-dimethylquinoxalin-6-yl)methanol (104 mg, 0.55 mmol) in THF (10 mL) was added DIPEA (214 mg, 1.66 mmol) and MsCl (95 mg, 0.83 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give (2,3- dimethylquinoxalin-6-yl)methyl methanesulfonate (133 mg, crude) as a yellow solid, which was used into the next step without any further purification. ESLMS: [M + H]+, 267.1. [0867] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)-l-((2,3- dimethylquinoxalin-6-yl)methyl)-lH-pyrazole-4-carboxamide. A mixture of (2,3- dimethylquinoxalin-6-yl)methyl methanesulfonate (66 mg, crude), N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (73 mg. 0.25 mmol) and CS2CO3 (163 mg, 0.50 mmol) in DMF (5 mL) was stirred at room temperature for 3 days. Water (30 mL) was added and was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to afford N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-((2,3-dimethylquinoxalin-6-yl)methyl)-lH-pyrazole-4- carboxamide (10 mg, yield: 8%) as a white solid. ESI-MS [M +H]+: 466.2. 1H NMR (400 MHz, DMSO) 5 8.33 (s, 1H), 8.08 (t, J = 4.0 Hz, 1H), 7.91 - 7.86 (m, 3H), 7.73 - 7.69 (m, 2H), 7.53 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 6.1 Hz, 1H), 6.58 (s, 2H), 5.52 (s, 2H), 4.55 (s, 2H), 2.62 (s, 3H), 2.61 (s, 3H), 2.47 (s, 3H), 2.45 (s, 3H).
Example 465
Synthesis of 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-
Figure imgf000501_0001
solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (600 mg, 3.6 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). The mixture was stirred at room temperature for 30 min. Then 3,5-dichloropyridazine (532 mg, 3.6 mmol) was added into the mixture and stirred for another 16 h. The reaction mixture was diluted with H2O (50 mL), pH of the mixture was adjusted to 6 by adding HC1 (aq. 1 N), and then extracted with iPrOH/CHCE (1/3, 30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH=10/l) to get 2-(4-(((5- chloropyridazin-3-yl)oxy)methyl)phenyl)acetic acid (300, yield: 30%) and 2-(4-(((6- chloropyridazin-4-yl)oxy)methyl)phenyl)acetic acid (400 mg, yield: 40%) as a yellow oil, which was used into the next step without further purification. ESI-MS [M +H]+: 279.1.
[0869] Synthesis of 2-(4-(((6-chloropyridazin-4-yl)oxy)methyl)phenyl)-N,N- dimethylacetamide. To a solution of 2-(4-(((6-chloropyridazin-4-yl)oxy)methyl)phenyl)acetic acid (400 mg, 1.4 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (170 mg, 2.1 mmol), HATU (798 mg, 2.1 mmol) and DIPEA (542 mg, 4.2 mmol). The mixture was stirred at room temperature for 12 h. The reaction was diluted with H2O (40 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified with Prep-TLC (DMC/MeOH = 10/1) to give 2-(4-(((6-chloropyridazin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (300 mg, yield: 70 %) as a yellow solid. ESI-MS [M +H]+: 306.2.
[0870] Synthesis of 2-(4-(((6-(((l-anino-5, 7-dimethylisoquinolin-6- yl)niethyl)amino)pyridazin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide. To a solution of 2-(4-(((6-chloropyridazin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (150 mg, 0.5 mmol) in DMF (10 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (151 mg, 0.75 mmol), Pd-PEPPSI-IPENT-Cl (o-picoline) (42 mg, 0.05 mmol) and CS2CO3 (489 mg, 1.5 mmol) was stirred at 100 °C for 2h under nitrogen. After cooled to room temperature, water (40 mL) was added and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated in vacuo to give the crude, which was purified by Prep-TLC (DCM/MeOH =10/1) to give 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (50 mg, yield: 21%) as a white solid. ESI-MS [M +H]+: 471.1 1HNMR (400 MHz, DMSO) 8 8.18 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 6.0 Hz, 1H), 6.72 (s, 2H), 6.58 (s, 1H), 5.73 (s, 1H), 5.32 (s, 2H), 4.44 (d, J = 4.4 Hz, 2H), 3.69 (s, 3H), 2.99 (s, 3H), 2.82 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H). Example 466 and 467
Synthesis of 2-(4-(((6-(((l-anino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrinudin-4- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-466) and 2-(4-(((6-((6-(aminomethyl)-5, 7- dimethylisoquinolin-l-yl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (I- 467).
Figure imgf000503_0001
[0871] Synthesis of 2-(4-(((6-chioropyrimidin-4-yI)oxy)methyl)phenyl)acetic acid To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (500 mg, 3 mmol) in DMF (1 mL) was added NaH (360 mg, 9 mmol, 60% dispersion in mineral oil) at 0 °C. The resulting reaction was stirred at 0 °C for 0.5 h. Then a solution of 4,6-dichloropyrimidine (447 mg, 3 mmol) in DMF (5 mL) was added thereto. The reaction was stirred at room temperature for 2 h. The reaction was quenched with H2O (20 mL), pH of the mixture was adjusted to 6 by adding HC1 (aq. 1 N) and then extracted with iPrOH/CHCh (1/3, 20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-15% of MeOH in DCM to give 2-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)phenyl)acetic acid (400 mg, yield: 48%) as a yellow solid. ESI-MS [M +H]+: 279.2.
[0872] Synthesis of 2-(4-(((6-chIoropyriniidin-4-yI)oxy)methyl)phenyi)-N,N- dimethylacetamide. A mixture of 2-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)phenyl)acetic acid (400 mg, 1.4 mmol), Me2NH«HCl (340 mg, 4.2 mmol), HATU (1.06 g, 2.8 mmol) and DIPEA (903 mg, 7 mmol) in DMF (20 mL) was stirred at room temperature for 12 h. The reaction was diluted with H2O (40 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaiSCh, concentrated to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to give 2-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (280 mg, 65%) as a yellow solid. ESI-MS [M +H]+: 306.1.
[0873] Synthesis of 2-(4-(((6-(((l-anhno-5, 7-dimethylisoquinolin-6- yl)niethyl)aniino)pyrimidin-4-yl)oxy)methyl)phenyl)-N,N-dimethyIacetami(le. A mixture of 2- (4-(((6-chloropyrimidin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (140 mg, 0.46 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (185 mg, 0.92 mmol), Pd-PEPPSI-IPentCl (o- picoline) (39 mg, 0.046 mmol) and CS2CO3 (456 mg, 1.4 mmol) in DMF (10 mL) was stirred at 125 °C for Ih under N2. After cooled to room temperature, the reaction was diluted with H2O (25 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (45 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-HPLC to give 2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin- 4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (14 mg, 6%) and 2-(4-(((6-((6-(aminom ethyl )- 5,7-dimethylisoquinolin-l-yl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (7 mg, 3%) as a white solid. Example 465: ESI-MS [M +H]+: 471.2. IH NMR (400 MHz, DMSO) 5 8.26 (s, IH), 7.92 (s, IH), 7.75 (d, J = 6.1 Hz, IH), 7.39 - 7.29 (m, 2H), 7.27 - 7.14 (m, 3H), 6.98 (d, J = 6.1 Hz, IH), 6.63 (s, 2H), 5.87 (s, IH), 5.26 (s, 2H), 4.60 (s, 2H), 3.66 (d, J = 7.8 Hz, 2H), 2.98 (s, 3H), 2.81 (d, J = 8.0 Hz, 3H), 2.45 (d, J = 9.8 Hz, 6H). Example 466: ESI-MS [M +H]+: 471.1. 1H NMR (400 MHz, MeOD) 5 8.47 (s, IH), 8.21 (s, IH), 8.09 (s, IH), 7.56 (d, J = 7.1 Hz, IH), 7.36 (d, J = 7.1 Hz, IH), 7.30 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 5.40 (s, IH), 5.07 (s, 2H), 4.63 (s, 2H), 3.75 (s, 2H), 3.05 (s, 3H), 2.94 (s, 3H), 2.65 (s, 3H), 2.60 (s, 3H).
Example 468
Synthesis of 4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-(((l-amino-5,7-dimethylisoquinolin- 6-yl)methyl)amino)-2-methylisoindolin-l-one (1-468).
Figure imgf000505_0001
[0874] Synthesis of 6-chloro-4-hydroxy-2-methylisoindolin-l-one. A mixture of 6-chloro-
4-iodo-2-methylisoindolin-l-one (500 mg, 1.63 mmol), NaOH (328 mg, 8.2 mmol), Cui (38 mg, 0.2 mmol) and glycolic acid (46 mg, 0.6 mmol) in DMSO (5 mL) and H2O (5 mL) was stirred at 120 °C for 16 h under N2. After cooled to room temperature, the reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL><3). The combined organic layers were washed with brine (40 mL) and dried over Na2SOr and concentrated to give the crude, which was purified by silica gel chromatography (DCM/MeOH=20/l) to give 6-chloro-4-hydroxy-2-methylisoindolin- 1-one (250 mg, yield: 77%) as a yellow solid. ESI-MS [M +H]+: 198.2.
[0875] Synthesis of 4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-chloro-2- methylisoindolin-l-one. A mixture of 6-chloro-4-hydroxy-2-methylisoindolin-l-one (70 mg, 0.35 mmol), l-(4-(chloromethyl)benzyl)-lH-pyrazole (87 mg, 0.42 mmol), K2CO3 (121 mg, 0.88 mmol) and Nal (15 mg, 0.1 mmol) in DMF (10 mL) was stirred at 60 °C for 2 h under N2. After cooled to room temperature, the reaction was diluted with water (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SOr and concentrated to give the crude, which was purified by silica gel column chromatography (DCM/MeOH=20/l) to give 4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-chloro-2- methylisoindolin-l-one (64 mg, yield: 50%) as a yellow solid. ESI-MS [M +H]+:368.2.
[0876] Synthesis of 4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-(((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)amino)-2-methylisoindolin-l-one. A mixture of 4-((4-((lH- pyrazol-l-yl)methyl)benzyl)oxy)-6-chloro-2-methylisoindolin-l-one (74 mg, 0.2 mmol), 6- (aminomethyl)-5,7-dimethylisoquinolin-l -amine (48 mg, 0.24 mmol), Pd-PEPPSI-IPENT-Cl (o-picoline) (17 mg, 0.02 mmol) and CS2CO3 (130 mg, 0.4 mmol), in dry DMF (5 mL) was stirred at 100 °C for 16 h under N2. After cooled to room temperature, the reaction was diluted with water (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over NaiSCb and concentrated to give the crude, which was purified by Prep-TLC (DCM / MeOH = 10/1) to get 4-((4-((lH-pyrazol-l- yl)methyl)benzyl)oxy)-6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-2- methylisoindolin-l-one (20 mg, yield: 19%) as a white solid. ESLMS [M +H]+: 533.2. 1H NMR (400 MHz, DMSO) 5 8.01 (s, 1H), 7.94 (m, 2H), 7.56 - 7.48 (m, 3H), 7.29 (d, J = 7.2 Hz, 2H), 7.09 (d, J = 5.6 Hz, 1H), 6.80 (s, 2H), 6.67 (d, J = 24.5 Hz, 2H), 6.33 (s, 1H), 5.93 (s, 1H), 5.40 (s, 2H), 5.18 (s, 2H), 4.41 - 4.28 (m, 4H), 3.09 (s, 3H), 2.53 (s, 6H).
Example 469
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((4-bromophenyl)diflu oromethyl)-lH-pyrazole-4-carboxamide (1-469).
Figure imgf000506_0001
[0877] Synthesis of l-bronio-4-(bromodifluoroniethyl)benzene. To a solution of 1-bromo-
4-(difluoromethyl)benzene (103 mg, 0.5 mmol) in CC14 (6 mL) was added l,3-dibromo-5,5- dimethylimidazolidine-2, 4-dione (213 mg, 0.75 mmol) and BPO (11.5 mg, 0.05 mmol). The reaction mixture was heated at 80 °C for 16 h. After cooled to room temperature, the reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by Prep-TLC(eluent: EtOAc/PE=l/2) to afford l-bromo-4- (bromodifluorome thyl)benzene (32 mg, yield: 22%) as a yellow solid. ESI-MS [M +H]+:285.0.
[0878] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)-l-((4- bromophenyl)difluoromethyl)-lH-pyrazole-4-carboxamide. To a solution of l-bromo-4- (bromodifluoromethyl)benzene (32 mg, 0.11 mmol) in DMF (3 mL) was added N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lEI-pyrazole-4-carboxamide (25 mg, 0.085 mmol) and CS2CO3 (108 mg, 0.33 mmol). The reaction was stirred at 60 °C for 4 h. After cooled to room temperature, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by Prep-TLC (eluent:MeOH/DCM=l/10) to afford N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((4- bromophenyl)difluoromethyl)-lEI-pyrazole-4-carboxamide (13.5 mg, yield: 32 %) as a pale solid. ESI-MS [M +H]+: 500.1. 1H NMR (400 MHz, DMSO) 8 8.63 (s, 1H), 8.27 (t, J = 4.4 Hz, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.76 - 7.71 (m, 6.3 Hz, 3H), 7.53 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 6.2 Hz, 1H), 6.68 (s, 2H), 4.56 (d, J = 4.5 Hz, 2H), 2.47 (s, 3H), 2.44 (s, 3H).
Example 470
Synthesis ofN-(6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)- 5, 7-dimethylisoquinolin-l-yl)acetamide (1-470).
Figure imgf000507_0001
[0879] To a solution of 6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine (112 mg, 0.24 mmol) in dry DCE (5 mL) was added AC2O (245 mg, 2.4 mmol) and pyridine (0.5 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude, which was purified by Prep-TLC (DCM / MeOH = 20 / 1) to give N-(6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l-yl)acetamide (18 mg, yield: 15%) as a white solid. ESLMS [M +H]+: 508.2. 1H NMR (400 MHz, DMSO) 5 10.35 (s, 1H), 8.28 (s, 2H), 7.85 - 7.75 (m, 3H), 7.47 -7.37 (m, 3H), 7.22 (d, J = 7.2 Hz, 2H), 6.81 (s, 1H), 6.33 (s, 1H), 6.26 (s, 1H), 5.33 (s, 2H), 5.07 (s, 2H), 4.73 (s, 2H), 2.66 (s, 3H), 2.53 (s, 3H), 2.18 (s, 3H).
Example 471
Synthesis of l-(4-((4-(l-(((l-amino-5, 7-diniethylisoquinolin-6-yl)methyl)amino)-2,2,2- trifhioroethyl)-lH-pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one (1-471).
Figure imgf000508_0001
[0880] Synthesis of l-(4-(hydroxymethyl)benzyl)pyridin-2(lH)-one. To a solution of methyl 4-((2-oxopyridin-l(2H)-yl)methyl)benzoate (4 g, 16.5 mmol) in THF/MeOH (50 mL / 5 mL) was added LiBHi (1.09 g, 49.5 mmol). The mixture was stirred at 50 °C for 2 h. After cooled to room temperature, the reaction was quenched with NFLCl (sat. aq., 100 mL), extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-5% MeOH in DCM to give l-(4- (hydroxymethyl)benzyl)pyridin-2(lH)-one (3.5 g, 98%) as a yellow solid. ESLMS [M +H]+: 216.1.
[0881] Synthesis of l-(4-(chloromethyl)benzyl)pyridin-2(l H)-one. To a solution of l-(4-
(hydroxymethyl)benzyl)pyridin-2(lH)-one (3.5 g, 16.2 mmol) in DCM (80 mL) was added SOCh (5.6 g, 48 mmol) at 0 °C. The reaction was stirred at room temperature for 3 h. The reaction was concentrated to give l-(4-(chloromethyl)benzyl)pyridin-2(lH)-one (4 g, crude) as a yellow solid, which was used into the next step without further purification. ESI-MS [M +H]+: 234.2.
[0882] Synthesis of l-(4-((4-iodo-lH-pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one. A mixture of l-(4-(chloromethyl)benzyl)pyridin-2(lH)-one (4 g, crude), 4-iodo-lH-pyrazole (6.2 g, 32 mmol) and CS2CO3 (21 g, 65 mmol) in DMF (80 mb) was stirred at room temperature for 14 h. The reaction was diluted with H2O (200 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-40% EtOAc in PE to give l-(4-((4-iodo-lH-pyrazol-l-yl)methyl)benzyl)pyridin- 2(lH)-one (4 g, yield: 62% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 392.2.
[0883] Synthesis of l-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)-lH-pyrazole-4- carbaldehyde. To a solution of l-(4-((4-iodo-lH-pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one (2 g, 5.1 mmol) in THF (60 mL) was added i-PrMgBr (5.1 mL, 5.1 mmol, 1 M solution in THF) at 0 °C. The reaction was stirred at 0 °C for 5 min. Then a solution of DMF (1.1 g, 15.3 mmol) in THF (5 mL) was added thereto. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with NH4CI (sat. aq., 80 mL), extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-35% EtOAc in PE to give l-(4-((2-oxopyridin- l(2H)-yl)methyl)benzyl)-lH-pyrazole-4-carbaldehyde (1 g, yield: 67%) as a yellow solid. ESI- MS [M +H]+: 294.2.
[0884] Synthesis of l-(4-((4-(2,2,2-trifluoro-l-hydroxyethyl)-lH-pyrazol-l- yl)methyl)benzyl)pyridin-2(lH)-one. To a solution of l-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)-lH-pyrazole-4-carbaldehyde (1 g, 3.4 mmol) in THF (20 mL) was added TBAF (4 mL, 4 mmol, 1 M solution in THF) and TMSCF3 (540 mg, 3.8 mmol) at 0 °C. After the reaction was stirred at room temperature for 5 h, the reaction was quenched with NH4CI (sat. aq., 50 mL), extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-45% EtOAc in PE to give 1- (4-((4-(2, 2, 2-trifluoro-l -hydroxy ethyl)- lH-pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one (840 mg, yield: 68%) as a yellow solid. ESI-MS [M +H]+: 364.2.
[0885] Synthesis of l-(4-((4-(2,2,2-trifliioroacetyl)-lH-pyrazol-l-yl)methyl)benzyl)pyridin- 2(lH)-one. To a solution of l-(4-((4-(2, 2, 2-trifluoro-l -hydroxyethyl)- IH-pyrazol-l- yl)methyl)benzyl)pyridin-2(lH)-one (840 mg, 2.3 mmol) in DCM (25 mL) was added Dess- Martin periodinane (1.5 g, 3.5 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was quenched with NH4CI (sat. aq., 50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na SCU, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-30% EtOAc in PE to give l-(4-((4-(2,2,2-trifluoroacetyl)-lH-pyrazol-l- yl)methyl)benzyl)pyridin-2(lH)-one (450 mg, yield: 54 %) as a yellow solid. ESI-MS [M +H]+:
362.2.
[0886] Synthesis of l-(4-((4-(l-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)- 2,2,2-trifiuoroethyl)-lH-pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one. A mixture of l-(4-((4- (2,2,2-trifluoroacetyl)-lH-pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one (250 mg, 0.69 mmol) and Ti(iPrO)4 (392 mg, 1.38 mmol) in THF (20 mL) was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was diluted with MeOH (10 mL) and NaBLL (105 mg, 2.76 mmol) was added thereto. The reaction was stirred at room temperature for another 2h. The reaction was quenched with NH4CI (sat. aq., 50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-HPCL to give l-(4-((4-(l-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)-2,2,2-trifluoroethyl)-lH-pyrazol-l- yl)methyl)benzyl)pyridin-2(lH)-one (50 mg, yield: 13%) as a white solid. ESI-MS [M +H]+:
547.2. 1H NMR (4OO MHz, DMSO) 5 8.28 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.77 -7.74 (m, 2H), 7.62 (s, 1H), 7.41 -7.39 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 6.1 Hz, 1H), 6.61 (s, 2H), 6.40 (d, J = 9.1 Hz, 1H), 6.24 - 6.21 (m, 1H), 5.33 (s, 2H), 5.07 (s, 2H), 4.44 (d, J = 8.6 Hz, 1H), 3.79 (d, J = 6.0 Hz, 2H), 2.39 (d, J = 5.7 Hz, 6H). Example 472
Synthesis ofN-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(difluoro(phenyl)methyl)- lH-pyrazoie-4-carboxamide (1-472).
Figure imgf000511_0001
[0887] To a solution of N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4- carboxamide (174 mg, 0.59 mmol) in DMF (4 mL) was added (chlorodifluoromethyl)benzene (96 mg, 0.59 mmol) and CS2CO3 (577 mg, 1.77 mmol). The reaction was stirred at 100 °C for 16 h. After cooled to room temperature, the reaction mixture was quenched by H2O (20 mL), and extracted by EtOAc (30 mL x 3). The organic layers were concentrated to afford the crude, which was purified by Prep-TLC (eluent: MeOH / DCM = 1/15) to get N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-l-(difluoro(phenyl)methyl)-lH-pyrazole-4-carboxamide (50 mg, yield: 20%) as a pale solid. ESLMS [M +H]+: 422.2. 1H NMR (400 MHz, DMSO) 5 8.49 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.47 - 7.37 (m, 5H), 6.86 - 6.81 (m, 3H), 4.43 (d, J = 4.3 Hz, 2H), 2.33 (s, 6H).
Example 473
Synthesis of 6-((6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5> 7- dimethylisoquinolin-l-amine (1-473).
Figure imgf000512_0001
[0888] Synthesis of (4-(bromomethyl)-3-chlorophenyl)methanol. To solution of methyl 4- (bromomethyl)-3 -chlorobenzoate (500 mg, 1.9 mmol) in THF (10 mb) was added DIBALH (IM in THF, 5.7 mb, 5.7 mmol) at 0 °C, the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with NH4Q (sat. aq., 50 mb) and extracted with EtOAc (40 mb x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified by column chromatography (eluent: EtOAc/PE = 0 ~ 30%) to give (4-(bromomethyl)-3-chlorophenyl)methanol (400 mg, yield: 90%) as a yellow oil. ESIMS [M +H] +: 235.1
[0889] Synthesis of methyl 2-(2-chloro-4-(hydroxymethyl)phenyl)acetate. A mixture of (4- (bromomethyl)-3-chlorophenyl)methanol (400 mg, 1.7 mmol), Pd(dppf) Ch (124 mg, 0.17 mmol) and TEA (515 mg, 5.1 mmol) in MeOH (15 mL) was stirred at 60 °C under CO atmosphere for 12 h. After cooled to room temperature, the reaction was diluted with H2O (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (45 mL), dried over NazSCL, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: EtOAc/PE = 1/1) to give methyl 2-(2-chloro-4-
(hydroxymethyl)phenyl)acetate (300 mg, yield: 82%) as a yellow solid. ESLMS [M +H]+: 215.2.
[0890] Synthesis of methyl 2-(2-chloro-4-(chloroniethyl)phenyl)acetate. To a solution of methyl 2-(2-chloro-4-(hydroxymethyl)phenyl)acetate (300 mg, 1.4 mmol) in DCM (10 mL) was added SOCh (1 mL) at 0 °C. The reaction was stirred at room temperature for 3 h. The reaction was concentrated in vacuo to give methyl 2-(2-chloro-4-(chloromethyl)phenyl)acetate (300 mg, crude) as a yellow solid, which was used into the next step without further purification. ESLMS [M +H]+: 233.2.
[0891] Synthesis of benzyl l-(3-chloro-4-(2-methoxy-2-oxoethyl)benzyl)-lH-pyrazole-4- carboxylate. A mixture of methyl 2-(2-chloro-4-(chloromethyl)phenyl)acetate (300 mg, crude), benzyl lH-pyrazole-4-carboxylate (285 mg, 1.4 mmol) and Cs2CO3 (913 mg, 2.8 mmol) in DMF (15 mL) was stirred at room temperature for 14 h. The reaction was diluted with H2O (40 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep- TLC (eluent: EtOAc/PE = 1/1) to give benzyl L(3-chloro-4-(2-methoxy-2-oxoethyl)benzyl)-lH- pyrazole-4-carboxylate (260 mg, yield: 47% over 2 steps) as a yellow solid. ESLMS [M +H]+: 399.2.
[0892] Synthesis of l-(3-chloro-4-(2-methoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylic acid. To a solution of (benzyl l-(3-chloro-4-(2-methoxy-2-oxoethyl)benzyl)-lH-pyrazole-4- carboxylate (260 mg, 0.65 mmol) in methanol (10 mL) was added Pd/C (30 mg) at room temperature under H2 atmosphere. The resulting reaction was stirred at room temperature for 6 h. The reaction mixture was filtered through the celite" and the filter cake was washed with MeOH (40 mL). The filtrate was concentrated in vacuo to give the crude product l-(3-chloro-4-(2- methoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylic acid (220 mg, crude) as a yellow solid, which was used into the next step without further purification. ESLMS [M +H]+: 309.2.
[0893] Synthesis of methyl 2-(4-((4-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)-2-chlorophenyl)acetate. To a solution of L(3- chloro-4-(2-methoxy-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxylic acid (220 mg, crude) in DMF (10 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (131 mg, 0.65 mmol), HATU (296 mg, 0.78 mmol) and DIPEA (252 mg, 1.95 mmol). Then the reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with H2O (40 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep- TLC (DMC/MeOH = 10/1) to give methyl 2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)-2-chlorophenyl)acetate (200 mg, yield: 63% over 2 steps) as a white solid. ESLMS [M +H]+: 492.2.
[0894] Synthesis of 2-(4-((4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)- lH-pyrazol-l-yl)methyl)-2-chlorophenyl)acetic acid. To a solution of methyl 2-(4-((4-(((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)-2- chlorophenyl)acetate (25 mg, 0.05 mmol) in THF (2 mL) and water (2 mL) was added LiOH’LEO (6 mg, 0.15 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated, and pH of the residue was adjusted to 6 by HC1 (aq. IN) and concentrated to give 2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)-2-chlorophenyl)acetic acid (30 mg, crude). ESLMS [M +H]+: 478.2.
[0895] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(azetidin-l- yl)-2-oxoethyl)-3-chlorobenzyl)-lH-pyrazole-4-carboxatnide. A mixture of 2-(4-((4-(((l - amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)methyl)-2- chlorophenyl)acetic acid (30 mg, crude), azetidine (6 mg, 0.1 mmol), HATU (27 mg, 0.07 mmol) and DIPEA (20 mg, 0.15mmol) in DMF (4 mL) was stirred at room temperature for 8 h. The reaction was diluted with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (DCM/MeOH = 10/1) to give N-((l-amino- 5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(azetidin-l-yl)-2-oxoethyl)-3-chlorobenzyl)-lH- pyrazole-4-carboxamide (5 mg, yield: 19 % over 2 steps) as a white solid. ESLMS [M +H]+: 517.2. 1H NMR (400 MHz, DMSO) 8 8.30 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.73 (s, 1H), 7.47 - 7.02 (m, 6H), 5.31 (s, 2H), 4.59 (s, 2H), 4.17 (s, 2H), 3.84 (s, 2H), 3.48 (s, 2H), 2.54 (s, 6H), 2.20 (s, 2H). Example 474
Synthesis of l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)-3-chlorobenzyl)-N-((l-amino- 5, 7-dimethylisoquinoHn-6-yl)methyI)-LH-pyrazole-4-carboxanude (1-474).
Figure imgf000515_0001
[0896] A mixture of 2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)- lH-pyrazol-l-yl)methyl)-2-chlorophenyl)acetic acid (20 mg, 0.04 mmol), 3- azabicyclo[3.1.0]hexane hydrochloride (8.5 mg, 0.07 mmol), HATU (27 mg, 0.07 mmol) and DIPEA (20 mg, 0.15 mmol) in DMF (4 mb) was stirred at room temperature for 8 h. Water (20 mL) was added to the reaction, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (DCM/MeOH = 10/1) to give l-(4-(2-(3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)-3-chlorobenzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (7 mg, yield: 32%) as a white solid. ESI-MS [M +H]+: 543.2. 1H NMR (400 MHz, DMSO) 8 8.29 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.70 (d, J = 6.2 Hz, 1H), 7.63 (s, 2H), 7.28-7.14 (m, 4H), 5.31 (s, 2H), 4.59 (s, 2H), 3.77 - 3.49 (m, 6H), 2.53 (s, 6H), 1.62-1.53 (m, 2H), 0.72 - 0.70 (m, 1H), 0.07 - 0.05 (m, 1H).
Example 475
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l-methyl-2-
Figure imgf000516_0001
[0897] Synthesis of methyl 3-cyano-2-(p-tolyl)propanoate. To a solution of methyl 2-(p- tolyl)acetate (1.0 g, 6.1 mmol) in THF (20 mL) was added LiHMDS (IM solution in THF, 9.2 mL, 9.2 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h, then a solution of 2- bromoacetonitrile (726 mg, 6.1 mmol) in THF (10 mL) was added. After the reaction mixture was stirred at 0 °C for 1 h, the reaction was quenched with NH4CI (sat. aq., 100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 10/1) to give methyl 3-cyano-2-(p- tolyl)propanoate (900 mg, yield: 73%) as a yellow oil. ESLMS [M +H]+: 204.2.
[0898] Synthesis of methyl 4-amino-2-(p-tolyl)butanoate. To a solution of 4,6- dichloropyrimidine-2-carboxylic acid (900 mg, 4.4 mmol) in MeOH (20 mL) was added NiCh’OHiO (209 mg, 0.88 mmol) and NaBHi (334 mg, 8.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with NH4CI (sat. aq., 50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give methyl 4-amino-2-(p- tolyl)butanoate (600 mg, yield: 66%) as a yellow oil. ESLMS [M +H]+: 208.2. [0899] Synthesis of 3-(p-tolyl)pyrrolidin-2-one. A mixture of methyl 4-amino-2-(p- tolyl)butanoate (600 mg, 2.9 mmol) in MeOH (10 mL) was stirred at 60 °C for 16 h. The mixture was concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give 3-(p-tolyl)pyrrolidin-2-one (350 mg, yield: 69%) as a yellow oil. ESI-MS [M +H]+: 176.2.
[0900] Synthesis of l-methyl-3-(p-tolyl)pyrrolidin-2-one. To a solution of 3-(p- tolyl)pyrrolidin-2-one (250 mg, 1.4 mmol) in THF (10 mL) was added LiHMDS (IM solution in THF, 1.4 mL, 1.4 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h, then a solution of Mel (199 mg, 1.4 mmol) in THF (5 mL) was added. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with NH4CI (sat. aq., 50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by column chromatography (eluent: PE/EtOAc = 5/1) to give l-methyl-3-(p-tolyl)pyrrolidin-2-one (150 mg, yield: 57%) as a white solid. ESLMS [M +H]+: 190.2.
[0901] Synthesis of 3-(4-(bromomethyl)phenyl)-l-methylpyrrolidin-2-one. A mixture of 1- methyl-3-(p-tolyl)pyrrolidin-2-one (100 mg, 0.53 mmol) and NBS (94 mg, 0.53 mmol) in CCI4 (5 mL) was stirred at 60 °C for 16 h. After cooled to room temperature, the reaction mixture was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give 3-(4-(bromomethyl)phenyl)-l-methylpyrrolidin-2-one (10 mg, yield: 7%) as a colourless oil. ESI-MS [M +H]+: 268.2.
[0902] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)-l-(4-(l-methyl-2- oxopyrrolidin-3-yl)benzyl)-lH-pyrazole-4-carboxanude. A mixture of 3-(4- (bromomethyl)phenyl)-l-methylpyrrolidin-2-one (10 mg, 0.04 mmol), N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (12 mg, 0.04 mmol) and CS2CO3 (13 mg, 0.12 mmol) in DMF (3 mL) was stirred at 60 °C for 16 h under N2. The reaction mixture was cooled to room temperature, quenched with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by Prep-HPLC to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l-methyl-2-oxopyrrolidin-3-yl)benzyl)- lH-pyrazole-4-carboxamide (4 mg, yield: 21%) as a white solid. ESI-MS [M +H]+: 483.2. 1H NMR (400 MHz, DMSO) 8 8.26 (s, 2H), 8.09 - 8.07 (m, 1H), 7.89 -7.87 (m, 2H), 7.76 (d, J = 6.1 Hz, 1H), 7.18 (s, 4H), 6.98 (d, J = 5.9 Hz, 1H), 6.61 (s,2H), 5.28 (s, 2H), 4.57 (d, J = 4.6 Hz, 2H), 3.66 - 3.45 (m, 3H), 2.77 (s, 3H), 2.69 - 2.67 (m, 1H), 2.48 (s, 6H), 2.34 - 2.32 (m, 1H).
Example 476
Synthesis ofN2-(4-((lH-pyrazol-l-yl)methyl)henzyl)-N6-((l-aniino-5, 7-dimethylisoquinolin-6- yl)methyl)pyrazine-2, 6-diamine (1-476).
Figure imgf000518_0001
[0903] Synthesis ofN-(4-((lH-pyrazol-l-yl)methyl)benzyl)-6-chloropyrazin-2-amine. A mixture of (4-((lH-pyrazol-l-yl)methyl)phenyl)methanamine (300 mg, 1.6 mmol), 2,6- dichloropyrazine (237 mg, 1.6 mmol) and K2CO3 (442 mg, 3.2 mmol) in CH3CN (10 mL) was stirred at 80 °C for 48 h. After cooled to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give N-(4-((lH-pyrazol-l- yl)methyl)benzyl)-6-chloropyrazin-2-amine (150 mg, yield: 31%) as a white solid. ESI-MS [M +H]+: 300.2.
[0904] Synthesis ofN2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N6-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrazine-2, 6-diamine. A mixture of N-(4-(( IH-pyrazol- 1 - yl)methyl)benzyl)-6-chloropyrazin-2-amine (30 mg, 0.1 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (20 mg, 0.1 mmol), Pd-PEPPSI-IPent’cl o-picoline (8 mg, 0.01 mmol) and CS2CO3 (98 mg, 0.3 mmol) in DMF (2.5 mL) was stirred at 100 °C for 3 h under N2. The reaction mixture was cooled to room temperature. The mixture was filtered through celite " and the filter cake was washed with DCM/MeOH (10/1, 30 mL). The filtrate was concentrated to give the crude, which was purified by Prep-HPLC to give N2-(4-((lH-pyrazol-l- yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrazine-2,6-diamine (5 mg, yield: 11%) as a white solid. ESI-MS [M +H]+: 465.2. 1H NMR (400 MHz, DMSO) 8 7.90 (s, 1H), 7.79 -7.76 (m, 2H), 7.44 (s, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7. 16 (d, J = 8.0 Hz, 2H), 7.07 - 6.99 (m, 4H), 6.74 (s, 2H), 6.53 (s, 1H), 6.25 (s, 1H), 5.29 (s, 2H), 4.49 (d, J = 4.0 Hz, 2H), 4.43 (d, J = 5.8 Hz, 2H), 2.44 (s, 3H), 2.40 (s, 3H).
Example 477
Synthesis of l-(4-(2-(3-azabicyclo[3.1.0]hexun-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH-pyrazole-4-carboxamide (1-477).
Figure imgf000519_0001
[0905] Synthesis of ethyl l-(tetrahydro-2H-pyran-2-yl)-LH-pyrazole-4-carboxylate. To a solution of ethyl lH-pyrazole-4-carboxylate (2.8 g, 20 mmol) in DMF (20 mL) was added p- toluenesulfonic acid (344 mg, 2 mmol) and DHP (2.5 g, 30 mmol) at room temperature. The resulting reaction was stirred at 80 °C for 24 h. After cooled to room temperature, the reaction was quenched with water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over NaiSCh, and concentrated in vacuo to give the crude, which was purified by column chromatography (EtOAc/PE from 0 to 20%) to give ethyl l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carboxylate (3.4 g, yield: 76%) as a white solid. ESI-MS [M +H] +: 225.1. [0906] Synthesis of ethyl 3-fluoro-lH-pyrazole-4-carboxylate. To solution of ethyl 1-
(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carboxylate (448 mg, 2.0 mmol) in THF (20 mL) was added LDA (2M in THF, 1.2 mL, 2.4 mmol) at -78 °C and the mixture was stirred at -78 °C for 1 h. NFSI (945 mg, 3.0 mmol) in THF(10 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction was quenched with NH4CI (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep-TLC (eluent: EtOAc / PE = 1/2) to give ethyl 3 -fluoro- lH-pyrazole-4-carboxylate (40 mg, yield: 13%) as colorless oil. ESIMS [M +H] +: 159.0.
[0907] Synthesis of 3-fhioro-lH-pyrazole-4-carboxylic acid. A mixture of ethyl 3-fluoro- lH-pyrazole-4-carboxylate (40 mg, 0.25 mmol) and LiOH*H2O (21 mg, 0.50 mmol) in THF/EtOHTLO (3mL/3 mL/1 mL) was stirred at 80 °C for 18 h. After cooled to room temperature, pH of the reaction was adjusted to 3 with HC1 (aq. IN) and concentrated to give 3- fluoro-lH-pyrazole-4-carboxylic acid (45 mg, crude) as a white solid. ESLMS [M +H] +: 131.1. [0908] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH- pyrazole-4-carboxamide. A mixture of 3-fluoro-lH-pyrazole-4-carboxylic acid (45 mg, crude), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (60 mg, 0.30 mmol), HATU (114 mg, 0.30 mmol) and DIPEA (97 mg, 0.75 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x 5). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give N-((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH-pyrazole-4-carboxamide (40 mg, yield: 51% over 2 steps) as a yellow solid. ESLMS [M +H]+: 314.1.
[0909] Synthesis of l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l- amino-5, 7-dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH-pyrazole-4-carboxamide. A mixture of N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH-pyrazole-4-carboxamide (40 mg, 0.13 mmol), l-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(chloromethyl)phenyl)ethan-l-one (50 mg, 0.20 mmol) and CS2CO3 (127 mg, 0.39 mmol) in DMF (4 mL) was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x 5). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH-pyrazole-4-carboxamide (5 mg, yield: 7 %) as a white solid. ESI-MS [M +H]+: 527.2. 1H NMR (400 MHz, DMSO) 5 8.19 (s, 2H), 8.02 (t, J = 4.5 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J = 6.1 Hz, 1H), 7.15 (s, 4H), 6.99 (d, J = 6.1 Hz, 1H), 6.69 (s, 2H), 5.14 (s, 2H), 4.55 (d, J = 4.5 Hz, 2H), 3.60-3.45 (m, 5H), 3.22 (dd, J = 11.6, 4.2 Hz, 1H), 2.60 - 2.42 (m, 6H), 1.50-1.46 (m, 2H), 0.66-0.64 (m, 1H), 0.02-0.01 (m, 1H).
Example 478
Synthesis of l-(4-(((2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyi)amino)pyriniidin-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-478).
Figure imgf000521_0001
[0910] Synthesis of l-(4-(((2-chloropyrimidin-4-yl)oxy)methyl)benzyl)pyridin-2(lH)-one. To a solution of l-(4-(hydroxymethyl)benzyl)pyridin-2(lH)-one (400 mg, 1.86 mmol) in THF (10 mL) was added 2,4-dichloropyrimidine (550 mg, 3.72 mmol) and t-BuOK (417 mg, 3.72 mmol). Then the mixture was stirred at 75 °C for 3 h. After cooled to room temperature, water
(20 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0 ~ 50% EtOAc in PE to give l-(4-(((2-chloropyrimidin-4-yl)oxy)methyl)benzyl)pyridin-2(lH)-one (500 mg, yield: 82%) as a yellow solid. ESLMS [M +H]+: 328.1.
[0911] Synthesis of l-(4-(((2-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)pyridin-2(lH)-one. To a solution of l-(4- (((2-chloropyrimidin-4-yl)oxy)methyl)benzyl)pyridin-2(lH)-one (100 mg, 0.3 mmol) in z-PrOH (5 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (60 mg, 0.3 mmol) and TEA (91 mg, 0.9 mmol). The mixture was stirred at 120 °C for 1.5 h under microwave. After cooled to room temperature, Water (20 mL) was added and extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give l-(4-(((2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (60 mg, yield: 40%) as a yellow solid. ESLMS [M +H]+: 493.2. 1H NMR (400 MHz, DMSO) 5 8.16 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (dd, J = 9.6, 6.6 Hz, 2H), 7.48 - 7.35 (m, 3H), 7.28 (d, J = 7.8 Hz, 2H), 7.22 (s, 1H), 7.00 (d, J = 6.1 Hz,lH), 6.76 (s, 2H), 6.41 (d, J = 9.0 Hz, 1H), 6.23 (t, J = 6.1 Hz, 1H), 6.07 (d, J = 5.6 Hz, 1H), 5.31 (s,2H), 5.09 (s, 2H), 4.64 (d, J = 4.5 Hz, 2H), 2.47 (s, 6H).
Example 479
Synthesis of l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino -5, 7- dimethylisoquinolin-6-yl)methyl)-4-fluoro-lH-pyrrole-3-carboxamide (1-479).
Figure imgf000522_0001
[0912] Synthesis of 4-fhioro-lH-pyrrole-3-carbaldehyde. To a solution of oxalyl dichloride (543 mg, 4.31 mmol) in di chloromethane (10 mL) at 0 °C was added dropwise a solution of DMF (315 mg, 4.31 mmol) in dichloromethane (2 mL) and the reaction was stirred at 0 °C for 30 min. Then a solution of 3-fluoro-l-(triisopropylsilyl)-lH-pyrrole (800 mg, 3.31 mmol) in di chloromethane (5 mL) was added thereto. The reaction was stirred at 40 °C for another 30 min. Then the mixture was concentrated to give the crude, which was quenched with NaHCCh (sat., 30 mL) and stirred at room temperature for 1 h. Then the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na SCU, concentrated in vacuo to give the crude, which was purified by silica gel chromatography (PE/EtOAc = 1/5) to give 4-fluoro-lH-pyrrole-3-carbaldehyde (250 mg, yield: 67%) as a yellow solid. ESLMS [M +H]+: 114.2.
[0913] Synthesis of l-(4-(2-(3-azabicyclo [3.1.0] hexan-3-yl)-2-oxoethyl) benzyl)-4-fluoro- 111- pyrrole-3-carbaldehyde. To a solution of 4-fluoro-lH-pyrrole-3-carbaldehyde (270 mg, 2.4 mmol) in DMF (10 mL) was added CS2CO3 (2.35 g, 7.2 mmol) and 1 -(3 -azabicyclo [3.1.0] hexan-3-yl)-2- (4-(chloromethyl) phenyl) ethan-l-one (600 mg, 2.4 mmol) at room temperature. The resulting mixture was stirred for 4 h. The reaction was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the crude, which was purified by silica gel chromatography (PE/EtOAc = 1/3) to afford l-(4-(2-(3 -azabicyclo [3.1.0] hexan-3-yl)-2- oxoethyl) benzyl)-4-fluoro-lH-pyrrole-3-carbaldehyde (350 mg, yield: 45%) as colorless oil. ESLMS [M +H]+: 327.1.
[0914] Synthesis of l-(4-(2-(3-azabicyclo [3.1.0] hexan-3-yl)-2-oxoethyl) benzyl)-4-fluoro- 1H- pyrrole-3-carboxylic acid. To a solution of l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2- oxoethyl)benzyl)-4-fluoro-lH- pyrrole-3-carbaldehyde (30 mg, 0.09 mmol) in DMSO (3 mL) was added a solution of NaLLPCL (77 mg, 0.63 mmol) and NaCICh (73 mg, 0.81 mmol) in H2O (1 mL) dropwise for 10 min. The resulting mixture was stirred at room temperature for 10 h. Water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude, which was purified by Prep-HPLC to give l-(4-(2-(3 -azabicyclo [3.1.0] hexan-3-yl)-2- oxoethyl) benzyl)-4-fluoro-lH-pyrrole-3- carboxylic acid (25 mg, yield: 81%) as a white solid. ESLMS [M +H]+: 343.1.
[0915] Synthesis of l-(4-(2-(3-azabicyclo [3.1. ] hexan-3-yl)-2-oxoethyl) benzyl)-N-((l- amino-5, 7-dimethylisoquinolin-6-yl)methyl)-4-fluoro-lH-pyrrole-3-carboxamide. A mixture of L(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-4-fluoro-lEI-pyrrole-3-carboxylic acid (20 mg, 0.06 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (14 mg, 0.07 mmol), HATU (46 mg, 0.12 mmol) and DIPEA (15 mg, 0.12 mmol) in DMF (4 mL) was stirred at room temperature for 2 h. Water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over NazSCU, filtered and concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH = 10: 1) to afford l-(4-(2-(3 -azabicyclo [3.1.0] hexan-3-yl)-2-oxoethyl) benzyl)-N-((l-amino-5, 7- dimethylisoquinolin-6-yl) methyl)-4-fluoro-lH-pyrrole-3-carboxamide (2 mg, yield: 6%) as a white solid. ESLMS [M +H]+: 526.2. 1H NMR (400 MHz, DMSO) S 7.88 (s, 1H), 7.75 (d, J = 6.0 Hz, 1H), 7.49 (s, 1H), 7.22-7.14 (m, 5H), 6.98 (d, J = 5.9 Hz, 1H), 6.81 (s, 1H), 6.59 (s, 2H), 4.96 (s, 2H), 4.55 (d, J = 4.1 Hz, 2H), 3.66 - 3.15 (m, 6H), 2.50 (s, 6H), 1.56-1.49 (m, 2H), 0.67- 0.63 (m, 1H), 0.02-0.00 (m, 1H).
Example 480 and Example 481
Synthesis of ethyl (6-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(4- ((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (1-480) and ethyl (6-(((l- ((ethoxycarbonyl)amino)-5,7-dinethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(4-((2- oxopyridin-1 (2H)-yl)methyl)benzyl)carbamate (1-481 )
Figure imgf000524_0001
[0916] Synthesis of ethyl (6-chloropyrimidin-4-yl)carbaniate. To a solution of 6- chloropyrimidin-4-amine (500 mg, 3.87 mmol) in THF (20 mL) was added ethyl chloroformate (628 mg, 5.81 mmol), DMAP (94 mg, 0.77 mmol) and TEA (1.17 g, 11.6 mmol). The resulting reaction mixture was stirred room temperature for 16 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0 ~ 50% EtOAc in PE to give ethyl (6-chloropyrimidin-4-yl)carbamate (300 mg, yield: 38.5%) as a yellow solid. ESI-MS [M +H]+: 202.1.
[0917] Synthesis of ethyl (6-chloropyrimidin-4-yl)(4-((2-oxopyridin-l(2H)~ yl)methyl)benzyl)carbamate. A mixture of ethyl (6-chloropyrimidin-4-yl)carbamate (201 mg, 1.0 mmol), l-(4-(chloromethyl)benzyl)pyridin-2(lH)-one (466 mg, 2.0 mmol), K2CO3 (414 mg, 3.0 mmol) and Nal (150 mg, 1 mmol) in DMF (15 mL) was stirred at room temperature for 12 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 15/1) to give ethyl (6-chloropyrimidin-4-yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (200 mg, yield: 50%) as a yellow solid. ESLMS [M +H]+: 399.2.
[0918] Synthesis of ethyl (6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate. A mixture of ethyl (6-chloropyrimidin-4-yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (100 mg, 0.25 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (75 mg, 0.375 mmol), Pd-PEPPSLIPENT-Cl (o-picoline) (21 mg, 0.025 mmol) and CS2CO3 (244 mg, 0.75 mmol) in DMF (10 mL) was stirred at 80 °C for 3 h. After cooled to room temperature, the reaction mixture was filtered, the filter cake was washed with DCM/MeOH (10: 1, 40 mL). The filtrate was concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give ethyl (6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (110 mg, yield: 78%) as a white solid. ESLMS [M +H]+: 564.3. 1H NMR (400 MHz, DMSO) 8 8.34 (s, 1H), 7.93 (s, 1H), 7.77 - 7.74 (m, 2H), 7.49 (s, 1H), 7.41( m, 1H), 7.20 - 7.16 (m, 4H), 7.02 - 7.00 (m, 2H), 6.74 (s, 2H), 6.40 (d, J = 9.1 Hz, 1H), 6.22 (t, J = 6.6 Hz, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 4.65 (s, 2H), 4.12 (q, J = 7.0 Hz, 2H), 2.48 (s, 6H), 1.14 (t, J = 7.1 Hz, 3H).
[0919] Synthesis of ethyl (6-(((l-((ethoxycarbonyl)amino)-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate. To a solution of ethyl (6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(4- ((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (100 mg, 0.18 mmol) in DMF (2 mL)/THF (10 mL) was added ethyl chloroformate (58 mg, 0.54 mmol), DMAP (11 mg, 0.09 mmol) and DIPEA (70 mg, 0.54 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with H2O (25 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give ethyl (6-(((l -((ethoxy carbonyl)amino)-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (20 mg, yield: 17.5%) as a white solid. ESI-MS [M +H]+: 636.3. 1HNMR (400 MHz, DMSO) 8 9.91 (s, 1H), 8.34 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.83 - 7.71 (m, 3H), 7.54 (s, 1H), 7.46-7.36 (m, 1H), 7.23 - 7.15 (m, 4H), 7.03 (s, 1H), 6.39 (d, J = 9.1 Hz, 1H), 6.22 (t, J = 6.7 Hz, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 4.70 (s, 2H), 4.16-4.06 (m, 4H), 2.65 (s, 3H), 2.52 (s, 3H), 1.31 - 1.21 (m, 3H), 1.13 (t, J = 7.0 Hz, 3H).
Example 482
Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl- 11 ,2,4]triazo!ol 1 ,5-a]pyridin-2-yl)methyl)-l H-pyrazole-4-carboxamide (1-482).
Figure imgf000526_0001
[0920] A mixture of 2-(chloromethyl)-6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridine (15 mg, 0.072 mmol), N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (23 mg, 0.079 mmol) and CS2CO3 (46 mg, 0.14 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. Water (30 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO-i, concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 5/1) to give N- ((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (16 mg, yield: 48%) as a yellow solid. ESI-MS [M +H]+: 467.2. 1H NMR (400 MHz, DMSO) 5 8.73 (s, 1H), 8.33 (s, 1H), 8.12 (t, J = 4.5 Hz, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 6.99 (d, J = 6.1 Hz, 1H), 6.63 (s, 2H), 5.55 (s, 2H), 4.59 (d, J = 4.5 Hz, 2H), 2.51 (s, 6H), 2.05-2.01 (m, 1H), 0.97 (d, J = 6.2, 2H), 0.78-0.75 (m, 2H).
Example 483 and 484
Synthesis of (Z)-N4-(4-(l-(lH-pyrazol-l-yl)prop-l-en-l-yl)benzyl)-S6-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (1-483) and N4-(4-(l-(lH-pyrazol-l- yl)propyl)henz,yl)-N6-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4, 6-diamine (1-484)
Figure imgf000527_0001
[0921] Synthesis of 4-((lH-pyrazol-l-yl)methyl)benzonitrile. A mixture of ethyl 4- (bromomethyl)benzonitrile (6.0 g, 30.8 mmol), IH-pyrazole (2.5 g, 37.0 mmol) and Cs2COs(20 g, 61.6 mmol) in DMF (100 mL) was stirred at room temperature for 18 h. The reaction was quenched with water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by column chromatography (EtOAc/PE from 0 to 20%) to give 4- ((lH-pyrazol-l-yl)methyl)benzonitrile (4.9 g, yield: 87%) as a white solid. ESLMS [M +H] +: 184.1.
[0922] Synthesis of (Z)-4-(l-(lH-pyrazol-l-yl)prop-l-en-l-yl)benzonitrile. To solution of 4-((lH-pyrazol-l-yl)methyl)benzonitrile (3.0 g, 16.4 mmol) in THF(30 mL) was added 1,2- dibromoethane (3.64 g, 19.7 mmol) followed by addition of LDA (2M in THF, 9.85 mL, 19.7 mmol) at -78 °C and the mixture was stirred at -78 °C for 1 h. The reaction was quenched with NH4Q (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified column chromatography (eluent: EtOAc / PE = 0 - 30%) to give (Z)-4-(l-(lH-pyrazol-l- yl)prop-l-en-l-yl)benzonitrile (1.1 g, yield: 32%) as a yellow oil. ESI-MS [M +H] +: 210.1.
[0923] Synthesis of (Z)-(4-(l-(lH-pyrazol-l-yl)prop-l-en-l-yl)phenyl)niethanamine. To a solution of (Z)-4-(l-(lH-pyrazol-l-yl)prop-l-en-l-yl)benzonitrile (350 mg, 1.67 mmol) in THF(10 mL) was added BH3-THF (IM in THF, 5.0 mL, 5.0 mmol) at 0 °C and the mixture was stirred at room temperature for 3 h. The reaction was quenched with NH4Q (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (Z)-(4-(l-(lH-pyrazol-l-yl)prop-l-en-l- yl)phenyl)methanamine (100 mg, yield: 28%) as a yellow oil. ESLMS [M +H] +: 214.1.
[0924] Synthesis of (Z)-N4-(4-(l-(lH-pyrazol-l-yl)prop-l-en-l-yl)benzyl)-N6-((l-amino-
5, 7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine. A mixture of (Z)-(4-(l-(lH- pyrazol-l-yl)prop-l-en-l-yl)phenyl)methanamine (100 mg, 0.47 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (147mg, 0.47 mmol), Pd-PEPSl-Ipent'cl o-picoline (42 mg, 0.05 mmol) and CS2CO (461 mg, 1.41 mmol) in DMF (10 mL) was stirred at 80 °C for 2 h under nitrogen. After cooled to room temperature, the reaction mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give (Z)-N4-(4- ( 1 -( 1 H-pyrazol- 1 -yl)prop- 1 -en- 1 -y l)benzy l)-N6-(( 1 -amino-5 , 7-dimethy li soquinolin-6- yl)methyl)pyrimidine-4,6-diamine (35 mg, yield: 15%) as a yellow solid. ESI-MS [M +H]+: 491.2. 1H NMR (400 MHz, DMSO) 5 8.00 (s, 1H), 7.90 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.75 (d, J = 6.1 Hz, 1H), 7.66 (s, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 5.9 Hz, 1H), 7.02-6.94 (m, 3H), 6.71 (s, 2H), 6.66 (s, 1H), 6.45 (s, 1H), 6.39 - 6.30 (m, 1H), 5.43 (s, 1H), 4.53 (s, 2H), 4.34 (s, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 1.61 (d, J = 6.9 Hz, 3H).
[0925] Synthesis of N -(4-(l-(l H-pyrazol-l-yl)propyl)benzyl)-N6-((l-amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrinudine-4,6-diamine. A mixture of (E)-N4-(4-(l-(lH- pyrazol-l-yl)prop-l-en-l-yl)benzyl)-N6-((l -amino-5, 7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (20 mg, 0.041 mmol) and Pd/C(10 mg) in MeOH (3 mL) was stirred at room temperature for 1 h under H2. The reaction mixture was filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 20 mL). The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give N4-(4-(l- (IH-pyrazol-l-y^propy^benzy^-b^-^l-amino-S^-dimethylisoquinolin-b-y^methy^pyrimidine- 4,6-diamine (3.8 mg, yield: 19%) as a white solid. ESI-MS [M +H]+: 493.2. 1H NMR (400 MHz, HDMSO) 5 7.99 (s, 1H), 7.90 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 6.2 Hz, 1H), 7.43 (s, 1H), 7.24 (q, J = 8.2 Hz, 4H), 7.10 (t, J = 6.0 Hz, 1H), 7.00 (d, J = 6.2 Hz, 1H), 6.72 (s, 2H), 6.65 (s, 1H), 6.22 (t, J = 1.9 Hz, 1H), 5.43 (s, 1H), 5.31-5.21 (m, 1H), 4.52 (s, 2H), 4.32 (s, 2H), 2.58 (s, 3H), 2.45 (s, 3H), 2.37-2.21 (m,lH), 2.17 - 1.99 (m, 1H), 0.76 (s, 3H).
Example 485
Synthesis qfN-((l-amino-5,7-diniethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-
Figure imgf000529_0001
[0926] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-lH-pyrrolo[3,2- b]pyridine-3-carboxamide. A mixture of lH-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.62 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (125 mg, 0.62 mmol), HATU (471 mg, 1.24 mmol) and DIPEA (400 mg, 3.1 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrrolo[3,2-b]pyridine-3-carboxamide (50 mg, yield: 23%) as a white solid. ESI-MS [M +H]+: 346.2.
[0927] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboxamide. A mixture of N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrrolo[3,2-b]pyridine-3- carboxamide (50 mg, 0.14 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[l,2-a]pyridine (58 mg, 0.28 mmol) and CS2CO3 (137 mg, 0.42 mmol) in DMF (5 m ) was stirred at 60 °C for 3 h. After cooled to room temperature, the reaction was quenched with water (50 m ) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by Prep- TLC (eluent: DCM/MeOH = 20/1) to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l- ((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboxamide (5 mg, yield: 7%) as a white solid. ESI-MS [M +H]+: 516.2. 1H NMR (400 MHz, DMSO) 5 8.85 (t, J = 5.3 Hz, 1H), 8.35 (d, J = 3.1 Hz, 2H), 8.28 (s, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.93 (s, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.75 (d, J = 10.7 Hz, 1H), 7.36 (d, J = 9.4 Hz, 1H), 7.21 (dd, J = 8.3, 4.8 Hz, 1H), 7.04 - 6.88 (m, 2H), 6.62 (s, 2H), 5.58 (s, 2H), 4.79 (d, J = 5.2 Hz, 2H), 2.63 (s, 2H), 2.58 (s, 2H), 1.88 (dd, J = 9.1, 4.1 Hz, 1H), 0.95 - 0.80 (m, 3H), 0.69 - 0.53 (m, 3H).
Example 486
Synthesis of 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)niethyl)amino)-6-((6-cyclopropyl- [l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (1-486).
Figure imgf000531_0001
[0928] Synthesis of ethyl 4,6-dichloropyrimidine-2-carboxylate. To a solution of 4,6- dichloropyrimidine-2-carboxylic acid (1.0 g, 5.2 mmol) in EtOH (20 mL) was added SOCh (1 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 5 h. After cooled to room temperature, the reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: DCM/MeOH = 50/1) to give ethyl 4,6-dichloropyrimidine-2- carboxylate (800 mg, yield: 70%) as a yellow oil. ESI-MS [M +H]+: 221.2.
[0929] Synthesis of 4-chloro-6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2- yl)methoxy)pyrimidine-2-carboxylic acid. To a solution of (6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyridin-2-yl)methanol (190 mg, 1.0 mmol) in THF (10 mL) was added NaH (60% in mineral oil, 80 mg, 2.0 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, then a solution of ethyl 4,6-dichloropyrimidine-2-carboxylate (220 mg, 1.0 mmol) in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO-i, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 4-chloro-6-((6-cyclopropyl-
[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (200 mg, yield: 58%) as a yellow solid. ESI-MS [M +H]+: 346.2.
[0930] Synthesis of tert-butyl 4-chloro-6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2- yl)methoxy)pyrimidine-2-carboxylate. A mixture of 4-chloro-6-((6-cyclopropyL
[1.2.4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (200 mg, 0.58 mmol), (BOC)2O (253 mg, 1.16 mmol) and DMAP (15 mg, 0.12 mmol) in Z-BuOH (10 mL) was stirred at 60 °C for 16 h. After cooled to room temperature, the reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give tert-butyl 4-chloro-6-((6-cyclopropyl-
[1.2.4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylate (150 mg, yield: 64%) as a colorless oil. ESLMS [M +H]+: 402.2.
[0931] Synthesis of tert-butyl 4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-
((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrinudine-2-carboxylate. A mixture of tert-butyl 4-chloro-6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2- yl)methoxy)pyrimidine-2-carboxylate (100 mg, 0.25 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (50 mg, 0.25 mmol), Pd-PEPPSI-IPenfcl o-picoline (21 mg, 0.025 mmol) and Cs2COi (245 mg, 0.75 mmol) in DMF (10 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was cooled to room temperature, filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 30 mL). The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl 4-(((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylate (40 mg, yield: 28%) as a white solid. ESLMS [M +H]+: 567.2. [0932] Synthesis of 4-(((l-annno-5, 7-ditnethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid. To a solution of tert-butyl 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylate (40 mg, 0.07 mmol) in DCM (2.5 m ) added TFA (0.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product, which was purified by Prep-HPLC to give 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (15 mg, yield: 42%) as a white solid. ESI-MS [M +H]+: 511.2. 1H NMR (400 MHz, DMSO) 8 8.76 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.69 (d, J = 9.4 Hz, 1H), 7.43 (dd, J = 9.2, 1.7 Hz, 1H), 7.00 (d, J = 6.1 Hz, 1H), 6.67 (s, 2H), 5.94 (s, 1H), 5.53 (s, 2H), 4.60 (s, 2H), 2.56 (s, 6H), 2.09 - 1.96 (m, 1H), 1.01 - 0.96 (m 2H), 0.81 - 0.79 (m, 2H).
Example 487
Synthesis of 4-(((l-annno-5, 7-dirnethylisoquinolin-6-yl)methyl)amino)-6-((6-
Figure imgf000533_0001
[0933] Synthesis of ethyl 4,6-dichloropyrimidine-2-carboxylate. To a solution of 4,6- dichloropyrimidine-2-carboxylic acid (1.0 g, 5.21 mmol) in dry EtOH (20 mL) was added SOCh (1 mL) at 0 °C and stirred at 80 °C for 2 h. The mixture was concentrated to give crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-2% MeOH in DCM to give ethyl 4,6-dichloropyrimidine-2-carboxylate (1 g, yield: 87 %) as a white solid. ESIMS [M +H]+: 221.1.
[0934] Synthesis of 4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidine-2-carboxyUc acid. To a solution of (6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methanol (376 mg, 2.0 mmol) in dry THF (15 mL) was added NaH (60% dispersion in mineral oil, 240 mg, 6.0 mmol) slowly at 0 °C, and the reaction mixture was stirred at rt for 0.5 h. Then a solution of ethyl 4,6-dichloropyrimidine-2-carboxylate (595 mg, 2.70 mmol) in dry THF (5 mL) was added. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) and stirred for 30 min. The pH of the mixture was adjusted to 5 by HC1 (aq. IN). The mixture was extracted with C LCl/z- PrOH (3/1) (50 mL x 5). The combined organic layers were dried and concentrated to give 4- chloro-6-((6-cyclopropylimidazo[l,2-a]pyri din-2 -yl)methoxy)pyrimidine-2-carboxylic acid (600 mg, crude) as a yellow solid, which was used into the next step without further purification. ESIMS [M +H]+: 345.1.
[0935] Synthesis of tert-butyl 4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidine-2-carboxylate. A mixture of 4-chloro-6-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (600 mg, crude), (Boc)2O (1.14 g, 5.23 mmol) and DMAP (43 mg, 0.35 mmol) in z-BuOH (15 mL) was stirred at 60 °C for 16 h. After cooled to room temperature, water (50 mL) was added and extracted by EtOAc (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO-i, and concentrated to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc = 1/1) to give tert-butyl 4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidine-2-carboxylate (450 mg, yield: 56% over 2 steps) as a yellow solid. ESIMS [M +H]+: 401.2.
[0936] Synthesis of tert-butyl 4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-
((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylate. A mixture of tert-butyl 4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidine-2- carboxylate (150 mg, 0.38 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (76 mg, 0.38 mmol), Pd-PEPPSI-IPenfcl o-picoline (34 mg, 0.04 mmol) and CszCCh (372 mg, 1.14 mmol) in DMF (15 mL) was stirred at 100 °C for 3 h under N2. The reaction mixture was cooled to room temperature, fdtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl 4-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidine-2- carboxylate (60 mg, yield: 28%) as a white solid. ESI-MS [M +H]+: 566.2.
[0937] Synthesis of 4-(((l-anuno-5, 7-dhnethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid To a solution of tert-butyl 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylate (80 mg, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep- HPLC to give 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (23 mg, yield: 32%) as a white solid. ESI-MS [M +H]+: 510.2. 1H NMR (400 MHz, DMSO) 8 8.34 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.84 (s, 3H), 7.70 (d, J = 6.7 Hz, 1H), 7.61 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.17 (d, J = 5.7 Hz, 1H), 7.07 - 6.96 (m, 1H), 5.97 (s, 1H), 5.40 (s, 2H), 4.69 (s, 2H), 2.57 (s, 6H), 2.00 - 1.89 (m, 1H), 1.05 - 0.75 (m, 2H), 0.75 - 0.59 (m, 2H).
Example 488
Synthesis of 4-(((l-anuno-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-
Figure imgf000536_0001
[0938] Synthesis of 4-chloro-6-((6-cyclopropyHnndazo[l,2-a]pyrimidin-2- yl)methoxy)pyrimidine-2-carboxylic acid. To a solution of (6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methanol (253 mg, 1.34 mmol) in THF (25 mL) was added NaH (60% in mineral oil, 160 mg, 4.0 mmol) at 0 °C slowly. The resulting mixture was stirred at 0 °C for 30 min. Then ethyl 4,6-dichloropyrimidine-2-carboxylate (440 mg, 2.0 mmol) was added at 0 °C. The mixture was stirred at room temperature for 5 h. The reaction was quenched with water (30 mL) and stirred for 30 min. The pH of the mixture was adjusted to 5 by HC1 (IM aq.) and then extracted with CHiCl/z-PrOH (10/1, 40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, concentrated in vacuo to give 4-chloro-6-((6- cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylic acid (400 mg, crude), which was used into next step without further purification. ESI-MS [M +H]+: 346.2.
[0939] Synthesis of tert-butyl 4-chloro-6-((6-cyclopropylinudazo[l,2-a]pyrinudin-2- yl)methoxy)pyrimidine-2-carboxylate. To a solution of 4-chloro-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylic acid (400 mg, crude) in Z-BuOH (20 mL) was added BOC2O (506 mg, 2.32 mmol) and DMAP (28 mg, 0.23 mmol) at room temperature. Then the mixture was stirred at 60 °C for 12 h. After cooled to room temperature, the reaction was quenched with H2O (40 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried with Na2SCh, concentrated in vacuo to give the crude, which was purified with combi flash chromatography with (DCM/MeOH = 20/1) to give tert-butyl 4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2- carboxylate (300 mg, yield: 56% over 2 steps) as a yellow solid. ESLMS [M +H]+: 402.2.
[0940] Synthesis of tert-butyl 4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6- ((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylate. A mixture of tert-butyl 4-chloro-6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2- carboxylate (160 mg, 0.4 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (96 mg, 0.48 mmol), Pd-PEPPSLIPENT-Cl (o-picoline) (34 mg, 0.04 mmol) and CS2CO3 (391 mg, 1.2 mmol) in DMF (15 mL) was stirred at 95 °C for 2 h. The reaction mixture was cooled to room temperature, filtered through celite® and the filter cake was washed with DCM/MeOH (10/1, 30 mL). The filtrate was concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH = 10/1) to give tert-butyl 4-(((Lamino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2- carboxylate (45 mg, yield: 20%) as a yellow solid. ESLMS [M +H]+: 567.2.
[0941] To a solution of tert-butyl 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)- 6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylate (45 mg, 0.08 mmol) in DCM (10 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was concentrated to give the crude, which was purified with Prep-HPLC to give 4- (((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylic acid (15 mg, yield: 37%) as a white solid. ESLMS [M +H]+: 511.2. 1H NMR (400 MHz, DMSO) 6 8.70 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.83-7.74 (m, 2H), 7.56 (s, 1H), 7.10 - 6.87 (m, 3H), 5.98 (s, 1H), 5.44 (s, 2H), 4.67 (s, 2H), 2.53 (s, 6H), 2.03-1.96 (m, 1H), 1.02 - 0.90 (m, 2H), 0.81 - 0.68 (m, 2H). Example 489
Synthesis of ethyl 4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylate (1-489).
Figure imgf000538_0001
[0942] To a solution of 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylic acid (15 mg, 0.03 mmol) in EtOH (5 mL) was added SOCh (0.5 mL) at 25 °C. The mixture was stirred at 70 °C for 4 h. After cooled to room temperature, the reaction was concentrated to give the crude, washed with NaHCCh (sat. aq., 20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude, which was purified with Prep-TLC (DCM/MeOH = 10/1) to give ethyl 4-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2- yl)methoxy)pyrimidine-2-carboxylate (10 mg, yield: 62.5%) as a white solid. ESI-MS [M +H]+: 439.2. 1H NMR (400 MHz, DMSO) 5 8.70 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.65 (s, 1H), 6.99 (d, J = 6.1 Hz, 1H), 6.65 (s, 2H), 6.01 (s, 1H), 5.42 (s, 2H), 4.66 (s, 2H), 4.41 - 4.32 (m, 2H), 2.50 (s, 6H), 2.03 - 1.96 (m, 1H), 1.35 (t, J = 13.7, 7.0 Hz, 3H), 1.00 - 0.96 (m, 2H), 0.77 - 0.76 (m, 2H).
Example 490
Synthesis ofN-((l-aniino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-sulfonamide (1-490).
Figure imgf000539_0001
[0943] Synthesis of N-((l-amino-5, 7-diniethylisoquinolin-6-yl)niethyl)-lH-pyrazole-4- sulfonamide. To a solution of 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (605 mg, 3.0 mmol) in THF/ DMSO (15 mL / 5 mL) was added lH-pyrazole-4-sulfonyl chloride (250 mg, 1.5 mmol) and DIPEA (387 mg, 3.0 mmol) at 0 °C. The resulting reaction was stirred at 0 °C for 1 h. The reaction was quenched with H2O (30 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SOr, concentrated in vacuo to give the crude, which was purified with silica gel (eluent: DCM/MeOH = 30/1) to give the N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-sulfonamide (300 mg, yield: 60%) as a yellow solid. ESLMS [M +H]+: 332.2.
[0944] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-sulfonamide. A mixture of N- ((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-sulfonamide (180 mg, 0.54 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[l,2-a]pyridine (93 mg, 0.45 mmol) and CS2CO3 (440 mg, 1.35 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. The reaction was diluted with H2O (25 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-HPLC to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)- l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-sulfonamide as a white solid. (25 mg, 11 %). ESLMS [M +H]+: 502.2. 1H NMR (400 MHz, DMSO) 8 8.38 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 7.85-7.78 (m, 2H), 7.74 (d, J = 6.1 Hz, 1H), 7.51 (t, J = 5.5 Hz, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.05-6.95 (m, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.65 (s, 2H), 5.48 (s, 2H), 4.07 (d, J = 5.5 Hz, 2H), 2.35 (s, 3H), 2.30 (s, 3H), 1.97 - 1.90 (m, 1H), 0.97 - 0.88 (m, 2H), 0.71-0.64 (m, 2H).
Example 491
Synthesis ofN-((l-anuno-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-cycIopropylimidazo[l,2-
Figure imgf000540_0001
[0945] Synthesis ((benzylthio)ethynyl)trimethylsilane. To a solution of ethynyltrimethylsilane (9.8 g, 100 mmol) in dry EtzO (150 mL) was added n-BuLi (42 mL, 2.4 M solution in hexane, 100.8 mmol) slowly at -78 °C. The reaction was stirred at -78 °C for 15 min. Then S (3.2 g, 100 mmol) was added to the reaction and stirred at -78 °C for another 15 min. The reaction was warmed to room temperature and stirred for 1 h until S was consumed. The reaction was cooled to 0 °C, BnBr (17.1 g, 100 mmol) was added to the reaction. The resulting mixture was stirred at room temperature for 14 h. The reaction was quenched with NH4CI (sat. aq. 100 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (eluent: PE) to give the product as a yellow oil (20 g, yield: 91%). ESI-MS [M +H]+: 221.2. [0946] Synthesis benzyl(ethynyl)sulfane. To a solution of ((benzylthio)ethynyl)trimethylsilane (15.5 g, 70 mmol) in THF (50 mL) was added TBAF (75 mL, 1 M solution in THF, 75 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction was concentrated and the residue was diluted with NH4CI (sat. aq., 100 mL), extracted with Et2O (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the product (8 g, crude) as a colorless oil, which was used into the next step without further purification. ESLMS [M +H]+: 149.2.
[0947] Synthesis benzyl(ethynyl)siilfane. To a solution of benzyl(ethynyl)sulfane (4 g, crude) and 2-(azidomethyl)-6-cyclopropylimidazo[l,2-a]pyridine (8.5 g, 40 mmol) in t-BuOH/ H2O (50 mL/ 50 mL) was added CuSCU (2.1 g, 13.2 mmol) and sodium ascorbate (2.61 g, 13.2 mmol). The reaction was stirred at room temperature for 12h. H2O (150 mL) was added, extracted with DCM (150 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH = 15/1) to give 2-((4-(benzylthio)-lH-l,2,3-triazol-l-yl)methyl)- 6-cyclopropylimidazo[l,2-a]pyridine (5 g, yield: 40% over 2 steps) as a black solid. ESLMS [M +H]+: 362.2.
[0948] Synthesis l-((6-cyclopropylinndazo[l,2-a]pyri(lin-2-yi)methyl)-lH-l,2,3-triazole-4- sulfonyl chloride. To a solution of 2-((4-(benzylthio)-lH-l,2,3-triazoLl-yl)methyl)-6- cyclopropylimidazo[l,2-a]pyridine (500 mg, 1.39 mmol) in AcOJLTLO (15 mL/5 mL) was added NCS (186 mg, 1.39 mmol). The reaction was stirred at room temperature for 5 h. The reaction was concentrated in vacuo to give the crude (600 mg crude), which was used into next step without further purification. ESLMS [M +H]+: 338.0.
[0949] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)niethyl)-lH-l,2,3-triazole-4-sulfonamide. A mixture of 1 -((6-cyclopropylimidazo[ 1 ,2-a]pyridin-2-yl)m ethyl)- 1 H- 1 ,2,3 -triazole-4-sulfonyl chloride (100 mg, crude), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (50 mg, 0.25 mmol) and DIPEA (116 mg, 0.90 mmol) in THF (5 mL) was stirred at room temperature for 12 h. The reaction was quenched with H2O (25 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-HPLC to give N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-l,2,3-triazole-4-sulfonamide (12 mg, yield: 10 % over 2 steps) as a white solid. ESI-MS [M +H]+: 503.2. 1H NMR (400 MHz, DMSO) 8 8.70 (s, 1H), 8.39 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.75 (d, J = 6.1 Hz, 1H), 7.43 (d, J = 9.4 Hz, 1H), 7.06-7.01 ( m, 1H), 6.91 (d, J = 6.1 Hz, 1H), 6.65 (s, 2H), 5.76 (s, 2H), 4.24 (s, 2H), 2.39-2.28 (m, 6H), 1.98-1.91 (m, 1H), 0.96-0.91 (m, 2H), 0.73 - 0.65 (m, 2H).
Example 492
Synthesis of 6-(((4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-
Figure imgf000542_0001
[0950] Synthesis of 2-(((2-chloropyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[l,2- ajpyridine. To a solution of (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol (164 mg, 0.87 mmol) in THF (10 mL) was added NaH (60% in mineral oil, 52 mg, 1.31 mmol) at 0 °C under N2, the mixture was stirred at room temperature for 20 min. Then a solution of 2,4- di chloropyrimidine (154 mg, 1.04 mmol) in THF (1 mL) was added. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated to give the crude, which was purified with Prep-TLC (eluent: MeOH/CTLCh = 1/50) to give the product (220 mg, yield: 84%) as a yellow solid. ESIMS [M +H]+: 301.2.
[0951] Synthesis of 6-(((4-(( 6-cyclopropylimidazo[l, 2-a]pyridin-2-yi) methoxy)pyrimidin-2- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine. To a solution of 2-(((2-chloropyrimidin-4- yl)oxy)methyl)-6-cyclopropylimidazo[l,2-a]pyridine (100 mg, 0.33 mmol) in z-PrOH (5 mL) was added 6-(aminomethyl)-5, 7-dimethylisoquinolin-l-amine (100 mg, 0.5 mmol) and DIPEA (129 mg, 1 mmol). The mixture was stirred at 120 °C under microwave for 1 h. After cooled to room temperature, H2O (20 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried with Na2SOr, concentrated to give the crude, which was purified with Prep-TLC (eluent: MeOH/DCM=l/20) to give the product (90 mg, yield: 58.6%) as a white solid. ESI-MS [M +H]+: 466.2. 1H NMR (400 MHz, DMSO) 8 8.31 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 6.1 Hz, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.23 (s, 1H), 7.02 - 6.94 (m, 2H), 6.59 (s, 2H), 6.08 (d, J = 5.6 Hz, 1H), 5.41 (s, 2H), 4.67 (d, J = 4.7 Hz, 2H), 2.51 (s, 3H), 2.49 (s, 3H), 1.99-1.88 (m, 1H), 0.98-0.88 (m, 2H), 0.73-0.64 (m, 2H).
Example 493
Synthesis of 6-(((6-(l-(6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)ethoxy)pyrimidin-4-
Figure imgf000543_0001
[0952] Synthesis of 6-cyclopropylimidazo[l,2-b]pyridazine-2-carb(ildehyde. A mixture of
(6-cy cl opropylimidazo[l,2-b]pyridazin-2-yl)m ethanol (140 mg, 0.74 mmol) and MnCb (644 mg, 7.4 mmol) in DCM (10 mL) was stirred at room temperature for 18 h. The reaction mixture was filtered and washed by DCM (50 mL). The filtrate was concentrated to give the crude 6- cyclopropylimidazo[l,2-b]pyridazine-2-carbaldehyde (140 mg, crude) as a colorless oil, which was used in the next step without further purification. ESI-MS[M + H]+: 188.1.
[0953] Synthesis of l-(6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)ethan-l-ol. To a solution of 6-cyclopropylimidazo[l,2-b]pyridazine-2-carbaldehyde (140 mg, crude) in THF (5 mL) was added MeMgBr (3M in THF, 0.75 mL, 2.25 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by NHrCl (sat. aq., 30 mL), extracted by EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to afford l-(6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)ethan-l-ol (110 mg, yield: 73% over 2 steps) as a yellow solid. ESI-MS[M + H]+: 204.2.
[0954] Synthesis of 2-(l-((6-chloropyrimidin-4-yl)oxy)ethyl)-6-cyclopropylimidazo[l,2- bjpyridazine. To a mixture of l-(6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)ethan-l-ol (100 mg, 0.50 mmol), 6-chloropyrimidin-4-ol (130 mg, 1.00 mmol) and PPhi (197 mg, 0.75 mmol) in THF (5 mL) was added DIAD (152 mg, 0.75 mmol) at 0°C. Then the mixture was stirred at 0 °C for 3 h. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO-i, concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 1/1) to give crude 2-(l-((6-chloropyrimidin-4-yl)oxy)ethyl)-6-cyclopropylimidazo[l,2-b]pyridazine (100 mg, yield: 63%) as a white solid. ESI-MS [M + H]+ : 316.2.
[0955] Synthesis of 6-(((6-(l-(6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)ethoxy)pyrimidin-
4-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine. A mixture of 2-(l-((6-chloropyrimidin- 4-yl)oxy)ethyl)-6-cyclopropylimidazo[l,2-b]pyridazine (100 mg, 0.32 mmol), 6-(aminomethyl)- 5,7-dimethylisoquinolin-l -amine (129 mg, 0.64 mmol) and DIPEA (124 mg, 0.96 mmol) in i- PrOH (5 mL) was stirred at 145 °C for 3 h under microwave. After cooled to room temperature, the reaction was diluted with water (20 mL), extracted by EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-HPLC to afford 6-(((6-(l-(6-cyclopropylimidazo[l,2- b]pyridazin-2-yl)ethoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (13 mg, yield: 8.5%) as a white solid. ESI-MS [M +H]+: 481.3. 1HNMR (400 MHz, DMSO) 5 8.26 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.12 (d, J = 9.4 Hz, 1H), 7.05 (s, 1H), 6.99 (d, J = 6.0 Hz, 1H), 6.64 (s, 2H), 6.11 - 6.02 (m, 1H), 5.23 (s, 1H), 4.42 (s, 2H), 2.45 (s, 6H), 2.24 - 2.14 (m, 1H), 1.72 (d, J = 7.1 Hz, 3H), 1.12 - 1.03 (m, 2H), 1.02 - 0.95 (m, 2H).
Example 494 and Example 495
Synthesis of 7-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-4-((6-cyclopropyiimidazoll,2- a]pyridin-2-yl) methoxy) -2, 7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (1-494) and 3-(((l- aniino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-5-((6-cyclopropylinudazo[l,2-a]pyridin-2- yl)methoxy)picolinic acid (1-495)
Figure imgf000545_0001
[0956] Synthesis of methyl 3-bromo-5-fluoropicolinate. To a solution of 3-bromo-5- fluoropicolinic acid (250 mg, 1. 14 mmol) in MeOH (10 mL) was added SOCI2 (401 mg, 3.4 mmol). The mixture was stirred at 60 °C for 2 h. After cooled to room temperature, the reaction was concentrated to give the crude product (260 mg, crude) as a yellow solid, which was used into the next step without purification. ESI-MS [M +H]+: 234. 1.
[0957] Synthesis of 3-bromo-5-((6-cyclopropylinudazo[l,2-a]pyridin-2- yl)niethoxy)picolinic acid To a solution of methyl 3-bromo-5-fluoropicolinate (260 mg, 1.1 mmol) in DMF (10 mL) was added (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol (207 mg, 1.1 mmol) and NaH (440 mg, 11 mmol, 60% dispersion in mineral oil). The resulting reaction mixture was stirred at room temperature for 3 h. Water (30 mL) was added and stirred for 30 min then extracted by EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaiSCL, filtered, and concentrated to give the crude product (420 mg, crude) as a yellow solid, which was used into the next step without purification. ESI-MS [M +H]+: 388.1.
[0958] Synthesis of methyl 3-bromo-5-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)picolinate. To a solution of 3-bromo-5-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)picolinic acid (420 mg, crude) in MeOH (10 mL) was added SOCh (0.5 mL). The resulting reaction mixture was stirred at 60 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCCh (sat. aq., 30 mL) and extracted by EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO-i, fdtered and concentrated to give the crude, which was purified by Prep-TLC (EtOAc :PE=1 : 1) to give the product (240 mg, yield: 53% over 3 steps) as a white solid. ESI-MS [M +H]+: 402.1.
[0959] Synthesis of 7-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-4-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)niethoxy)-2, 7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one. To a solution of methyl 3-bromo-5-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)picolinate (30 mg, 0.075 mmol) in Toluene (5 mL) was added 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (27 mg, 0.134 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), xantphos (17 mg, 0.029 mmol) and CS2CO3 (73 mg, 0.224 mmol). The resulting reaction mixture was stirred at 100 °C for 4 h under N2. After cooled to room temperature, the reaction was diluted with H2O (20 mL) and extracted by EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO-i, filtered and concentrated and purified by Prep- TLC (MeOH : DCM=1 : 10) to give the product (30 mg, yield: 82%) as a green solid. ESI-MS [M +H]+: 491.1. 1H NMR (400 MHz, DMSO) 8 8.62 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 8.1 Hz, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 5.47 (s, 2H), 3.87 (s, 2H), 2.60 (s, 3H), 2.58 (s, 3H), 1.97 -1.91 (m, 1H), 0.95 - 0.90 (m, 2H), 0.71 -0.67 (m, 2H).
[0960] Synthesis of 3-(((l-antino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-5-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)picolinic acid To a solution of 7-((l-amino-
5.7-dimethylisoquinolin-6-yl)methyl)-4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)-
2.7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (30 mg, 0.06 mmol) in THF/H2O (6 mL/2 mL) was added NaOH (12 mg, 0.30 mmol), then the mixture was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was concentrated to give the crude, which was purified by Prep- HPLC to give the product (15 mg, yield: 50%) as a green solid. ESI-MS [M +H]+: 509.0. 1H NMR (400 MHz, DMSO) 8 14.38 (s, 1H), 9.48 (s, 1H), 8.32 (t, J = 23.6 Hz, 2H), 8.20- 8.05 (m, 2H), 7.41 (dd, J = 28.9, 7.4 Hz, 2H), 7.00 (d, J = 9.2 Hz, 1H), 5.33 (d, J = 35.5 Hz, 2H), 4.06 (s, 2H), 2.63 (d, J = 9.9 Hz, 6H), 1.95 -1.85 (m, 1H), 1.01 - 0.72 (m, 2H), 0.77 - 0.47 (m, 2H). Example 496 and Example 497
Synthesis of 7-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-4-(((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)amino)-2, 7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (1-496) and 3-(((l- amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-5-(((6-cyclopropylimidazo[l,2-a]pyridin-2- y I) methyl) amino)picolinic acid (1-497)
Figure imgf000547_0001
[0961] Synthesis of methyl 3-bromo-5-fluoropicolinate. To a solution of 3-bromo-5- fluoropicolinic acid (240 mg, 1.1 mmol) in MeOH (5 mL) was added SOCh (401 mg, 3.4 mmol), then the mixture was stirred at 60 °C for 2 h. Then concentrated to give the crude product (240 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS [M +H]+: 234.1.
[0962] Synthesis of methyl 3-bromo-5-(((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)amino)picolinate. A mixture of methyl 3-bromo-5-fluoropicolinate (240 mg, crude), (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanamine (206 mg, 1.1 mmol) and DIPEA (1.42 g, 1 Immol) in DMF (5 mL) was stirred at 80 °C for 16 h. After cooled to room temperature, the reaction was diluted with water (20 mL) and extracted by EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered, and concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH = 20: 1) to give the product (150 mg, yield: 34% over 2 steps) as a white solid. ESLMS [M +H]+: 401.1.
[0963] Synthesis of 7-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-4-(((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)amino)-2,7-diazabicyclo[4.2.0]octa-l,3,5-trien- 8-one. To a solution of methyl 3-bromo-5-(((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)amino)picolinate (30 mg, 0.075 mmol) in Toluene (5 mL) was added 6- (aminomethyl)-5,7-dimethylisoquinolin-l -amine (27 mg, 0.134 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), xantphos (17 mg, 0.029 mmol) and CS2CO3 (73 mg, 0.224 mmol). Then the mixture was stirred at 100 °C for 4 h under N2. After cooled to room temperature, the reaction was diluted with water (20 mL) and extracted by EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, fdtered and concentrated and purified by Prep- TLC (DCM/MeOH = 10/1) to give the product (30 mg, yield: 82%) as a green solid. ESLMS [M +H]+: 490.2. 1HNMR (400 MHz, DMSO) 8 8.57 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 15.1 Hz, 1H), 7.41 (dd, J = 15.0, 8.7 Hz, 2H), 6.99 (d, J = 10.7 Hz, 2H), 4.56 (d, J = 5.1 Hz, 2H), 3.87 (s, 2H), 2.60 (s, 3H), 2.57 (s, 3H), 1.95 -1.85 (m, 1H), 0.92 - 0.86 (m, 2H), 0.67 - 0.63 (m, 2H).
[0964] Synthesis of 3-(((l-amino-5, 7-diniethylisoquinolin-6-yl)methyl)amino)-5-(((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)amino)picolinic acid To a solution of 7-((l- amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-(((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)amino)-2,7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (30 mg, 0.06 mmol) in THF/ H2O (4 mL/2 mL) was added NaOH (12 mg, 0.30 mmol). Then the mixture was stirred at 80 °C for 8 h. After cooled to room temperature, the reaction was concentrated and purified by Prep- HPLC to give the product (15 mg, yield: 49%) as a green solid. ESLMS [M +H]+: 508.3. 1H NMR (400 MHz, DMSO) 8 14.11 (d, J = 133.0 Hz, 1H), 8.97 (d, J = 15.0 Hz, 1H), 8.32 - 8.29 (m, 2H), 8.11 - 7.92 (m, 2H), 7.91-7.49 (m,lH), 8 7.92 - 7.17 (m, 2H), 7.00 - 6.91 (m, 1H), 4.57 - 4.37 (m, 2H), 4.25 - 4.05 (m, 2H), 2.59 (s,6H), 1.25 - 1.20 (m, 1H), 0.98 - 0.32 (m, 4H).
Example 498
Synthesis of 6-(((2-(( 6-cyclopropylimidazo[l , 2-a]pyridin-2-yl) methyl)-[l, 2,4]triazolo[l, 5-
Figure imgf000548_0001
[0965] Synthesis of 3-brotno-2-iminopyrazin-l (2H)-amine 2,4, 6- trimethylbenzenesulfonate. To a stirred solution of O-(mesitylsulfonyl)hydroxylamine (1.48 g, 6.89 mmol) in DCM (20 mL) was added 3-bromopyrazin-2-amine (1.2 g, 6.89 mmol) in portions at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and rinsed with DCM (20 mL). The filter cake was collected and dried in vacuo to afford 3-bromo-2-iminopyrazin-l(2H)-amine 2,4,6-trimethylbenzenesulfonate (1.6 g, yield: 59%) as a white solid. ESI-MS [M + H]+: 189.0.
[0966] Synthesis of 8-chloro-2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-
[1.2.4]triazolo[l,5-a]pyrazine. A mixture of 3-bromo-2-iminopyrazin-l(2H)-amine 2,4,6- trimethylbenzenesulfonate (450 mg, 1.16 mmol) and 2-(6-cyclopropylimidazo[l,2-a]pyri din-2 - yl)acetic acid (250 mg, 1.16 mmol) in POCh (10 mL) was stirred at 100 °C for 30 min. After cooled to room temperature, the reaction mixture was poured into water (30 mL) at 0 °C, neutralized with NaHCCh (sat. aq., 30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over NazSCU, concentrated and purified by silica gel chromatography (DCM/MeOH = 10/1) to give 8-chloro-2-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrazine (40 mg, yield: 11%) as a yellow solid. ESIMS [M + H]+: 325.1.
[0967] Synthesis of 6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-
[1.2.4]triazolo[l,5-a]pyrazin-8-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine. A mixture of 8-chloro-2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrazine (40 mg, 0.123 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine (50 mg, 0.246 mmol) and DIPEA (159 mg, 1.23 mmol) in z-PrOH (5 mL) was stirred at 140 °C for 3 h under microwave. The reaction mixture was cooled to room temperature, concentrated and purified by Prep-TLC (DCM/MeOH = 10/1) to give 6-(((2-((6-cyclopropylimidazo[l,2-a]pyri din-2 - yl)methyl)-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine (10 mg, yield: 17%) as a yellow solid. ESLMS [M +H]+: 490.2. 1H NMR (400 MHz, DMSO) 8 8.24 (s, 1H), 8.09 (d, J = 4.6 Hz, 1H), 7.94 (t, J = 4.7 Hz, 1H), 7.89 (s, 1H), 7.74 (d, I = 6.2 Hz, 1H), 7.64 D 7.57 (m, 2H), 7.31 (d, J = 9.2 Hz, 1H), 6.99 (d, J = 6.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.72 (s, 2H), 4.82 (d, J = 4.7 Hz, 2H), 4.24 (s, 2H), 2.54 (s, 3H), 2.53 (s, 3H), 1.92 -1.84 (m, 1H), 0.92 - 0.86 (m, 2H), 0.66 - 0.62 (m, 2H). Example 538
Synthesis ofN-((l-aniino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)oxazolo[5,4-dpyrimidin- 7-amine (1-538).
Figure imgf000550_0001
[0968] Synthesis of 2-(3-chloroquinolin-6-yl)-N-(4,6-dichloropyrinndin-5-yl)acetamide. To a stirred solution of 4,6-dichloropyrimidin-5-amine (1 g, 6.1 mmol) and 2-(3-chloroquinolin-6- yl)acetic acid (1.34 g, 6.1 mmol) in ethyl acetate (20 mL) and pydine (20 mL) was added l,3,5,2,4,6-trioxatriphosphorinane,2,4,6-tripropyl-,2,4,6-trioxide (10 m L, 15.7 mmol) at -10 oC. The mixture was stirred at room temperature overnight. After the completion of reaction, the mixture was quenched with saturated sodium bicarbonate and washed with brine, dried over sodium sulfate, evaporated and purified by silical gel chromatography to give 2-(3- chloroquinolin-6-yl)-N-(4,6-dichloropyrimidin-5-yl)acetamide (1 g, yield: 45%) as a yellow solid. ESI-MS [M + H]+: 367.0, 1H NMR (400 MHz, DMSO-d6) 8 10.64 (s, 1H), 8.87 (t, J = 2.4 Hz, 2H), 8.59 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.80 (dd, J = 8.8, 1.6 Hz, 1H), 3.99 (s, 2H).
[0969] Synthesis of 7-chloro-2-((3-chloroquinolin-6-yl)methyl)oxazolo[5,4-d]pyrimidine. To a stirred solution of 2-(3-chloroquinolin-6-yl)-N-(4,6-dichloropyrimidin-5-yl)acetamide (400 mg, 1.1 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60%, 160 mg, 4.0 mmol). After stirring at 60 oC for 1 hour, the reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with brine, dried, evaporated and purified by Prep-TLC (Petroleum ether/Ethyl acetate = 2/1) to afford 7-chloro-2- ((3-chloroquinolin-6-yl)methyl)oxazolo[5,4-d]pyrimidine (20 mg, yield: 5.6%) as a yellow solid. ESI-MS [M + H]+: 1H NMR (400 MHz, DMSO-d6) 8 8.90-8.89 (m, 2H), 8.58 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 4.72 (s, 2H).
[0970] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)oxazolo[5,4-d]pyrimidin-7-amine. To a stirred solution of 7- chloro-2-((3-chloroquinolin-6-yl)methyl)oxazolo[5,4-d]pyrimidine (20 mg, 0.06 mmol), 6- (aminomethyl)-5,7-dimethylisoquinolin-l- (12 mg, 0.06 mmol) and 2 drops of ethyl diisopropylamine in N,N-Dimethylformamide (1 mb) was added potassium iodide (10 mg, 0.06 mmol). After stirring at 60 oC overnight, the reaction was quenched by water and the resulting suspension was filtered. The crude solid was purified by Prep-TLC (Dichloromethane/Methanol/Ammonium hydroxide = 120/8/1) to give N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazolo[5,4-d]pyrimidin-7- amine (8 mg, yield: 27%) as a yellow solid. ESI-MS [M + H]+: 496.1, 1H NMR (400 MHz, DMSO-de) 58.86 (d, J = 2.4 Hz, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.41-8.36 (m, 2H), 8.09 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 4.88-4.86 (m, 2H), 4.54 (s, 2H), 2.67-2.66 (m, 6H).
Example 539
Synthesis of 6-(((8-((3-chloroquinolin-6-yl)niethyl)-9-methyl-9H-purin-6-yl)amino)methyl)- 5, 7-dimethylisoquinolin-l-anhne (1-539).
Figure imgf000551_0001
[0971] Synthesis of 6-chloro-N-methyl-5-nitropyrimidin-4-amine. Acetic acid glacial (3 mL) was carefully added to methylamine aqueous solution (6 mL). The solution was cooled to 5 °C and then dropwise added to a stirred solution of 4,6-dichloro-5-nitropyrimidine (2.2 g, 0.011 mol) in 1,4-dixone (5 mL) which was previously cooled to 0 °C. The inside temperature was maintained at 10 °C and the addition of the solution of methylamine took 1 hour. After all the methylamine had been added, 30 mL of water was added dropwise during 2 hours. The inside temperature was maintained at 10 °C during this time. Finally the yellow solid was fdtered and washed with ice-water to give 6-chloro-N-methyl-5-nitropyrimidin-4-amine (1.7 g, yield: 81%) as a yellow solid. ESLMS [M + H]+: [M + H]+189.0.
[0972] Synthesis of 6-chloro-N4-methylpyrimidine-4,5-diamine. To a stirred solution of 6- chloro-N-methyl-5-nitropyrimidin-4-amine (1.1 g, 5.85 mmol) in tetrahydrofuran (10 mL) and saturated ammonium chloride (10 mL) was added zinc (1.9 g, 29 mmol). The mixture was stirred at room temperature for 2 hour. After the completion of reaction, the mixture was concentrated, the diluted with water and ethyl acetate, filtered, separated. The organic layer was washed with brine, dried, evaporated and purified by silical gel chromatography (Petroleum ether/Ethyl acetate = 20/1) to give 6-chloro-N4-methylpyrimidine-4,5-diamine (0.28 g, yield: 30%) as a yellow solid. ESLMS [M + H]+: 159.0, 'H NMR (400 MHz, DMSO-de) 8 7.75 (s, 1H), 6.86 (d, J = 4.0 Hz, 1H), 4.95 (s, 2H), 2.88 (d, J = 4.8 Hz, 3H).
[0973] Synthesis ofN-(4-chloro-6-(methylamino)pyrimidin-5-yl)-2-(3-chloroquinolin-6- yl)acetamide. To a stirred solution of 6-chloro-N4-methylpyrimidine-4,5-diamine (0.28 g, 1.77 mmol) and 2-(3-chloroquinolin-6-yl)acetic acid (0.392 g, 1.77 mmol) in N,N- dimethylformamide(8 mL) was added HATU (0.808 g, 2.12 mmol) and ethyldiisopropylamine (0.84 mL, 5.31 mmol). The mixture was stirred at room temperature for 2 hours. After the completion of reaction, the mixture was added water and filtered, washed with water and petroleum ether to give N-(4-chloro-6-(methylamino)pyrimidin-5-yl)-2-(3-chloroquinolin-6- yl)acetamide (0.2 g, yield: 31%) as a yellow solid. ESLMS [M + H]+ 362.0, ‘H NMR (400 MHz, DMSO-de) 5 9.64 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.80 (dd, J = 2.0, 8.8 Hz, 1H), 7.49 (d, J = 4.4 Hz, 1H), 3.91 (s, 2H), 2.87 (d, J = 4.8 Hz, 3H).
[0974] Synthesis of 3-chloro-6-((6-chloro-9-methyl-9H-purin-8-yl)methyl)quinoline. To a stirred solution of N-(4-chloro-6-(methylamino)pyrimidin-5-yl)-2-(3-chloroquinolin-6- yl)acetamide (150 mg, 0.41 mmol) in phosphorus oxychloride (6 mL) was added ethyldiisopropylamine (0.15 mL, 0.82 mmol). The mixture was stirred at 110 °C for 4 hours. After the completion of reaction, the mixture was concentrated, diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried, evaporated and purified by Prep-TLC (Petroleum ether/ Ethyl acetate = 1 / 1) to afford 3-chloro- 6-((6-chloro-9-methyl-9H-purin-8-yl)methyl)quinoline (80 mg, yield:30%) as a yellow solid. ESLMS [M + H]+: 343.9, ’H NMR (400 MHz, DMSO-ds) 8 8.87 (d, J = 2.4 Hz, 1H), 8.74 (s, 1 H), 8.55 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.79 (dd, J = 2.0, 8.8 Hz, 1H), 4.66(s, 2 H), 3.79 (s, 3H).
[0975] Synthesis of 6-(((8-((3-chloroquinolin-6-yl)methyl)-9-methyl-9H-purin-6- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-annne. To a stirred solution of 3-chloro-6-((6- chloro-9-methyl-9H-purin-8-yl)methyl)quinoline (80 mg, 0.23 mmol), (50 mg, 0.24 mmol) and ethyldiisopropylamine (0.1 mL) in N,N-dimethylformamide (2 mL) was added potassium iodide (40 mg, 0.23 mmol). After stirred at 60 °C overnight, the mixture was diluted with water and filtered. The solid crude was purified by Prep-TLC (Dichloromethane/Methanol/Ammonium hydroxide = 120/8/1) to give 6-(((8-((3-chloroquinolin-6-yl)methyl)-9-methyl-9H-purin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (45 mg, yield: 38%) as a yellow solid. ESL MS [M + H]+: 509.1, 1H NMR (400 MHz, DMSO-de) 8 8.82 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 8.79 (d, J = 8.8 Hz, 1H), 7.77 (s, 2H), 7.71-7.68 (m, 2H), 7.62 (s, 2H), 7.11 (d, J = 6.8 Hz, 1H), 4.92 (s, 2H), 4.49 (s, 2H), 2.56-2.55 (m, 6H).
Example 540
Synthesis of 5, 7-diniethyl-6-(((6-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
Figure imgf000553_0001
[0976] Synthesis of (4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6- yl)(naphthalen-2-yl)niethanol. To a stirred solution of 4-chloro-7-(phenylsulfonyl)-7H- pyrrolo[2,3-d]pyrimidine (2 g, 6.8 mmol) in tetrahydrofuran (40 mL) was added n-butyllithium (2.5 M solution in hexane) (2.5 M in THF, 5 mL, 12.5 mmol ) at -78 °C under Nitrogen. After 30 minutes, a solution of 2-naphthaldehyde (1.6 g, 10.3 mmol) in tetrahydrofuran (10 mL) was added. The mixture was stirred at -78 °C for 2 hours. Atfer the completion of reaction by TLC, the reaction was quenched by saturated ammonium chloride, and extracted with Ethyl acetate. The organic layer was washed with brine, dried, evaporated and purified by silical gel chromatography (Petroleum ether / Ethyl acetate = 5 / 1) to give (4-chloro-7-(phenylsulfonyl)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)(naphthalen-2-yl)methanol (1 g, yield: 33%) as a yellow solid. ESLMS [M + H]+: 450.1, XH NMR (400 MHz, DMSO-de) 8 12.66 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 7.91 (t, J = 8.8 Hz, 3H), 7.62 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 4.0 Hz, 2H), 6.45 (d, J = 4.0 Hz, 1H), 6.41 (s, 1H), 6.07 (d, J = 4.0 Hz, 1H).
[0977] Synthesis of (4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)-7-
(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(naphthalen-2-yl)methanol. To a solution of (4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(naphthalen-2-yl)methanol (500 mg, 1.1 mmol) and 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (223 mg, 1.1 mmol) in N,N-dimethylformamide (10 mL) was added ethyl diisopropylamine (0.4 mL, 2.2 mmol) and potassium iodide (180 mg, 1.1 mmol). The mixture was stirred at 60 °C overnight. After the completion of reaction, the mixture was quenched with water, filtered and washed with methanol to give (4-((( 1 -ami no-5 , 7 -dimethyli soquinolin-6-yl)methyl)amino)-7-(phenyl sulfonyl)-7H- pyrrolo[2,3-d]pyrimidin-6-yl)(naphthalen-2-yl)methanol (450 mg, yield: 65%) as a yellow solid. ESLMS [M + H]+: 615.3, XH NMR (400 MHz, DMSO-ds) 88.33 (s, 1H), 7.96 (d, J = 8.0 Hz, 4H), 7.90-7.82 (m, 5H), 7.71 (d, J = 6.4 Hz, 1 H), 7.63 (t, J = 7.6 Hz,lH), 7.50-7.47 (m, 3H), 7.41 (t, J = 8.0 Hz, 2H), 7. 17 (s, 2H), 7.03 (d, J = 6.8 Hz, 1H), 6.70 (s, 1H), 6.59 (d, J = 5.2 Hz, 1H), 6.26 (d, J = 6.4 Hz, 1H), 4.74 (d, J = 3.2 Hz, 2H), 2.46 (s, 3H), 2.44 (s, 3H).
[0978] Synthesis of 5, 7-dimethyl-6-(((6-(naphthalen-2-ylmethyl)-7-(phenylsulfonyl)-7H- pyrrolo[2,3-dJpyrimidin-4-yl)amino)methyl)isoquinolin-l-amine. To a stirred solution of (4- (((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-7-(phenylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yl)(naphthalen-2-yl)methanol (250 mg, 0.4 mmol) in acetonitrile (5 mL) was added tetrahydrofuran (0.5 mL) and tri ethyl silane (0.5 mL). The mixture was stirred at 80 °C overnight. After the completion of reaction, concentrated, queched with saturated Sodium bicarbonate, extracted with ethyl acetate. The organic layer was washed with brine, dried by Sodium sulfate, evaporated and purified by prepare-TLC (Ethyl acetate) to afford 5,7-dimethyl- 6-(((6-(naphthalen-2-ylmethyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)isoquinolin-l-amine(150 mg yield: 61%) as a yellow solid. ESI-MS [M + H]+:
599.1.
[0979] Synthesis of 5, 7-dimethyl-6-(((6-(naphthalen-2-ylmethyl)~ 7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)methyl)isoquinolin-l-amine. To a stirred solution of 5,7-dimethyl-6- (((6-(naphthalen-2-ylmethyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine (90mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added a solution of sodium hydroxide (36 mg, 1.5 mmol) in water (0.5 mL). The mixture was stirred at 65 °C overnight. After the completion of reaction, the mixture was evaporated and purified by Prep-HPLC to give 5,7-dimethyl-6-(((6-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine (10 mg, yield: 14%) as a yellow solid. ESI-MS [M + H]+:
459.2, XH NMR (400 MHz, DMSO-de) 5 11.55 (s, 1H), 8.14(s, 1H), 7.88-7.81 (m, 4H), 7.76-7.73 (m, 2H), 7.46-7.40 (m, 3H), 7.23 (t, J = 4.0 Hz, 1H), 6.96 (d, J = 7.0 Hz, 1H), 6.57 (s, 2H), 6.15 (s, 1H), 4.76 (d, J = 4.8 Hz, 2H), 4.12 (s, 2H), 2.49 (s, 3H), 2.46 (s, 3H).
Example 499
Synthesis of 6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-imidazo[4,5- c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l -amine (1-499).
Figure imgf000555_0001
[0980] Synthesis of 2-chloro-N-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-5- nitropyridin-4-amine. To a solution of 2,4-dichloro-5-nitropyridine (1.0 g, 5.2 mmol) in THF (30 mL) was added (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanamine (1.66 g, 8.9 mmol) and DIPEA (2.7 g, 20.8 mmol). The resulting mixture was stirred at 60 °C for 6 h. After cooled to room temperature, the reaction was quenched with H2O (100 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (70 mL), dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH/DCM = 1/20) to give the product (1.6 g, yield: 90%) as a yellow solid. ESI-MS [M +H]+: 344.1.
[0981] Synthesis of 6-chloro-N4-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)pyridine-3,4-diamine. To a solution of 2-chloro-N-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (500 mg, 1.46 mmol) in EtOH/ EEO (20 mL/4 mL) was added iron (812 mg, 14.5 mmol) and NELCl (768 mg, 14.5 mmol). The mixture was stirred at 100 °C for 3 h. After cooled to room temperature, the mixture was filtered and the filter cake was washed with MeOH (40 mL). The filtrate was concentrated to give the crude product (450 mg, crude) as a yellow solid, which was used into the next step without further purification. ESI-MS [M +H]+: 314.2.
[0982] Synthesis of 6-chloro-l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH- imidazo[4,5-c]pyridine. To a solution of 6-chl oro-N4-((6-cy cl opropylimidazo[l,2-a]pyri din-2 - yl)methyl)pyridine-3,4-diamine (450 mg, crude) in CH(OMe)3 (15 mL) was added p-TsOH (52 mg, 0.3 mmol), the mixture was stirred for 2 h at 60 °C. After cooled to room temperature, the reaction was quenched by NaHCOi (sat. aq. 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH/DCM = 1/10) to give the product (320 mg, yield: 68% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 324.2.
[0983] Synthesis of 6-(((l-((6-cyclopropylinudazo[l,2-a]pyridin-2-yl)methyl)-lH- imidazo[4,5-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine. To a solution of 6-chloro-l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyridine (90 mg, 0.28 mmol) in DMF (5 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (66 mg, 0.33 mmol), CS2CO3 (274 mg, 0.84 mmol) and Pd-PEPPSLiPent-Cl o-picoline (24 mg, 0.028 mmol). The mixture was stirred at 85 °C for 16 h under N2. After cooled to room temperature, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated to give the crude, which was purified by silica gel chromatography (DCM/MeOH = 10/1) to afford the product (40 mg, yield: 29%) as a white solid. ESI-MS [M +H]+: 489.3. 1H NMR (400 MHz, DMSO) 5 8.47 (s, 1H), 8.28 (s, 1H), 8.19 (s, 2H), 8.11 (s, 1H), 7.90 (s, 1H), 7.74 (d, J = 6.2 Hz, 1H), 7.65 (s, 1H), 7.36 (d, J = 9.4 Hz, 1H), 7.02-6.94 (m, 2H), 6.75 (s, 2H), 6.56 (s, 1H), 6.13 (s, 1H), 5.38 (s, 2H), 4.56 (d, J = 4.0 Hz, 2H), 2.52 (s, 3H), 2.48 (s, 3H), 1.95-1.84 (m, 1H), 0.95-0.84 (m, 2H), 0.69 - 0.55 (m, 2H).
Example 500
Synthesis of 6-(((2-((6-cyclopropylinudazo[l,2-a]pyridin-2-yl)methyl)-3H-imidazo[4,5- c]pyridin-4-yl)amino)methyl)-5, 7-dimethylisoquinolin-l -amine (1-500).
Figure imgf000557_0001
[0984] Synthesis of 4-chloro-2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3H- imidazo[4,5-c]pyridine. To a solution of 2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)acetic acid (500 mg, 2.3 mmol) in POCh (10 m ) was added 2-chloropyridine-3,4-diamine (400 mg, 2.78 mmol). The reaction mixture was stirred at 100 °C for 8 h. After cooled to room temperature, the reaction was concentrated and the residue was neutralized with NaHCCh (sat. aq., 40 mL), then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified by AI2O3 column chromatography (eluent: MeOH/DCM = 1/50) to give the product as a yellow solid (200 mg, yield: 27%). ESLMS [M +H]+: 324.2.
[0985] Synthesis of 6-(((2-((6-cyclopropylinudazo[l,2-a]pyridin-2-yl)methyl)-3H- imidazo[4,5-c]pyridin-4-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine. To a solution of 4-chloro-2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3H-imidazo[4,5-c]pyridine (100 mg, 0.31 mmol) in DMF (5 ml) was added 6-(aminomethyl)-5, 7-dimethylisoquinolin-l-amine (92 mg, 0.46 mmol), Pd-PEPPSLiPent-Cl o-picoline (25 mg, 0.03 mmol) and CS2CO3 (303 mg, 0.93 mmol). The reaction mixture was stirred at 140 °C for 4 h under N2 by Microwave. After cooled to room temperature, the reaction was diluted with. H2O (20 ml) and extracted with MeOH/EtOAc (1 : 10, 40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, concentrated to give the crude, which was purified by Prep-HPLC to give the product (20 mg, yield: 13%) as a white solid. ESLMS [M +H]+: 489.3. 1H NMR (400 MHz, DMSO) 8 8.27 (d, J = 6.8 Hz, 3H), 7.91 (s, 1H), 7.76 - 7.74 (m, 2H), 7.65 (s, 1H), 7.34 (d, J = 9.2 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.75 - 6.70 (m, 3H), 6.18 (s, 1H), 4.78 (d, J = 4.1 Hz, 2H), 4.21 (s, 2H), 2.56 (s, 3H), 2.52 (s, 3H), 1.93 - 1.86 (m, 1H), 0.92 - 0.87 (m, 2H), 0.66 - 0.62 (m, 2H).
Example 501
Synthesis of 6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolol4,5-
Figure imgf000558_0001
[0986] Synthesis of 6-chloro-l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-
[1.2.3]triazolo[4,5-c]pyridine. To a solution of 6-chloro-N4-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)pyridine-3,4-diamine (500 mg, 1.59 mmol) in AcOH (15 mL) was added a solution of NaNO2(165 mg, 2.38 mmol) in H2O (15 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 30 min. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the residue, which was purified by chromatography on silica gel (MeOH: DCM = 1 :20) to give 6-chloro-l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolo[4,5-c]pyridine (400 mg, yield: 77%) as a yellow solid. ESLMS [M +H]+: 325.1.
[0987] Synthesis of 6-(((l-((6-cyclopropylinudazo[l,2-a]pyridin-2-yl)methyl)-lH-
[1.2.3]triazolo[4,5-c]pyridin-6-yl)a iino)methyl)-5, 7-dimethylisoquinolin-l-a une. To a solution of 6-chloro- 1 -((6-cyclopropylimidazo[ 1 ,2-a]pyridin-2-yl)methyl)- 1H- [l,2,3]triazolo[4,5-c]pyridine (30 mg, 0.09 mmol) in DMF(4 mL) was added 6-(aminomethyl)- 5,7-dimethylisoquinolin-l-amine (22 mg, 0.11 mmol), Cs2CO.3 (88 mg, 0.27 mmol) and Pd- PEPPSLiPent-Cl o-picoline (17 mg, 0.02 mmol). The reaction mixture was stirred at 110 °C for 16 h under N2. After cooled to room temperature, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated to give the residue, which was purified by chromatography on silica gel (MeOH:DCM = 1 : 10) to give 6-(((l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolo[4,5-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (10 mg, yield: 23%) as a yellow solid. ESIMS [M +H]+: 490.2. 1H NMR (400 MHz, DMSO) 8 = 8.99 (s, 1H), 8.30 (s, 1H), 7.90 (s, 1H), 7.83 - 7.65 (m, 2H), 7.38-7.34 (m, 1H), 7.00-6.95 (m, 1H), 6.83-6.76 (m, 1H), 6.60 (s, 1H), 6.54 (s, 1H), 5.82 (s, 2H), 4.62-4.51 (m, 2H), 2.51 (s, 3H), 2.47 (s, 3H), 1.94 - 1.87 (m, 1H), 0.92 - 0.84 (m, 2H), 0.69 - 0.59 (m, 2H).
Example 502
Synthesis of 6-((l2-azanyl)methyl)-N-(l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-
[l,2,3]triazolo[4,5-c]pyridin-6-yl)-5,7-dimethylisoquinolin-l-amine (1-502).
Figure imgf000559_0001
[0988] To a solution of 6-chl oro-1 -((6-cy cl opropylimidazo[ 1, 2-a]pyridin-2-yl)methyl)- 1H-
[l,2,3]triazolo[4,5-c]pyridine (50 mg, 0.15 mmol) in 1,4-Dioxane(10 mL) was added 6- (aminomethyl)-5,7-dimethylisoquinolin-l-amine (32 mg, 0.16 mmol), Cs2CC>3 (150 mg, 0.46 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (17 mg, 0.03 mmol). The mixture was stirred at 110 °C for 16 h under N2. After cooled to room temperature, the reaction was diluted with water (20 mL) extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the residue, which was purified by chromatography on silica gel (MeOH:DCM = 1:20) to give 6-((12-azanyl)methyl)-N-(l-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolo[4,5-c]pyridin-6-yl)-5,7- dimethylisoquinolin-1 -amine (10 mg, yield: 14%) as a yellow solid. ESI-MS [M +H]+: 490.2. 1H NMR (400 MHz, DMSO) 5 = 9.75 (s, 1H), 9.224-9.18(m, 1H), 8.68 (s, 1H), 8.40 (s,lH),8.37 (s, 1H), 8.05-7.99 (m, 1H), 7.93 (s, 1H), 7.46-7.40 (m, 1H), 7.39-7.35(m, 1H), 7.03-6.95 (m, 1H), 6.00 (s, 2H), 3.95 (s, 2H), 2.63 (s, 3H), 2.58 (s, 3H), 1.94-1.88 (m, 1H), 0.93-0.88 (m, 2H), 0.68-0.63 (m, 2H).
Example 503
Synthesis of 6-(((l-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl)-lH-imidazo[4,5- c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l -amine (1-503).
Figure imgf000560_0001
[0989] Synthesis of 2-chloro-N-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl)- 5-nitropyridin-4-amine. To a mixture of (6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2- yl)methanamine (100 mg, 0.53 mmol) and 2,4-dichloro-5-nitropyridine (123 mg, 0.64 mmol) in THF (15 mL) was added DIPEA (273 mg, 2.12 mmol). The resulting mixture was stirred at 60 °C for 6 h. After cooled to room temperature, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaiSCL, concentrated in vacuo to give the crude, which was purified by Prep- TLC (DCM/CH3OH = 20/1) to give the 2-chloro-N-((6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (160 mg, yield: 88%) as a yellow solid. ESLMS [M +H]+: 345.1. [0990] Synthesis of 6-chloro-N4-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2- yl)methyl)pyridine-3,4-diamine. To a solution of 2-chloro-N-((6-cyclopropyl-
[1.2.4]triazolo[l,5-a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (160 mg, 0.465 mmol) in EtOH/FLO (20 mL/4mL) was added iron (156 mg, 2.79 mmol) and NH4CI (30 mg, 0.558 mmol). The resulting mixture was stirred at 100 °C for 3 h. After cooled to room temperature, the reaction was filtered and concentrated. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the 6-chloro-N4-((6-cyclopropyL[l,2,4]triazolo[l,5- a]pyridin-2-yl)methyl)pyridine-3,4-diamine (150 mg, crude) as a yellow solid, which was used into the next step without further purification. ESLMS [M +H]+: 315.1.
[0991] Synthesis of 2-((6-chloro-lH-imidazo[4,5-c]pyridin-l-yl)methyl)-6-cyclopropyl-
[1.2.4]triazolo[l ,5-a]pyridine. A mixture of 6-chloro-N4-((6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyridin-2-yl)methyl)pyridine-3,4-diamine (150 mg, crude) and TsOH (17 mg, O.lmmol) in CH(OMe)3 (10 mL) was stirred at 60 °C under N2 for 12 h. After cooled to room temperature, the reaction was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by Prep-TLC (DCM/CH3OH = 10/1) to give the 2-((6-chloro- lH-imidazo[4, 5-c]pyridin- 1 -yl)methyl)-6-cyclopropyl-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine (100 mg, yield: 66% over 2 steps) as a white solid. ESLMS [M +H]+: 325.1.
[0992] Synthesis of 6-(((l-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl)-lH- imidazo[4,5-c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine. A mixture of 2- ((6-chloro-lH-imidazo[4,5-c]pyridin-l-yl)methyl)-6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridine (100 mg, 0.31 mmol), 6-(aminomethyl)-5, 7-dimethylisoquinolin-l-amine (117 mg, 0.58 mmol), Pd-PEPPSLiPent-Cl o-picoline (26 mg, 0.031mmol) and CS2CO3 (303 mg, 0.93 mmol) in DMF (5 mL) was stirred at 140 °C by microwave for 2 h. After cooled to room temperature, the reaction was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by Prep-HPLC to give 6-(((l-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl)- lH-imidazo[4,5-c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine (10 mg, yield: 6.5%) as a white solid. ESLMS [M +H]+: 490.2. 1H NMR (400 MHz, DMSO) 8 = 9.75 (s, 1H), 9.224-9.18(m, 1H), 8.68 (s, 1H), 8.40 (s,lH),8.37 (s, 1H), 8.05-7.99 (m, 1H), 7.93 (s, 1H), 7.46- 7.40 (m, 1H), 7.39-7.35(m, 1H), 7.03-6.95 (m, 1H), 6.00 (s, 2H), 3.95 (s, 2H), 2.63 (s, 3H), 2.58 (s, 3H), 1.94-1.88 (m, 1H), 0.93-0.88 (m, 2H), 0.68-0.63 (m, 2H).
Example 504
Synthesis of 6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyridin- 6-yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine (1-504).
Figure imgf000562_0001
[0993] Synthesis of 2-chloro-N-((5-cyclopropyl-3a, 7a-dihydrothieno[2,3-b]pyridin-2- yl)methyl)-5-nitropyridin-4-aniine. To a mixture of (5-cyclopropyl-3a,7a-dihydrothieno[2,3- b]pyridin-2-yl)methanamine (412 mg, 2 mmol) and 2,4-dichloro-5-nitropyridine (384 mg, 2 mmol) in THF (30 mL) was added DIPEA (774 mg, 6 mmol). The resulting mixture was stirred at 60 °C for 6 h. After cooled to room temperature, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaiSCL, concentrated in vacuo to give the crude, which was purified with silica gel (PE/EtOAc = 1/1) to give the 2-chloro-N-((5-cyclopropyl-3a,7a-dihydrothieno[2,3-b]pyridin- 2-yl)methyl)-5-nitropyridin-4-amine (430 mg, yield: 59%) as a yellow solid. ESLMS [M +H]+: 363.1.
[0994] Synthesis of6-chloro-N4-((5-cyclopropyi-3a, 7a-dihydrothieno[2,3-b]pyridin-2- yl)methyl)pyridine-3,4-diamine. To a solution of 2-chloro-N-((5-cyclopropyl-3a,7a- dihydrothieno[2,3-b]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (430 mg, 1.19 mmol) in EtOH/ELO (20 mL/2 mL) was added iron (400 mg, 7.14 mmol) and NH4CI (760 mg, 14.28 mmol). The resulting mixture was stirred at 100 °C for 3 h. After cooled to room temperature, the reaction was filtered and concentrated. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated in vacuo to give the crude 6-chloro-N4-((5-cyclopropyl-3a,7a- dihydrothieno[2,3-b]pyridin-2-yl)methyl)pyridine-3,4-diamine (400 mg, crude) as a yellow solid. ESI-MS [M +H]+: 333.1.
[0995] Synthesis of 2-((6-chloro-lH-imidazo[4,5-c]pyridin-l-yl)methyl)-5-cyclopropyl- 3a, 7a-dihydrothieno[2,3-b]pyridine. A mixture of 6-chloro-N4-((5-cyclopropyl-3a,7a- dihydrothieno[2,3-b]pyridin-2-yl)methyl)pyridine-3,4-diamine (400 mg, crude) and TsOH (43 mg, 0.25 mmol) in CH(OMe)r (10 mb) was stirred at 60 °C under N2 for 12 h. After cooled to room temperature, the reaction was quenched with NaHCCh (sat. aq. 30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, concentrated in vacuo to give the crude, which was purified with silica gel (DCM/CH3OH = 10/1) to give the 2-((6-chloro-lH-imidazo[4,5-c]pyridin-l-yl)methyl)-5- cyclopropyl-3a,7a-dihydrothieno[2,3-b]pyridine as a white solid. (310 mg, 76% over 2 steps). ESI-MS [M +H]+: 343.1.
[0996] Synthesis of 6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-lH- iniidazo[4,5-c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin-l-amine. A mixture of 2- ((6-chloro-lH-imidazo[4,5-c]pyridin-l-yl)methyl)-5-cyclopropyl-3a,7a-dihydrothieno[2,3- b]pyridine (100 mg, 0.29 mmol), 6-(aminomethyl)-5, 7-dimethylisoquinolin-l-amine (105 mg, 0.52 mmol), Pd-PEPPSLiPent-Cl o-picoline (24 mg, 0.029 mmol) and CS2CO3 (284 mg, 0.87 mmol) in DMF (15 mL) was stirred at 100 °C for 12 h. After cooled to room temperature, the reaction was quenched with H2O (20mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine ( 40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by Preparation to give 6-(((l-((5-cyclopropylthieno[2,3- b]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyridin-6-yl)amino)methyl)-5, 7-dimethylisoquinolin- l-amine (22 mg, yield: 15%) as a white solid. ESI-MS [M +H]+: 506.2. 1H NMR (400 MHz, DMSO) 8 8.50 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 6.2 Hz, 1H), 7.20 (s, 1H), 6.97 (d, J = 6.1 Hz, 1H), 6.61 (s, 2H), 6.56 (s, 1H), 6.21 (t, J = 4.0 Hz, 1H), 5.67 (s, 2H), 4.56 (d, J = 4.3 Hz, 2H), 2.54 (s, 3H), 2.46 (s, 3H), 2.07 - 2.00 (m, 1H), 1.04 - 0.98 (m, 2H), 0.76 - 0.72 (m, 2H). Example 505
Synthesis of 2-((4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)aniino)-6-oxopyrimidin-
Figure imgf000564_0001
[0997] Synthesis of tert-butyl (tert-butoxycarbonyl)(2-oxo-l,2-dihydropyrimidin-4- yl)carbamate. To a solution of 4-aminopyrimidin-2(lH)-one (5 g, 45 mmol) and DMAP (550 mg, 4.5 mmol) in THF (50 mL) was added BOC2O (34 g, 157.5 mmol) at 0 °C. The resulting reaction was stirred at room temperature for 12 h. The reaction diluted with MeOH (50 mL), NaHCCh (sat. aq., 100 mL) was added and stirred for 30 min. The reaction was concentrated, aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SOr, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-30% EtOAc in PE to give tert-butyl (tert-butoxycarbonyl)(2-oxo-l,2-dihydropyrimidin-4-yl)carbamate (8.5 g, 61%) as a yellow solid. ESLMS [M +H]+: 312.3.
[0998] Synthesis of tert-butyl (tert-butoxy carbonyl) (l-cyclopropyl-2-oxo-l, 2- dihydropyrimidin-4-yl)carbamate. A mixture of tert-butyl (tert-butoxy carbonyl)(2-oxo- 1,2- dihydropyrimidin-4-yl)carbamate (8.5 g, 27.3 mmol), cyclopropylboronic acid (4.7 g, 54.7 mmol), Pd(OAc)2 (611 mg, 2.73 mmol) and CS2CO3 (26.7 g, 81.9 mmol) in 1,4-dioxane (200 mL) was stirred at 80 °C for 14 h under N2 atmosphere. After cooled to room temperature, the reaction mixture was filtered, filter cake was washed with DCM (100 mL x 3). The filtrate was concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-25% EtOAc in PE to give tert-butyl (tert- butoxycarbonyl)(l-cyclopropyl-2-oxo-l,2-dihydropyrimidin-4-yl)carbamate (5.5 g, yield: 57%) as a yellow solid. ESI-MS [M +H]+: 352.3.
[0999] Synthesis of 4-amino-l-cyclopropylpyrimidin-2(lH)-one. To a solution of tert-butyl
(tert-butoxycarbonyl)(l-cyclopropyl-2-oxo-l,2-dihydropyrimidin-4-yl)carbamate (2.5 g, 7.1 mmol) in 1,4-dioxane (25 mL) was added HC1 (5 mL, 20 mmol, 4M solution in 1,4-dioxane). The resulting reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo. The residue was neutralized with NaHCCh (sat. aq., 80 mL), extracted with EtOAc (50 mL x 3). The combined organic layers washed with brine (80 mL), dried over Na2SC>4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-65% EtOAc in PE to give 4-amino-l- cyclopropylpyrimidin-2(lH)-one (1 g, yield: 93%) as a yellow solid. ESLMS [M +H]+: 152.3.
[1000] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one. A mixture of 4-amino-l-cyclopropylpyrimidin-2(lH)-one (500 mg, 3.3 mmol) and 1,3- dichloropropan-2-one (832 mg, 6.6 mmol) in DMF (15 mL) was stirred at 110 °C for 13 h. After cooled to room temperature, the reaction washed with NaHCOs (sat. aq., 50 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-5% MeOH in DCM to give 2-(chloromethyl)-6- cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (120 mg, yield: 16%) as a yellow solid. ESI-MS [M +H]+: 224.1.
[1001] Synthesis of 2-((4-chloro-6-oxopyrimidin-l(6H)-yl)methyl)-6- cyclopropylimidazo[l,2-c]pyrinndin-5(6H)-one. A mixture of 2-(chloromethyl)-6- cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (30 mg, 0.13 mmol), 6-chloropyrimidin-4-ol (34 mg, 0.26 mmol), K2CO3 (55 mg, 0.4 mmol) and Nal (2 mg, 0.013 mmol) in DMF (4 mL) was stirred at 60 °C for 12 h. After cooled to room temperature, the reaction was diluted with FEO (20 mL) and extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 15/1) to give 2-((4-chloro-6-oxopyrimidin-l(6H)- yl)methyl)-6-cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (25 mg, yield: 60%) as a yellow solid. ESI-MS [M +H]+: 318.2. [1002] Synthesis of2-((4-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)aniino)-6- oxopyrimidin-1 (6H)-yl)methyl)-6-cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one. A mixture of 2-((4-chloro-6-oxopyrimidin- 1 (6H)-yl)methyl)-6-cy clopropylimidazof 1 ,2-c]pyrimidin-5(6H)- one (25 mg, 0.079 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (40 mg, 0.2 mmol) and DIPEA (52 mg, 0.4 mmol) was stirred at 140 °C by microwave for 2 h. The reaction was cooled to room temperature, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM/MeOH = 10/1) to give 2-((4-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-6-oxopyrimidin- 1 (6H)-yl)methyl)-6-cy clopropylimidazof 1 ,2-c]pyrimidin- 5(6H)-one (6 mg, yield: 16%) as a white solid. ESLMS [M +H]+: 483.2. 1H NMR (400 MHz, DMSO) 3 8.28 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.60 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 4.4 Hz, 1H), 6.99 (d, J = 6.2 Hz, 1H), 6.63 (s, 2H), 6.54 (d, J = 7.8 Hz, 1H), 5.20 (s, 1H), 4.99 (s, 2H), 4.43 (s, 2H), 2.49 (s, 3H), 2.46 (s, 3H), 2.01 - 1.91 (m, 1H), 1.04 - 0.96 (m, 2H), 0.94 - 0.91 (m, 2H).
Example 506
Synthesis of N2-((l-amino-5, 7-dimethylisoquinolin-6-yl)niethyl)-N3-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyridine-2,3-diamine (1-506).
Figure imgf000566_0001
[1003] Synthesis of 2-bronio-N-((6-cyclopropylinudazo[l>2-a]pyridin-2-yl)methyl)pyridin- 3-amine. To a solution of 6-cyclopropylimidazo[l,2-a]pyridine-2-carbaldehyde (186 mg, 1 mmol) in dry DCM (20 mL) was added 2-bromopyridin-3-amine (172 mg, 1 mmol) and AcOH (2 drops). The mixture was stirred at room temperature for 3 h, then NaBH(OAc)3 (636 mg, 3 mmol) was added at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over NazSCh, concentrated in vacuo and purified by silica gel chromatography (DCM/MeOH = 25/1) to give 2-bromo-N-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyridin-3-amine (150 mg, yield: 44%) as a yellow oil. ESI-MS [M +H]+: 343.2.
[1004] Synthesis of N2-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N3-((6- cyclopropylimidazo[l,2-(i]pyridin-2-yl)methyl)pyridine-2,3-diamine. To a solution of 2-bromo- N-((6-cy cl opropylimidazo[l,2-a]pyridin-2-yl)methyl)pyri din-3 -amine (100 mg, 0.3 mmol) in DMF (10 mL) and DME (10 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (88 mg, 0.44 mmol), Pd-PEPPSI-IPent-Cl o-picoline (185 mg, 0.22 mmol) and CS2CO3 (430 mg, 1.32 mmol). The reaction was stirred at 120 °C for 2 h by Microwave. After cooled to room temperature, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, fdtered and concentrated to give the crude, which was purified by silica gel chromatography (DCM/MeOH = 10/1) to afford N2-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N3-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyridine-2,3-diamine (12 mg, yield: 8.6%) as a white solid. ESI-MS [M +H]+: 464.2. 1H NMR (400 MHz, DMSO) 5 8.26 (s, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 5.0 Hz, 1.4 Hz, 1H), 7.33 (d, J = 9.3 Hz, 1H), 7.00 (d, J = 6.1 Hz, 1H), 6.93 (dd, J = 9.3 Hz, 1.7 Hz, 1H), 6.64 - 6.61 (m, 2H), 6.44 (dd, J = 7.6 Hz, 5.0 Hz, 1H), 5.69 (t, J = 4.1 Hz, 1H), 5.58 (t, J = 5.4 Hz, 1H), 4.63 (d, J = 4.0 Hz, 2H), 4.28 (d, J = 4.8 Hz, 2H), 2.53 (s, 3H), 2.51 (s, 3H), 1.90 - 1.85 (m, 1H).O.91 - 0.86 (m, 2H), 0.66 - 0.61 (m, 2H).
Example 507
Synthesis of l-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-3-(5-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)urea (1-507).
Figure imgf000567_0001
[1005] Synthesis of 5-((6-cyclopropyliniidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4- amine. To a solution of 4-aminopyrimidin-5-ol (294 mg, 2.65 mmol) in DMF (10 mL) was added 2-(chloromethyl)-6-cyclopropylimidazo[l,2-a]pyridine (600 mg, 2.91 mmol) and CS2CO3 (1.73 g, 5.30 mmol). The reaction mixture was stirred at 60 °C for 13 h under N2. After cooled to room temperature, the reaction was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaiSCL, concentrated in vacuo to give the crude, which was purified by Prep-TLC (PE/EtOAc = 1/1) to give the product (360 mg, yield: 48%) as a white solid. ESI-MS [M +H]+: 282.1.
[1006] Synthesis of l-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-3-(5-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrinudin-4-yl)urea. To a solution of 5-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-amine (100 mg, 0.36 mmol) in THF (10 mL) was added CDI (292 mg, 1.80 mmol) and TEA (364 mg, 3.60 mmol). The mixture was stirred at 45 °C for 13 h under N2. Then a solution of 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (72 mg, 0.36 mmol) in THF (5 mL) was added. The mixture was stirred at the 45 °C for 4 h. After cooled to room temperature, the reaction was quenched with H2O (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by Prep-TLC (DCM/MeOH = 10/1) to give the product (65 mg, yield: 36%) as a yellow solid. ESI-MS [M +H]+: 509.2. 1H NMR (400 MHz, DMSO) 8 9.14 (t, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.35 - 8.29 (m, 2H), 7.97 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.43 (d, J = 9.3 Hz, 1H), 7.08 - 6.94 (m, 2H), 6.63 (s, 2H), 5.37 (s, 2H), 2.59 (s, 3H), 2.55 (s, 3H), 1.99 - 1.84 (m, 1H), 0.98 - 0.83 (m, 2H), 0.73 - 0.62 (m, 2H).
Example 508
Synthesis of 4-(2-(((6-(((l-anuno-5, 7-dimethylisoquinolin-6-yl)niethyl)amino)pyrinudin-4-
Figure imgf000568_0001
[1007] Synthesis of ethyl 3-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)propanoate. To a solution of ethyl 3-(5-cyclopropyl-2- (hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)propanoate (150 mg, 0.52 mmol) in dry DMF (10 mL) was added 4,6-dichloropyrimidine (115 mg, 0.78 mmol) and CS2CO3 (518 mg, 1.59 mmol). The reaction mixture was stirred at 60 °C for 16 h. After cooled to room temperature, the reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaiSCh, concentrated to give the crude product, which was purified by silica gel column chromatography (DCM/MeOH = 20/1) to give ethyl 3-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7- yl)propanoate (150 mg, yield: 72%) as yellow oil. ESI-MS [M +H]+: 401.1.
[1008] Synthesis of 4-(2-(((6-chIoropyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5- a]pyridin-7-yl)-2-methylbutan-2-ol. To a solution of ethyl 3-(2-(((6-chloropyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)propanoate (70 mg, 0.175 mmol) in dry THF (10 mL) was added MeMgBr (IM in THF, 0.5 mL, 0.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with NH4CI (sat. aq., 20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were washed with brine (20 mL), dried over Na2SO-i, concentrated to give the crude product, which was purified by silica gel chromatography to give (DCM/MeOH = 20/1 ) to give 4-(2-(((6-chloropyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2-methylbutan-2-ol (30 mg, yield: 44%) as a yellow solid. ESLMS [M +H] +: 387.1.
[1009] Synthesis of 4-(2-(((6-(((l-annno-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2- methylbutan-2-ol. To a solution of 4-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2-methylbutan-2-ol (30 mg, 0.078 mmol) in z-PrOH (3 mL) was added 6-(aminomethyl)-5,7-dimethylnaphthalen-l-amine (16 mg, 0.078 mmol) and DIPEA (50 mg, 0.39 mmol). The mixture was stirred at 140 °C under microwave for 3 h. After cooled to room temperature, the reaction was concentrated and purified by Prep-TLC (DCM/MeOH = 10/1) to give 4-(2-(((6-(((5-amino-l,3-dimethylnaphthalen-2- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2- methylbutan-2-ol (12 mg, yield: 28%) as a white solid. ESLMS [M +H]+: 552.2. 1H NMR (400 MHz, DMSO) 5 8.29 (s, 1H), 7.92 (s, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.25 (d, J = 4.3 Hz, 1H), 7.22 (s, 1H), 7.00 (d, J = 6.2 Hz, 1H), 6.66 (s, 2H), 6.45 (d, J = 3.5 Hz, 2H), 5.89 (s, 1H), 5.44 (s, 2H), 4.61 (s, 2H), 4.35 (s, 1H), 3.09 - 3.05 (m, 2H), 2.47 (s, 6H), 1.99 - 1.93 (m, 1H), 1.84 - 1.80 (m, 2H), 1.18 (s, 6H), 1.00 - 0.95 (m, 2H), 0.77 - 0.73 (m, 2H).
Example 509
Synthesis of 3-(2-(((6-(((l-annno-5,7-diniethylisoquinolin-6-yl)methyl)amino)pyrinndin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l, 5-a]pyridin- 7-yl)-2,2-dimethylpropanamide (1-509).
Figure imgf000570_0001
[1010] Synthesis of 3-(2-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)niethyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l ,5-a]pyridin-7-yl)-2,2- dimethylpropanoic acid. A mixture of ethyl 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropanoate (97 mg, 0.16 mmol) and LiOH«H2O (67 mg, 1.6 mmol) in THF (3 mL) / MeOH (3 mL) / H2O (2 mL) was stirred at 50 °C for 3 h. After cooled to room temperature, pH of the reaction solution was adjusted to 5 by HC1 (aq. IM), and concentrated to give 3-(2-(((6- (((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoic acid (150 mg, crude) as a white solid. ESI-MS [M +H]+: 566.2.
[1011] Synthesis of 3-(2-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropananiide. A mixture of 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropanoic acid (150 mg, crude), NH4CI (339 mg, 6.4 mmol), EDCI (157 mg, 0.82 mmol), HOBT (115 mg, 0.82 mmol) and DIPEA (826 mg, 6.4 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. Water (50 mL) was added and extracted with DCM/MeOH(10/l, 50 mL x 3). The combined organics were dried over Na2SO4, concentrated and purified by silica gel chromatography (DCM/MeOH = 10/1) to give 3-(2-(((6-(((l-amino- 5 , 7 -dimethyli soquinolin-6-yl)methy l)amino)pyrimidin-4-y l)oxy )methyl)-5 - cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanamide (65 mg, yield: 72% over 2 steps) as a white solid. ESLMS [M +H]+: 565.3. ESLMS [M +H]+: 521.3. 1HNMR (400 MHz, DMSO) 6 8.28 (s, 1H), 7.92 (s, 1H), 7.81 - 7.73 (m, 1H), 7.34 - 7.18 (m, 3H), 7.08 - 6.96 (m, 2H), 6.64 s, 2H), 6.44 (s, 1H), 6.41 - 6.34 (m, 1H), 5.88 (s, 1H), 5.42 (s, 2H), 4.61 (s, 2H), 3.37 (s, 2H), 2.49 (s, 3H), 2.47 (s, 3H), 1.96 - 1.86 (m, 1H), 1.11 (s, 6H), 1.03 - 0.92 (m, 2H), 0.75 - 0.63 (m, 2H).
Example 510
Synthesis of 3-(2-(((6-(((l-annno-5,7-diniethylisoquinolin-6-yl)methyl)amino)pyrinndin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l, 5-a]pyridin- 7-yl)-2,2-dimethylpropanenitrile (1-510).
Figure imgf000571_0001
[1012] Synthesis of 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropanoic acid A mixture of ethyl 3-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoate (215 mg, 0.5 mmol) and LiOH- H2O (84 mg, 2.0 mmol) in THF/McOH/FFO (3 mL/3 mL/2 mL) was stirred at 40 °C for 4 h. After cooled to room temperature, pH of the reaction was adjusted to 4~5 with HC1 (aq. 1 M) and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product (100 mg, crude) as a white syrup, which was used in the next step without purification. ESLMS [M +H]+: 289.2.
[1013] Synthesis of 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropanamide. A mixture of 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l,5- a]pyridin-7-yl)-2,2-dimethylpropanoic acid (100 mg, crude), NH4CI (375 mg, 6.94 mmol), EDCI (200 mg, 1.04 mmol), HOBT (141 mg, 1.04 mmol) and DIPEA (448 mg, 3.47 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude, which was purified by silica gel chromatography (PE/EtOAc = 1/1) to give 3-(5-cyclopropyl-2-(hydroxymethyl)pyrazolo[l,5- a]pyridin-7-yl)-2,2-dimethylpropanamide (80 mg, yield: 56% over 2 steps) as a white solid. ESIMS [M + H]+: 288.2.
[1014] Synthesis of 3-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5- ajpyridin- 7-yl)-2,2-dimethylpropanamide. A mixture of 3-(5-cyclopropyl-2- (hydroxymethyl)pyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanamide (80 mg, 0.28 mmol), 4,6-dichloropyrimidine (83 mg, 0.56 mmol) and CS2CO3 (271 mg, 0.83 mmol) in DMF (5 mL) was stirred at 50 °C for 10 h. After cooled to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude product, which was purified by silica gel chromatography (EtOAc/PE = 1/1) to give 3-(2-(((6-chloropyrimidin- 4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanamide (70 mg, yield: 63%) as a yellow solid. ESI-MS [M + H]+: 400.1.
[1015] Synthesis of 3-(2-(((6-chIoropyriniidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5- a]pyridin-7-yl)-2,2-dimethylpropanenitrile. A mixture of 3-(2-(((6-chloropyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanamide (70 mg, 0.175 mmol) in POOL (3 mL) was stirred at 60 °C for 1 h. After cooled to room temperature, the reaction mixture was concentrated, the residue was neutralized with NaHCCh (sat. aq., 20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc/PE = 1/1) to 3-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanenitrile (8 mg, yield: 12%) as a yellow solid. ESI-MS [M + H]+: 382.1.
[1016] Synthesis of 3-(2-(((6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropanenitrile. A mixture of 3-(2-(((6-chloropyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanenitrile (8 mg, 0.021 mmol), 6- (aminomethyl)-5,7-dimethylisoquinolin-l-amine (13 mg, 0.063 mmol) and DIPEA (81 mg, 0.63 mmol) in z-PrOH (1 mL) was stirred at 130 °C for 4 h under microwave. The reaction mixture was cooled to room temperature and concentrated, the residue was purified by Prep-TLC (DCM/MeOH = 10/1) to give 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2- dimethylpropanenitrile (5 mg, yield: 44%) as a yellow solid. ESI-MS [M +H]+: 547.2. 1H NMR (400 MHz, DMSO) 5 8.27 (s, 1H), 7.91 (s, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.23 (t, I = 4.4 Hz, 1H), 6.99 (d, J = 6.1 Hz, 1H), 6.64 (s, 2H), 6.57 (d, J = 1.9 Hz, 1H), 6.48 (s, 1H), 5.88 (s, 1H), 5.42 (s, 2H), 4.61 (s, 2H), 3.46 (s, 2H), 2.49 (s, 3H), 2.47 (s, 3H), 2.01 - 1.94 (m, 1H), 1.34 (s, 6H), 1.05 - 0.98 (m, 2H), 0.80 - 0.72 (m, 2H).
Example 511
Synthesis of N3-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N5-((6-
Figure imgf000573_0001
[1017] Synthesis of 3-chloro-N- ( ( 6-cyclopropylimidazo[l, 2-a]pyridin-2-yl) methyl)-!, 2, 4- thiadiazol-5-amine. To a solution of (6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanamine (200 mg, 1.07 mmol) in z-PrOH(10 mL) was added 3,5-dichloro-l,2,4-thiadiazole (181 mg, 1.18 mmol) and DIPEA(276 mg, 2.14 mmol). The reaction was stirred at 80 °C for 3 h. After cooled to room temperature, the reaction mixture was concentrated and purified by Prep-TLC (EtOAc / PE=1/1) to afford 3-chloro-N-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-l,2,4- thiadiazol-5-amine (200 mg, yield: 61%) as yellow oil. ESI-MS [M +H]+:306.2.
[1018] Synthesis of N3-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N5-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)niethyl)-l,2,4-thiadiazole-3,5-diamine. A mixture 3 - chloro-N-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-l,2,4-thiadiazol-5-amine (150 mg, 0.49 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (98 mg, 0.49 mmol) and DIPEA(126 mg, 0.98 mmol) in DMSO (5 mL) was heated to 120 °C for 1 h. After cooling to room temperature, the reaction was diluted with water (20 mL) and extracted by EtOAc (20 mL x 3). The combined organic layers were washed by brine (20 mL), dried over Na2SO4, concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH = 10/1) to afford N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-((6-cyclopropylimidazo[l,2-a]pyridin- 2-yl)methyl)-l,2,4-thiadiazole-3,5-diamine (30 mg, yield: 13%) as a pale solid. ESI-MS [M +H]+: 471.2. 1H NMR (400 MHz, DMSO) 5 8.53 (t, J = 7.1 Hz, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 6.2 Hz, 1H), 7.68 (s, 1H), 7.38 (d, J = 9.3 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.90 - 6.74 (m, 3H), 4.51 - 4.45 (m, 4H), 2.52 (s, 6H), 1.95 - 1.88 (m, 1H), 0.92-0.89 (m, 2H), 0.69 - 0.65 (m, 2H).
Example 512 and Example 513
Synthesis of 6-(((6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropyliniidazo[l,2- a]pyridin-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinoIin-l -amine (1-512) and (3S,5R)-l-(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)-5-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)pyrrolidin-3-ol (1-513)
Figure imgf000575_0001
[1019] Synthesis of methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate. To the mixture of
(2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid (5 g, 38.2 mmol) in MeOH (50 mL) was added SOCh (5 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 14 h. After cooled to room temperature, the reaction was concentrated to afford methyl (2R,4S)-4-hydroxypyrrolidine-2- carboxylate (6.5 g, crude) as a white solid, which was used in next step directly without further purification. ESLMS [M +H] +: 146.1.
[1020] Synthesis of 1-benzyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-l,2-dicarboxylate. To the mixture of methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate (6.5 g, crude) and NaHCOs (9.6 g, 114.5 mmol) in THF/H2O (150 mL/150 mL) was added CbzCI (9.7 g, 57.3 mmol) at 0 °C. The mixture was then warmed to room temperature and stirred for 12 h. The reaction was concentrated and aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EA/PE from 0 to 100%) to afford 1 -benzyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-l,2-dicarboxylate (5.8 g, 54% yield for two steps) as a white solid. ESI-MS [M +H] +: 280.1.
[1021] Synthesis of 1-benzyl 2-methyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-
1,2-dicarboxylate. To a mixture of 1-benzyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-l,2- dicarboxylate (5.8 g, 20.8 mmol) and Imidazole (4.2 g, 62.4 mmol) in DMF (50 mL) was added TBSC1 (4.7 g, 31.2 mmol) and the mixture was stirred at room temperature for 18 h. Water (50 mL) was added and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO-i and concentrated. The residue was purified by silica gel column chromatography (EtOAc /PE from 0 to 15%) to afford 1-benzyl 2-methyl (2R,3S,4R)-3,4-bis((tert-butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylate (6 g, 73% yield) as a white solid. ESI-MS [M +H] +: 394.2.
[1022] Synthesis of (2R,4S)-l-((benzyloxy)carbonyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid A mixture of 1-benzyl 2-methyl (2R,4S)- 4-((teroom temperature-butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylate (4.0 g, 10.2 mmol) and LiOEEELO (0.85 g, 20.4 mmol) in MeOH /THF/H2O (30 mL/30 mL/10 mL) was stirred at room temperature for 18 h. The reaction was concentrated, pH of the residue was adjusted to ~5 by HC1 (aq. 2M) and extracted with iPrOH/CHCh (1/3, 50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4 and concentrated to afford (2R,4S)-1- ((benzyloxy)carbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (3.4 g, crude) as a colorless oil, which was used in next step directly. ESI-MS [M +H]+: 380.2.
[1023] Synthesis of benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2- chloroacetyl)pyrrolidine-l-carboxylate. To a solution of (2R,4S)-l-((benzyloxy)carbonyl)-4- ((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (400 mg, 1.05 mmol) in DCM (10 mL) was added oxalyl chloride (162 mg, 1.27 mmol) and a drop of DMF at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction was concentrated, the residue was redissolved in DCM (10 mL). TMSCH2N2 (1.06 mL, 2M in hexane, 2.12 mmol) was added at 0 °C and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to remove the solvent and the residue was re-dissolved in THF (10 mL), HC1 (0.32 mL, 4M in dioxane, 1.27 mmol) was added at 0 °C. After the mixture was stirred at 0 °C for 0.5 h, the reaction was concentrated to give the crude, which was purified by Prep-TLC (PE/EtOAc = 20%) to afford benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-chloroacetyl)pyrrolidine-l- carboxylate (170 mg, 39% yield) as a yellow solid. ESI-MS [M +H]+: 412.2.
[1024] Synthesis of benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6- cyclopropylimidazo[l ,2-a]pyridin-2-yl)pyrrolidine-l -carboxylate. A mixture of benzyl (2R,4S)- 4-((tert-butyldimethylsilyl)oxy)-2-(2-chloroacetyl)pyrrolidine-l -carboxylate (250 mg, 0.61mmol), 5-cyclopropylpyridin-2-amine (165 mg, 1.22 mmol) and DIPEA (235 mg, 1.82mmol) in 1,4-dioxane (5 mL) was stirred at 95 °C for 12 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NazSO4 and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 10%) to afford benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6- cy cl opropylimidazo[l,2-a]pyridin-2-yl)pyrrolidine-l -carboxylate (120 mg, 40% yield) as a yellow oil. ESI-MS [M +H]+: 492.3.
[1025] Synthesis of 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6- cyclopropylimidazo[l,2-a]pyridine. A mixture of benzyl (2R,4S)-4-((tert- butyldimethylsilyl)oxy)-2-(6-cy cl opropylimidazo[l,2-a]pyridin-2-yl)pyrrolidine-l -carboxylate (460 mg, 0.95 mmol) and Pd/C (460 mg) in THF/MeOH (5 mL/5 mL) was stirred at room temperature under Hi for 2 h. The reaction was filtered and washed with MeOH (30 mL). The filtrate was concentrated to afford crude 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2- yl)-6-cyclopropylimidazo[l,2-a]pyridine (360 mg, crude) as brown oil, which was used in the next step directly. ESI-MS [M +H]+: 358.2.
[1026] Synthesis of 2-((2R,4S)-4-((tert -butyldiniethylsilyl)oxy)-l-(6-chloropyriniidin-4- yl)pyrrolidin-2-yl)-6-cyclopropylimidazo[l,2-a]pyridine. To a mixture of 2-((2R,4S)-4-((tert- butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[l,2-a]pyridine (180 mg, 0.5 mmol), 4,6-dichloropyrimidine (148 mg, 1.0 mmol) and DIPEA (194 mg, 1.5 mmol) in z-PrOH (5 mL) was stirred at 80 °C for 3 h. After cooled to room temperature, the reaction was diluted with water (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over NaiSOi and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 8%) to afford 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-l-(6- chloropyrimidin-4-yl)pyrrolidin-2-yl)-6-cyclopropylimidazo[l,2-a]pyridine (200 mg, 85% yield) as a yellow oil. ESI-MS [M +H]+: 470.2.
[1027] Synthesis of 6-(((6-((2R,4S)-4-((teroom temperature-butyldimethylsilyl)oxy)-2-(6- cyclopropylimidazo[l,2-a]pyridin-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-l-amine. To a mixture of 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-l-(6- chloropyrimidin-4-yl)pyrrolidin-2-yl)-6-cyclopropylimidazo[l,2-a]pyridine (80 mg, 0.17 mmol) and 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (86 mg, 0.43 mmol) in NMP (2 mL) was stirred at 160 °C under microwave for 6 h. After cooled to room temperature, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 10%) to afford 6-(((6-((2R,4S)-4-((tert- butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)pyrrolidin-l-yl)pyrimidin- 4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (52 mg, 48% yield) as a white solid. ESIMS [M +H]+: 635.3. 1H NMR (4OO MHz, cd3od) 8 8.47 (s, 1H), 8.22-8.16 (m, 2H), 8.05 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.42 (d, J = 7.2 Hz, 1H), 5.84 (s, 1H), 5.56 (s, 1H), 4.81-4.70 (m, 3H), 4.08 (d, J = 6.7 Hz, 1H), 3.64 (s, 1H), 2.75-2.57 (m, 7H), 2.46 - 2.38 (m, 1H), 2.13-2.01 (m, 1H), 1.15-1.05 (m, 2H), 0.91 (s, 9H), 0.85 - 0.79 (m, 2H), 0.15 (d, J = 3.7 Hz, 6H).
[1028] Synthesis of (3S,5R)-l-(6-(((l-amino-5, 7-dimethylisoquinolin-6- yl)niethyi)aniino)pyrimidin-4-yl)-5-(6-cyclopropyliniidazo[ 1 ,2-a]pyridin-2-yl)pyrrolidin-3-ol. To the mixture of 6-(((6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[l,2- a]pyridin-2-yl)pyrrolidin-l-yl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (40 mg, 0.063 mmol) in THF (3 mL) was added TBAF (0.063 mL, 0.126 mmol) and the mixture stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SOi and concentrated. The residue was purified by Prep-HPLC to afford (3S,5R)-l-(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)-5-(6- cyclopropylimidazo[l,2-a]pyridin-2-yl)pyrrolidin-3-ol (16 mg, 50% yield) as a white solid. ESIMS [M +H]+: 521.3. 1H NMR (400 MHz, MeOD) 8 8.42 (s, 1H), 8.11-8.00 (m, 3H), 7.56-7.50 (m, 2H), 7.35 (d, J = 9.3 Hz, 1H), 7.29 (d, J = 6.9 Hz, 1H), 7.05 (d, J = 9.4 Hz, 1H), 5.43 (s, 1H), 5.16 (s, 1H), 4.56-4.47 (m, 3H), 3.98-3.90 (m, 1H), 3.72 (s, 1H), 2.55-2.44 (m, 7H), 2.39 - 2.29 (m, 1H), 1.96 - 1.86 (m, 1H), 1.02 - 0.90 (m, 2H), 0.77 - 0.62 (m, 2H).
Example 514
Synthesis ofN-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)isonicotinamide (1-514).
Figure imgf000579_0001
[1030] Synthesis of 2-amino-5-cyclopropyl-l-(prop-2-yn-l-yi)pyridin-l-ium bromide. A mixture of 2-amino-5-cyclopropylpyridine (6.70 g, 50.0 mmol) and propargyl bromide (80% w/v in toluene, 11.1 mL, 100 mmol) in 2-propanol (120 mL) was heated at 80°C for 2 h, then allowed to cool to room temperature. The resulting red-brown slurry was cooled in an ice bath and ethyl acetate (50 mL) was added. The mixture was stirred for 1 h and then the solid was collected by filtration to give 2-amino-5-cyclopropyl-l-(prop-2-yn-l-yl)pyridin-l-ium bromide (6.150 g, 49%), as a buff solid. LCMS RT = 1.58 min; [M]+ 173. 'HNMR (400 MHz, CD3SOCD3, ppm) 5 8.46 (br s, 2H), 8.00 (s, 1H), 7.68 (dd, J 1.6, 9 Hz, 1H), 7.01 (d, J 9 Hz, 1H),
5.02 (d, ./ 3 Hz, 2H), 3.79 (t, J 3 Hz, 1H), 1.91-1.85 (m, 1H), 0.96-0.92 (m, 2H), 0.69-0.65 (m, 2H). [1031] Synthesis of ethyl 2f(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinate. A mixture of ethyl 2-iodoisonicotinate (5.611 g, 20.3 mmol), ZiA(triphenylphosphine) palladium chloride (852 mg, 1.22 mmol) and copper (I) iodide (577 mg, 3.04 mmol) in anhydrous N,N- dimethylformamide (100 mL) at 20 °C was degassed thoroughly (vacuum/nitrogen backfill) three times. Triethylamine (11.3 mL, 81.0 mmol) and 2-amino-5-cyclopropyl-l -(prop-2 -yn-1- yl)pyridin-l-ium bromide (6.150 g, 24.3 mmol) were added and the mixture was degassed again (three times). The resulting red solution was stirred at 20 °C for 19 h. The solution was poured into methyl tert-butyl ether (600 mL) and saturated aqueous sodium bicarbonate (200 mL) and filtered through Dicalite. The filtrate layers were separated and the aqueous phase was extracted with methyl tevz-butyl ether (2 x 200 mL). The combined organic solutions were washed with water (200 mL) and brine (3 x 200 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and adsorbed onto silica gel (30 g), which was applied to a chromatography column (silica gel 300 g), which was eluted with ethyl acetate : tri ethylamine = 100:1. The product containing fractions were combined and concentrated under reduced pressure to give a dark brown oil (3.2 g). This material was dissolved in ethyl acetate and further purified by flash chromatography (200g silica gel) eluting with a gradient of ethyl acetate : methanol : acetic acid = 100:0: 1 - 100: 10: 1. Fractions containing the lower running spot by tic were concentrated to give ethyl 2-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinate (2.501 g, 39%), as a brown oil. LCMS RT = 2.48 min [M + H]+ 322. XH NMR (400 MHz, CDCh, ppm) 6 8.69 (d, J 6 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.68 (d, ./ 6 Hz, 1H), 7.41 (d, J9 Hz, 1H), 7.33 (s, 1H), 6.88 (dd, J 9, 2 Hz, 1H), 4.37 (q, J 7.6 Hz, 2H), 4.36 (s, 2H), 1.88-1.81 (m, 1H), 1.37 (t, J 7.6 Hz, 3H), 0.95-0.90 (m, 2H), 0.65-0.61 (m, 2H).
[1032] Synthesis of 2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinic acid. Ethyl 2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinate (2.501 g, 7.79 mmol) was dissolved in industrial methylated spirits (70 mL) under nitrogen at room temperature and degassed (vacuum/nitrogen backfill x 2). Aqueous sodium hydroxide (2M, 15.6 mL, 33.2 mmol) was added and the mixture was degassed again twice. The mixture was stirred at room temperature for 1 h, neutralised with dilute hydrochloric acid to pH 5 and concentrated under reduced pressure. The residue was dissolved in water (15 mL) made basic with concentrated aqueous ammonia and gentle heating. The sample was purified by reverse-phase chromatography (Biotage Ultra 120 g cartridge), eluting with water : acetonitrile + 0.1% ammonia = 95:5 for 2 column volumes and then water : acetonitrile + 0.1% ammonia from 95:5 to 50:50 over 10 column volumes. Fractions containing the product were combined and concentrated under reduced pressure. The residue was dissolved in 30 mL water and freeze- dried to afford 2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinic acid (1.69 g, 72%), as an off-white powder. LCMS RT = 1.68 min [M + H]+ 294. XH NMR (400 MHz, CD3SOCD3, ppm) 5 8.42 (d, J 5 Hz, 1H), 8.28 (s, 1H), 7.57 (s, 2H), 7.50 (d, J 5 Hz, 1H), 7.34 (d, J 9.6 Hz, 1H), 6.94 (dd, J 9.6, 2 Hz, 1H), 4.15 (s, 2H), 1.94-1.87 (m, 1H), 0.92-0.87 (m, 2H), 0.68-0.64 (m, 2H).
[1033] Synthesis of N-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-2-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinamide. To a mixture of 2-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinic acid (45 mg, 0.15 mmol) in DMF (5 mL) was added 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (30 mg, 0.15 mmol), HOBT (29 mg, 0.22 mmol), EDCI (42 mg, 0.22 mmol) and DIPEA (58 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 12 h under N2. The reaction weas diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SOr, filtered and concentrated to give the crude, which was purified by Prep-TLC (DCM/MeOH = 20/1) to give N-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)-2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)isonicotinamide (16 mg, yield: 22%) as a white solid. ESI-MS [M +H]+: 477.2. 1H NMR (400 MHz, DMSO) 6 8.85-8.80 (m, 1H), 8.57 (d, J = 5.1 Hz, 1H), 8.27 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 6.1 Hz, 1H), 7.70 (s, 1H), 7.61-7.58 (m, 1H), 7.57 (s, 1H), 7.33 (d, J = 9.3 Hz, 1H), 6.98 (d, J = 6.1 Hz, 1H), 6.95-6.92(m, 1H), 6.62 (s, 2H), 4.64 (d, J = 4.7 Hz, 2H), 4.18 (s, 2H), 2.57 - 2.40 (m, 6H), 1.97 - 1.84 (m, 1H), 0.97 - 0.80 (m, 2H), 0.75 - 0.51 (m, 2H).
Example 515
Synthesis of 5, 7-diniethyl- 6-(((5-( (2-methylquinolin- 6-yl) methyl)-5H-pyrrolo[3,2-c]pyridazin- 3-yl)anuno)niethyl)isoquinolin-l-amine (1-515).
Figure imgf000582_0001
[1034] Synthesis of 6-(chloromethyl)-2-methylquinoline. Methylsulfonyl chloride (0.07 mL, 0.953 mmol) was added to a stirred solution of (2-methylquinolin-6-yl)m ethanol (150 mg, 0.866 mmol) and NEt3 (0.18 mL, 1.30 mmol) in DCM (3.0 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h and then allowed to warm to room temperature and stirred for 18 h. The reaction was diluted with DCM (40 mL) and washed with KHSO-i (10% aq. sol., 20 mL), water (20 mL) and brine (20 mL). The combined organics were dried over MgSCU then concentrated in vacuo to give the title compound as a dark oil (98 mg) used in the next step without further purification. ESLMS (M+H)+: 192.0, 'H NMR (400 MHz, DMSO) 5 8.94 (d, J=8.1 Hz, 1H), 8.32 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 5.03 (s, 2H), 2.92 (s, 3H).
[1035] Synthesis of 6-((3-chloro-5H-pyrrolo[3,2-c]pyridazin-5-yl)methyl)-2- methylquinoline. 3-chloro-5//-pyrrolo[3,2-c]pyridazine (70 mg, 0.453 mmol) in DMF (1.0 mL) was added dropwise to a stirred suspension of NaH (60% in mineral oil, 54 mg, 1.36 mmol) in DMF (1.0 mL) at 0 °C, the reaction was stirred at 0 °C for 30 min. 6-(chloromethyl)-2- methylquinoline (95.5 mg, 0.498 mmol) in DMF (0.5 mL) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSCL then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0 - 100% EtOAc in DCM to give the title compound (33 mg, 25%). ESLMS (M+H)+: 309.0, ’H NMR (400 MHz, DMSO) S 8.21 - 8.17 (m, 2H), 8.11 (d, J=3.4 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.61 (dd, J=2.0, 8.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.02 (dd, J= 1.0, 3.5 Hz, 1H), 5.66 (s, 2H), 2.63 (s, 3H). [1036] Synthesis of 5, 7-dimethyl-6-(((5-((2-methylquinolin-6-yl)methyl)-5H-pyrrolo[3,2- c]pyridazin-3-yl)amino)niethyl)isoquinolin-l-amine. 6-((3-chloro-5//-pyrrolo[3,2-c]pyridazin- 5-yl)methyl)-2-methylquinoline (33 mg, 0.107 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (28 mg, 0.139 mmol), BHT (71 mg, 0.32 mmol), CS2CO3 (105 mg, 0.32 mmol) and Pd-PEPPSI-IPENTcl(o-picoline) (5 mg, 0.005 mmol) were suspended in DMF (1.0 mL) and degassed with N2 for 5 min. The reaction was then heated to 75 °C under a N2 environment for 90 min. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL), the layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The combined organics were dried over MgSCL then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (4.4 mg, 9%). ESLMS (M+H)+: 474.2, >H NMR (400 MHz, DMSO) 8 8.15 (d, J=8.4 Hz, 1H), 7.87 (d, J=11.6 Hz, 2H), 7.75 (d, J=6.1 Hz, 1H), 7.68 (d, J=3.6 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.52 (dd, J=2.0, 8.7 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 6.97 (d, J=6.0 Hz, 1H), 6.71 (d, J=0.8 Hz, 1H), 6.67 (dd, J=0.9, 3.5 Hz, 1H), 6.58 (s, 2H), 6.26 (t, J=4.6 Hz, 1H), 5.43 (s, 2H), 4.66 (d, J=4.6 Hz, 2H), 2.62 (s, 3H), 2.47 (s, 3H). One methyl peak is obscured by the DMSO signal.
Example 516
Synthesis of N4-((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6- cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-N6-(2,2,2-trifluoroethyl)pyrimidine-4,6- diamine (1-516).
Figure imgf000583_0001
[1037] Synthesis of 6-cyclopropyliniidazo[l,2-b]pyridazine-2-carbaldehyde. To a solution of (6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methanol (650 mg, 3.42 mmol) in DCM (30 mL) was added MnCh (4.46 g, 51.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 6 h. The mixture was then filtered, and filtrate cake was washed with DCM/MeOH (10/1, 200 mL). The filtrate was concentrated and purified by column chromatography on silica gel (DCM/MeOH = 10: 1) to afford 6-cyclopropylimidazo[l,2- b]pyridazine-2-carbaldehyde (400 mg, yield: 62%) as a yellow solid. ESI-MS [M + H ]+: 188.2.
[1038] Synthesis of N-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-2,2,2- trifluoroethan-l-amine. A mixture of 6-cyclopropylimidazo[l,2-b]pyridazine-2-carbaldehyde (200 mg, 1.07 mmol), 2,2,2-trifluoroethan-l-amine (127 mg, 1.28 mmol) and Ti(EtO)4 (1.09 g, 4.77 mmol) in MeOH (4 mL) and DCM (2 mL) was stirred at 60 °C for 4 h. The mixture was concentrated and purified by column chromatography on silica gel (DCM/MeOH = 20: 1) to afford N-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-2,2,2-trifluoroethan-l-amine (220 mg, yield: 76%) as a white solid. ESI-MS [M + H]+: 271.1.
[1039] Synthesis of 6-chloro-N-((6-cyclopropylinndazo[l,2-b]pyridazin-2-yl)methyl)-N- (2,2,2-trifluoroethyl)pyrimidin-4-amine. A solution of N-((6-cyclopropylimidazo[l,2- b]pyridazin-2-yl)methyl)-2,2,2-trifluoroethan-l -amine (80 mg, 0.3 mmol) and 4,6- dichloropyrimidine (179 mg, 1.2 mmol) in 'PrOH (3 mL) was stirred at 140 °C for 5 h under microwave condition. The mixture was cooled to room temperature, concentrated and purified by column chromatography on silica gel (DCM/MeOH = 20: 1) to give 6-chloro-N-((6- cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine (10 mg, yield: 9%) as a white solid. ESI-MS [M + H ]+: 383.1.
[1040] Synthesis of N4-((l-annno-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6- cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-N6-(2,2,2-trifluoroethyl)pyrimidine-4,6- diamine. A solution of 6-chloro-N-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-N- (2,2,2-trifluoroethyl)pyrimidin-4-amine (10 mg, 0.026 mmol) and 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (20 mg, 0.1 mmol) in 'PrOH (3 mL) was stirred at 145 °C for 2 h under microwave condition. The mixture was concentrated and purified by Prep-HPLC to give N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-cyclopropylimidazo[l,2- b]pyridazin-2-yl)methyl)-N6-(2,2,2-trifluoroethyl)pyrimidine-4,6-diamine (5.4 mg, yield: 38%) as a white solid. ESI-MS [M + H ]+: 548.2. Example 517
Synthesis of 5, 7-diniethyl-6-(((l-(quinolin-6-ylnwthyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)isoquinolin-l-amine (1-517).
Figure imgf000585_0001
[1041] Synthesis of quinolin-6-ylmethanol. To a solution of methyl quinoline-6-carboxylate (2.0 g, 11 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (10.7 mL, IM in THF, 10.7 mmol). After stirring at room temperature for 2 hours, the reaction was quenched by adding water (1 mL), 1 mL 15% Sodium hydroxide (1 mL) and water (3 mL) sequentially. After filtration, the filtrate was concentrated to afford the residue which was used to next step without further purification.
[1042] Synthesis of 6-(chloromethyl)quinolone. A solution of quinolin-6-ylmethanol (2) (1.75 g, 0.011 mol) in thionyl chloride (20 mL) was stirred at room temperature for 2 hours. Upon removal of the solvent, the residue was used in the next step without further purification. ESLMS [M +H]+: 178.0
[1043] Synthesis of 6-((6-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)methyl)quinolone. To a solution of 6-chloro-U/-pyrrolo[3,2-c]pyridine (200 mg, 1.13 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (136 mg, 3.39 mmol) slowly at 0 °C. After the mixture was stirred at 0 °C for 0.5 hour, 6-(chloromethyl)quinolone (200 mg, 1.13 mmol) was added to the reaction solution. The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours, then the reaction was quenched by water. The mixture was extracted with ethyl acetate three times, washed by brine, and dried over anhydrous sodium sulfate. Upon removal of the solvent, the residue was purified by silica gel chromatograph (Petroleum ether/Ethyl acetate = 1 : 1) to give 6-((6-chloro-l/f-pyrrolo[3,2-c]pyridin-l-yl)methyl)quinolone (5) (200 mg, yield: 61%) as a yellow solid. ESI-MS [M +H]+: 294.0
[1044] Synthesis of 5, 7-dimethyl-6-(((l-(quinolin-6-ylmethyl)-l H-pyrrolo[3,2-c]pyridin- 6- yl)amino)methyl)isoquinolin-l-amine. To a solution of 6-((6-chl oro-17/-pyrrolo[3,2-c]pyridin- l-yl)methyl)quinoline (50 mg, 0.17 mmol) and 6-(aminomethyl)-5, 7-dimethylisoquinolin-l- amine (34 mg, 0.17 mmol) in N,N-dimethylformamide (2 mb) was added cesium carbonate (132 mg, 0.40 mmol). Then Pd-Peppsi (15 mg, 0.017 mmol) was added to reaction solution under nitrogen atmosphere. The mixture was stirred was heated under microwave irradiation at 120 °C for 3 hours. After cooling down the reaction mixture was added water, extracted by ethyl acetate three times, washed by brine, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by Prep-TLC (dichloromethane : methanol = 10: 1) to give 5,7-dimethyl-6- (((l-(quinolin-6-ylmethyl)- 177-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)isoquinolin-l -amine (23 mg, yield: 30%) as a yellow solid. ESI-MS [M +H]+: 459.0[M + H]+, ’H NMR (400 MHz, DMSO-fifc) 5 8.86 (s, 1H), 8.39 (s, 1H), 8.27 (d, J= 8.0 Hz, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.89 (s, 1H), 7.73 (t, J = 6.4.0 Hz ,2H), 7.57 (d, J = 8.8 Hz, 1H), 7.51 -7.49 (m, 1H), 7.30 (d, J= 3.2 Hz, 1H), 6.98 (d, J= 6.0 Hz, 1H), 6.72 (s, 2H), 6.49 -6.45 (m, 2H), 5.85 (d, J= 8.0 Hz, 1H), 5.45 (s, 2H), 4.53 (d, J= 4.0 Hz, 2H), 2.45-2.38 (m, 6H).
Example 518
Synthesis of 6-(((l-((3-chloroquinolin-6-yl)methyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5> 7-dimethylisoquinolin-l-amine (1-518)
Figure imgf000586_0001
[1045] Synthesis of methyl 3-chloroquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (1) (4.5g, 24.0mmol) and N-chlorosuccinimide (12.9 g, 96.0mmol) was dissolved in /V,A'-dimethylformamide (100 mL). Then the solution was heated to 120 °C with stirring overnight. After cooling, the reaction was quenched by water (100 mL), and extracted with ethyl acetate (50 mL x 4). The organic layer was washed with water (50 mL><4), dried over anhydrous sodium sulphate and evaporated under vacuum to give the residue which was purified by a silica gel column chromatography (light petrol : ethyl acetate = 10 : 1) to afford methyl 3- chloroquinoline-6-carboxylate (2) (2.3 g, yield: 43%) as a yellow solid. ESI-MS [M +H]+: 222.0 [1046] Synthesis of(3-chloroquinolin-6-yl)methanol. To a cooled (0 °C) solution of methyl 3-chloroquinoline-6-carboxylate (2) (1.0 g, 4.5 mmol) in tetrahydrofuran (20 mL), was added lithium aluminumhydride (1.8 mL, 2.5 N in THF, 4.5 mmol) slowly. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with sodium sulfatedecahydrate. After stirring at room temperature for 30 minutes, the mixture was filtered through a celite pad. The filtrate was concentrated to give a residue which was purified by a silica gel column chromatography (light petrol : ethyl acetate = 3:1) to afford (3-chloroquinolin-6-yl)methanol (740 mg, yield: 84%) as a white solid. ESI-MS [M +H]+: 194.0
[1047] Synthesis of 3-chloro-6-(chloromethyl)quinoline. A solution of (3-chloroquinolin-6- yl)methanol (3) (740 mg, 7.9 mmol) in thionyl chloride (5 mL) was stirred at room temperature for one hour. The result mixture was concentrated and the residue was diluted with di chloromethane (20 mL), washed with aqueous solution of sodium bicarbonate. The organic phase was concentrated and purified by Prep-TLC (light petrol : ethyl acetate = 3 : 1) to give 3- chloro-6-(chloromethyl)quinoline (458 mg, yield: 56%) as a yellow solid. ESI-MS [M +H]+: 212.0
[1048] Synthesis of 6-((6-bromo-lH-pyrrolo[3,2-c]pyridin-l-yl)methyl)-3-chloroquinoline. A solution of 6-bromo-l/f-pyrrolo[3,2-c]pyridine (5) (500mg, 2.5 mmol) in N,N- dimethylformamide (10 mL), was added potassium carbonate (1.05 g, 7.6 mmol) slowly. After the mixture was stirred at room temperature for 30 minutes, 3-chloro-6-(chloromethyl)quinoline (4) (538 mg, 2.5 mmol) was added. The mixture was stirred at room temperature over night. The resulting mixture was diluted with water and filtered to get solid crude product which was recrystallized from dichloromethane to give 6-((6-brorno-1 7-pyrrolo[3,2-c]pyridin-l-yl)methyl)- 3 -chloroquinoline (800 mg, yield: 84%) as a gray solid. ESI-MS [M +H]+: 372.0 [1049] Synthesis of 6-(((l-((3-chloroquinolin-6-yl) methyl)-! H- pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l-anune. A solution of 6-((6-bromo- 17/-pyrrolo[3,2- c]pyridin-l-yl)methyl)-3 -chloroquinoline (100 mg, 0.27mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (7) (54 mg, 0.27mmol) and cesium carbonate (264 mg, 0.81 mmol) in N,N-dimethylformamide (2 mL) was degassed with nitrogen for five minutes. Catalyst Pd- peppsi (30 mg, 0.03mmol) was added. The result mixture was heated to 90 °C and kept stirring under nitrogen atmosphere for three hours. After cooling down, the mixture was diluted with ethyl acetate, washed with water for four times, and then concentrated to give a residue. The residue was purified by Prep-TLC (dichloromethane : methanol = 10: 1, ammonia) to get 6-(((l- ((3-chloroquinolin-6-yl)methyl)-l/7-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (6.5 mg, 4.8%) as a yellow solid. ESI-MS [M +H]+: 493.0 [M+H]+, LH NMR (400 MHz, CD3OD) 8 8.78-8.77 (m, 1H), 8.39 (s, 1H), 8.30 (m, 1H), 8.03- 7.99 (m, 2H), 7.62-7.56 (m, 3H), 7.29-7.27 (m, 2H), 6.62 (s, 2H), 5.54 (s, 2H), 4.59 (s, 2H), 2.61 (s, 3H), 2.56 (s, 3H).
Example 519
Synthesis of 6-(((3-((3-chloroquinolin-6-yl)niethyl)-[l,2,4]triazolo[4,3-a]pyridin-6-
Figure imgf000588_0001
[1050] Synthesis ofN'-(5-bromopyridin-2-yl)-2-(3-chloroquinolin-6-yl)acetohydrazide. To a stirred solution of 2-(3-chloroquinolin-6-yl)acetic acid (0.5g, 2.26mmol), 1- hydroxybenzotriazole (0.37 g, 2.74 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.1 g, 5.72 mmol) in N,N-dimethylformamide (10 m ) was added ethyl diisopropylamine (2.0 mL, 12.1 mmol). The mixture was stirred at room temperature for 30 minutes, then added 5-bromo-2-hydrazinylpyridine (0.51 g, 2.71 mmol) and kept stirring at room temperature overnight. After the completion of reaction, the mixture was quenched with water, filtered, and washed with water to give A'-(5-bromopyridin-2-yl)-2-(3-chloroquinolin-6- yl)acetohydrazide (0.65 g crude) as a brown solid. ESI-MS [M +H]+: 391.0
[1051] Synthesis of 6-((6-bromo-[l,2,4]triazolo[4,3-a]pyridin-3-yl)niethyl)-3- chloroquinoline. A solution of A"-(5-bromopyridin-2-yl)-2-(3-chloroquinolin-6- yl)acetohydrazide (0.65 g, 1.67 mmol) in phosphorus oxychloride (12 mL) was stirred at 100 °C for 3 hours. After the completion of reaction, the mixture was concentrated, the reside was diluted with saturated sodium bicarbonate carefully and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, evaporated and purified by Prep-TLC (Ethyl acetate) to give 6-((6-bromo-[l,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-chloroquinoline (0.24 mg, yield: 29% over 2 steps) as a yellow solid. ESI-MS [M +H]+: 373.0, 'H NMR (400 MHz, DMSO-t/e) 8 8.88 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.83 (s, 1H), 7.79-7.76 (m, 2H), 7.47 (dd, J= 2.0, 10.0 Hz, 1H), 4.77 (s, 2H).
[1052] Synthesis of 6-(((3-((3-chloroquinolin-6-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridin-6- yl)amino)niethyl)-5, 7-diniethylisoquinolin-l-amine. To a stirred solution of 6-((6-bromo- [1, 2, 4]triazolo[4, 3 -a]pyri din-3 -yl)methyl)-3 -chloroquinoline (100 mg, 0.27 mmol) and 6- (aminomethyl)-5,7-dimethylisoquinolin-l-amine (56 mg, 0.27 mmol) in N,N- dimethylformamide (4 mL) was added cesium carbonate (280 mg, 0.86 mmol) and Pd-peppsi (40 mg, 0.048 mmol) under nitrogen atmosphere. The mixture was stirred at 90 °C for 4 hours. After the completion of reaction, the mixture was added water and filtered. The solid crude was purified by Prep-TLC (Dichloromethane / Methanol / Ammonium hydroxide = 200 / 20 / 1) to give 6-(((3-((3-chloroquinolin-6-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)amino)methyl)- 5,7-dimethylisoquinolin-l -amine (25 mg, yield: 19%) as a green solid. ESI-MS [M +H]+: 494.0, ‘HNMR (400 MHz, DMSO-fifc) 6 8.86 (d, J= 2.4 Hz, 1H), 8.56 (d, J= 2.4 Hz, 1H), 8.03 (t, J = 4.8 Hz, 2H), 7.91 (s, 1H), 7.80 (dd, J = 8.8, 1.6 Hz, 1H), 7.75 (d, J= 6.4 Hz, 1H), 7.57 (d, J = 10.0 Hz, 1H), 7.47 (s, 1H), 7.26-7.24 (brs, 2H), 7.09-7.03 (m, 2H), 5.94-5.92 (m, 1H), 4.74 (s, 2H), 4.16 (d, J= 4.4 Hz, 2H), 2.48 (s, 3H), 2.41 (s, 3H). Example 520
Synthesis of 6-(((3-( (3-chloroquinolin- 6-yl)methyl) imidazo L, 5-a]pyridin- 6-yl) amino) methyl)- 5, 7-dimethylisoquinolin-l-amine (1-520)
Figure imgf000590_0001
[1053] Synthesis of N-((5-bromopyridin-2-yl)methyl)-2-(3-chloroquinolin-6-yl)acetamide.
To a stirred solution of (5-bromopyridin-2-yl)methanamine (300 mg, 1.16 mmol) and 2-(3- chloroquinolin-6-yl)acetic acid (281 mg, 1.27 mmol) in N,N-dimethylformamide (10 mL) was added l-[bis(dimethylamino)methylene]-l//-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (882 mg, 2.32 mmol), ethyldiisopropylamine (450 mg, 2.48 mmol). The mixture was stirred at room temperature for 1 hour. After the completion of reaction, the mixture was added water and fdtered. The solid crude was washed with water, ethyl acetate, and then dissolved in dichloromethane. The organic phase was washed with water, brine, dried over magnesium, and concentrated to afford A-((5-bromopyridin-2-yl)methyl)-2-(3 -chi oroquinolin-6- yl)acetamide (3) (370 mg, yield: 82%) as a white solid. ESI-MS [M +H]+: 392.0.
[1054] Synthesis of 6-((6-bromoimidazo[l,5-a]pyridin-3-yl)methyl)-3-chloroquinoline. A solution of A-((5-bromopyridin-2-yl)methyl)-2-(3-chloroquinolin-6-yl)acetamide (370 mg, 0.95 mmol) in phosphorus oxychloride (10 mL) was stirred at 100 °C for 3 hours. After the completion of reaction, the mixture was diluted with water and 15% aqueous solution of sodium hydroxide carefully, then extracted with a mixed solvent (di chloromethane : methanol = 10: 1). The organic layers were washed with water, brine and concentrated. The solid crude was purified by Prep-TLC (Dichloromethane : methanol = 10 : 1) to give 6-((6-bromoimidazo[l,5-rz]pyridin- 3 -yl)methyl)-3 -chloroquinoline (300 mg, yield: 85%) as a yellow solid. XH NMR (400 MHz, CDCh) 8 8.78 (d, J= 2.0 Hz, 1H), 8.04 (d, J= 8.8 Hz, 2H), 7.78 (s, 1H), 7.59 (t, J= 8.8 Hz, 1.6 Hz, 1H), 7.48 (d, J= 13.6 Hz, 1H), 7.35 (d, J= 9.6 Hz, 2H), 7.26 (s, 1 H), 4.57 (s, 2H). [1055] Synthesis of (6-(((3-((3-chloroquinolin-6-yl)methyl)imidazo[l,5-a]pyridin-6- yl)amino)methyl)-5, 7-dimethylisoquinolin-l-aminefffo a stirred solution of 6-((6- bromoimidazo[l,5-r/]pyridin-3-yl)methyl)-3-chloroquinoline (100 mg, 0.27 mmol), (6- (aminomethyl)-5,7-dimethylisoquinolin-l -amine) (54.0 mg, 0.127 mmol) and cesium carbonate (264. Omg, 0.81 mmol) in N,N-dimethylformamide (2.5 mL) was added Pd-Peppsi (30.0 mg). The mixture was stirred at 90 °C for 4 hours. After the completion of reaction, the mixture was added water and fdtered. The solid crude was purified by Prep-TLC (dichloromethane : methanol = 10 : 1) to give (6-(((3-((3-chloroquinolin-6-yl)methyl)imidazo[l,5-a]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l-amine) (40 mg, yield: 30%) as a brown solid. ESIMS [M +H]+: 493.1, ^ NMR (400 MHz, DMSO-Js) 8 8.84 (d, J= 2.4 Hz, 1H), 8.74-8.69 (m, 2H), 8.54 (s, 1H), 8.30 (s, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.88 (s, 1H), 7.76-7.69 (m, 2H), 7.40 (d, J = 9.6 Hz, 1H), 7.33-7.30 (m, 2H), 7.28 (d, J= 6.8 Hz, 1H), 6.55-6.53 (m, 1H), 6.73-6.72 (m, 1H), 4.64 (s, 2H), 4.49 (d, J= 3.6 Hz, 1H), 2.52 (s, 3H), 2.44 (s, 3H).
Example 521
Synthesis of (6-(((l -anti no- 5, 7-dimethylisoquinolin-6-yl) methyl) amino) imidazofl, 2-a]pyridin-
3-yl) (naphtha! en-2-yl)methanol (1-521 ).
Figure imgf000591_0001
[1056] Synthesis of ((6-bromoimidazo[l,2-a]pyridin-3-yl)(naphthalen-2-yl)methanol). To a stirred solution of 6-bromoimidazo[l,2-rz]pyridine-3-carbaldehyde (1) (2.0 g, 8.92 mmol) in tetrahydrofuran, was added 2-naphthylmagnesium bromide (35.7 mL, 17.6 mmol, 0.5 M in THF). After stirring at room temperature overnight, the mixture was added into water, and extracted with ethyl acetate. The combined organic layers were concentrated to give crude product which was washed with dichloromethane to give 6-bromoimidazo[l,2-a]pyridin-3- yl)(naphthalen-2-yl)methanol (2.4 g, yield: 77%) as a white solid. ESLMS [M +H]+: 354.2, ’H NMR (400 MHz, DMSO-c/6) 8 8.59 (d, J= 0.8 Hz, 1H), 7.88-7.82 (m, 3H), 7.78 (s, 1H), 7.58 (d, ./ - 9,6 Hz, 1H), 7.49-7.4 l(m, 4H), 7.33 (dd, J= 9.6, 2.0 Hz, 1H), 4.49 (s, 2H). [1057] Synthesis of (6-(((l-amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)imidazo[l,2- a]pyridin-3-yl)(naphthalen-2-yl)methanol. To a stirred solution of 6-bromoimidazo[l,2- tz]pyridin-3-yl)(naphthalen-2-yl)methanol (200 mg, 0.56 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (136.6 mg , 0.68 mmo), and cesium carbonatein (365mg, 1.12mol) in N,N-dimethylformamide (3.0 mL) was added Pd-Peppsi (60.0 mg). The mixture was stirred at 120 °C for 3 hours. After the completion of reaction, the mixture was added into water and fdtered. The solid crude was purified by Prep-TLC (Di chloromethane : methanol = 15: 1) to give (6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)imidazo[l,2-a]pyri din-3- yl)(naphthalen-2-yl)methanol (30 mg, yield: 11%) as a yellow solid. ESI-MS [M +H]+: 474.2 'H NMR (400 MHz, DMSO-t/c) 8 8.15 (s, 1H), 8.11 (s, 1H), 7.96-7.89 (m, 3H), 7.75-7.67 (m, 4H), 7.56-7.50 (m, 3H), 7.42 (d, J= 9.2 Hz, 1H), 7.14-7.13 (m, 2H), 7.04 (d, J= 9.6 Hz, 1H), 6.35 (s, 2H), 5.73 (s, 1H), 4.22-4.07 (m, 2H), 2.42 (s, 3H), 2.39 (s, 3H).
Example 522
Synthesis of 5, 7-diniethyl-6-(((3-(naphthalen-2-ylmethyl)iniidazo[l,2-a]pyridin-6-
Figure imgf000592_0001
[1058] Synthesis of ((6-bromo-3-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyridine). To a solution of 6-bromoimidazo[l,2-<i]pyridin-3-yl)(naphthalen-2-yl)methanol (1.4 g, 3.96 mmol) in acetonitrile (20 mL) was trifluoroacetic acid (3 mL) and triethylsilane(3 mL). The resulting mixture was stirred at 80 °C overnight. After the completion of reaction, the mixture was added into water, extracted with dichloromethane, and concentrated to give crude product which was washed with ethyl acetate to give ((6-bromo-3-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyridine) (5) (0.76 g, yield: 57%) as a white solid. ESI-MS [M +H]+:338.2. ’H NMR (400 MHz, DMSO- d ) 8 8.66 (d, J= 1.2 Hz, 1H), 8.06 (s, 1H), 7.96-7.79 (m, 3H), 7.59-7.51 (m, 4H), 7.39 (dd, J = 9.6, 1.6 Hz, 1H), 7.17 (s, 1H), 6.39 (s, 2H).
[1059] Synthesis of 5, 7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyridin-6- y I) ami no) methyl) isoquinolin-l-amine. To a stirred solution of 6-bromo-3-(naphthalen-2- ylmethyl)imidazo[l,2-a]pyridine (60 mg, 0.178 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (35.7 mg, 0.178 mmol) and cesium carbonatein (174.0 mg, 0.534 mmol) in N,N-Dimethylformamide (1.0 mL) was added Pd-PEPPSi (18.0 mg). The mixture was stirred at 120°C for 3 hours. After the completion of reaction, the mixture was added water and fdtered. The solid crude was purified by Prep-TLC (Di chloromethane: methanol = 10:1) to give 5,7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyridin-6- yl)amino)methyl)isoquinolin-l -amine (20 mg, yield: 24.5%) as a green solid. ESI-MS [M +H]+: 458.2, 'HNMR (400 MHz, DMSO-tL) 5 8.00 (s, 1H), 7.90-7.84 (m, 4H), 7.76 (d, J= 6.4 Hz, 1H), 7.48-7.47 (m, 4H), 7.05 (d, J= 6.4 Hz, 1H), 6.99 (d, J= 9.6 Hz, 1H), 5.65 (s, 1H), 4.45 (s, 2 H), 4.13 (d, J= 3.6 Hz, 1H), 2.45 (s, 3H), 2.36 (s, 3H).
Example 523
Synthesis of 5, 7-diniethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,5-a]pyrazin-6-
Figure imgf000593_0001
[1060] Synthesis of 2-((5-chloropyrazin-2-yl)niethyl)isoindoline-l, 3-dione. To a solution of
(5-chloropyrazin-2-yl)methanol (2 g, 13.8 mmol), isoindoline- 1,3 -dione (2.4 g, 16.6 mmol) and triphenylphosphine (4.4 g, 16.6 mmol) in anhydrous tetrahydrofuran (50 mL) was added diisopropyl azodicarboxylate (3.3 mL, 16.6 mmol) dropwise. After stirring at room temperature for 12 hours, the reaction mixture was concentrated and purified by silica gel chromatography (Petro ether : Dichloromethane : Ethyl acetate = 8: 1 : 1 to 6:2:1) to yield 2-((5-chloropyrazin-2- yl)methyl)isoindoline-l, 3-dione (2.7 g, yield: 71%) as a white solid. ’H NMR (400 MHz, DMSO-rL) 5 8.68 (s, 1H), 8.67 (s, 1 H), 7.93-7.87 (m, 4 H), 5.01 (s, 2 H).
[1061] Synthesis of (5-chloropyrazin-2-yl)methanamine. To a solution of 2-((5- chloropyrazin-2-yl)methyl)isoindoline- 1,3-dione (1.0 g, 3.66 mmol) in dichloromethane (20 mL) was added hydrazine hydrate (0.45 mL, 9.16 mmol) at room temperature. After 2 hours, methanol (15 mL) was added and the mixture was stirred at reflux for 19 hours. The reaction was cooled to room temperature and the white precipitate that formed was filtered off. The resultant solid was re-dissolved in ethyl acetate and filtered again. The solution was concentrated to afford crude (5-chloropyrazin-2-yl)methanamine (0.6 g crude) as a yellow oil which was used in next step without further purification.
[1062] Synthesis ofN-((5-chloropyrazin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide. To a solution of (5-chloropyrazin-2-yl)methanamine (200 mg, 1.39 mmol) in dichloromethane (5 mL) was added ethyldiisopropylamine (0.69 mL, 4.18 mmol) and 2-(naphthalen-2-yl)acetyl chloride (285 mg, 1.39 mmol). After stirring at room temperature for 3 hours, the reaction was diluted with water, extracted with dichloromethane for 3 times. The combined organic layers were washed with water, brine and concentrated. The crude product was washed with ether to yield N- ((5-chloropyrazin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (240 mg, yield: 55% over 2 steps) as an off-white solid. [ESI-MS [M +H]+: 312.0.
[1063] Synthesis of 6-chloro-3-(naphthalen-2-ylmethyl)imidazo[l,5-a]pyrazine. To a suspension of A-((5-chloropyrazin-2-yl)methyl)-2-(naphthalen-2-yl)acetamide (120 mg, 0.39 mmol) in acetonitrile (5 mL) was added phosphorus oxychloride (0.36 mL, 3.9 mmol) and triethylamine (0.16 mL, 1.16 mmol) under nitrogen atmosphere, then the reaction was heated to 85 °C for 6 hours. The reaction mixture was concentrated, diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried, concentrated and purified by Prep-TLC (Petro ether : Ethyl acetate=l : l) to yield 6-chloro-3-(naphthalen-2-ylmethyl)imidazo[l,5-a]pyrazine (7) (78 mg, yield: 69%) as a colourless oil. ESI-MS [M +H]+: 294.0. 'H NMR (400 MHz, DMSO-t/e) 8 8.91 (s, 1 H), 8.44 (s, 1 H), 7.93 (s, 1 H), 7.88-7.82 (m, 3 H), 7.74 (s, 1 H), 7.49-7.45 (m, 2 H), 7.38-7.36 (m, 1 H), 4.58 (s, 2 H). [1064] Synthesis of 5, 7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,5-a]pyrazin-6- yl)aniino)niethyl)isoquinolin-l-amine. To a stirred solution of 6-chl oro-3 -(naphthal en-2- ylmethyl)imidazo[l,5-a]pyrazine (72 mg, 0.245 mmol), (6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine) (74 mg, 0.368 mmol) and cesium carbonate (240 mg, 0.735 mmol) in N,N-dimethylformamide (2.0 mL) was added Pd-PPESi (15 mg). The mixture was stirred under microwave irradiation at 120 °C for 2 hours. After the completion of reaction, the mixture was diluted with water and filtered. The solid crude was purified by Prep-TLC (dichloromethane : methanol=10:l) to give 5,7-dimethyl-6-(((3-(naphthalen-2- ylmethyl)imidazo[l,5-a]pyrazin-6-yl)amino)methyl)isoquinolin-l -amine (42 mg, yield: 37.5%) as a yellow solid. ESLMS [M +H]+: 459.1. 1 H NMR (400 MHz, DMSO-fifc) 5 8.80 (s, 1H), 7.90 (s, 1H), 7.87-7.81 (m, 3H), 7.79 (s, 1H), 7.76 (d, J= 5.6 Hz, 1H), 7.68 (s, 1H), 7.50-7.46 (m, 2H), 7.41 (d, J= 9.2 Hz, 1H), 7.23 (s, 1H), 6.98 (d, J= 6.0 Hz, 1H), 6.66 (s, 2H), 5.80 (t, J= 4.4 Hz, 1H), 4.54 (s, 2H), 4.30 (d, J= 4.8 Hz, 2H), 2.48 (s, 3H), 2.43 (s, 3H).
Example 524
Synthesis of 5, 7-dimethyl- 6-(((l -methyl-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2, 3-c]pyridin- 5-yl)amino)methyl)isoquinolin-l-amine (1-524).
Figure imgf000595_0001
[1065] Synthesis of 6-bronw-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde. To a solution of
6-bromo-17/-pyrrolo[2,3-/>]pyridine (3 g, 15.2 mmol) in acetic acid (10 mL) and water (20 mL) was added urotropine (3.2 g, 22.8 mmol). After stirring at 120 °C under reflux for 6 hours, the reaction mixture was concentrated, diluted with saturated sodium bicarbonate solution, extracted with ethyl acetate three times, washed by brine, and dried. Upon removal of the solvent, the residue was purified by silica gel chromatograph (Petroleum ether/Ethyl acetate=2: 1) to give 6- bromo-l//-pyrrolo[2,3-/>]pyridine-3-carbaldehyde(2.5 g, yield: 73%) as a yellow solid. ESI-MS [M +H]+: 222.6
[1066] Synthesis of tert-butyl 6-bromo-3-formyl-lH-pyrrolo[2,3-b]pyridine-l -carboxylate.
To a solution of 6-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.2 g, 5.3 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (424 mg, 10.6 mmol). The reaction solution was stirred at 0 °C for 0.5 hour and then iodomethane (1.5 g, 10.6 mmol) was added. After stirring at room temperature overnight, the mixture was diluted with ammonium chloride solution, and extracted by ethyl acetate for three times. The combined organic layer were washed with brine, dried, concentrated and then purified by silica gel chromatograph (Petroleum ether/Ethyl acetate=l : l) to give 6-bromo-l-methyl-177-pyrrolo[2,3-/>]pyridine-3-carbaldehyde (0.9 g, yield: 70%) as a yellow solid. ESI-MS [M +H]+: 240.9
[1067] Synthesis of (6-bronw-l-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)(naphthalen-2- yl)methanol. To a solution of 6-bromo-l-methyl-l//-pyrrolo[2,3-Z>]pyridine-3-carbaldehyde (0.9 g, 3.8 mmol) in tetrahydrofuran (10 mL) was added (naphthal en-2-ylmethyl)magnesium bromide (15.2 mL, 7.6 mmol) at 0 °C. After stirring at room temperature overnight, the mixture was diluted with ammonium chloride solution, and extracted by ethyl acetate for three times. The combined organic layer were washed with brine, dried, concentrated and then purified by silica gel chromatograph (Petroleum ether/Ethyl acetate = 2: 1) to give (6-bromo-l -methyl- 1H- pyrrolo[2,3-Zi]pyridin-3-yl)(naphthalen-2-yl)methanol (1.0 g, yield: 72%) as a yellow solid. ESI- MS [M +H]+: 366.9 [M + H]+.
[1068] Synthesis of 6-bromo-l-methyl-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3- bjpyridine. To a solution of(6-bromo-l-methyl-17/-pyrrolo[2,3-£>]pyridin-3-yl)(naphthalen-2- yl)methanol (300 mg, 0.66 mmol) in acetonitrile (5 mL) was added trifluoroacetic acid (1 mL) and tri ethyl si lane (1 mL). After stirring at 80 °C overnight, the mixture was concentrated, diluted with saturated sodium bicarbonate solution, extracted with ethyl acetate three times, washed with brine, and dried. Upon removal of the solvent, the residue was purified by Prep-TLC (Petroleum ether : Ethyl acetate=l : l) to give 6-bromo-l-methyl-3-(naphthalen-2-ylmethyl)-177-pyrrolo[2,3- Z>]pyridine (200 mg, yield: 89%) as a yellow solid.
[1069] Synthesis of 5, 7-dimethyl-6-(((l-methyl-3-(naphthalen-2-ylniethyl)-lH-pyrrolo[2,3- c]pyridin-5-yl)amino)methyl)isoquinolin-l-amine. To a stirred solution of 6-bromo-l -methyl - 3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridine (50 mg, 0.14 mmol), (6-(aminomethyl)- 5,7-dimethylisoquinolin-l -amine) (34.6 mg, 0.17 mmol) and cesium carbonatein (140. Omg, 0.43 mmol) in N,N-dimethylformamide (1.0 mL) was added Pd-PPESi (15.0 mg). The mixture was stirred at 90 °C for 3 hours then quenched by water and fdtered. The solid crude was purified by Prep-TLC (dichloromethane: methanol = 20: 1) to give 5,7-dimethyl-6-(((l-methyl-3- (naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-c]pyridin-5-yl)amino)methyl) isoquinolin- 1 -amine (15 mg, yield: 22%) as a yellow solid. ESI-MS [M +H]+: 472.2, 1H NMR (400 MHz, DMSO-tfc) 5 8.32 (s, 1 H), 7.74 (s, 1H), 7.84-7.74 (m, 4H), 7.72 (d, J= 6.4 Hz, 1H), 7.46-7.38 (m, 4H), 7.22 (s, 1H), 7.04 (d, J= 6.0 Hz, 1H), 6.56 (s, 1H), 6.61 (m, 1H), 4.52 (d, J= 4.8 Hz, 1H), 4.07 (s, 2H), 3.73 (s, 3 H), 2.55 (s, 3H), 2.47 (s, 3H).
Example 525
Synthesis of 5, 7-dimethyl-6-(((2-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyrazin-8- yl)amino)methyl)isoquinolin-l-aniine (1-525).
Figure imgf000597_0001
[1070] Synthesis of 2-(naphthalen-2-yl)acetyl chloride. To a solution of 2-(naphthalen-2- yl)acetic acid (2.0 g, 10.8 mmol) in dry dichloromethane (50 mL) was added oxalylchloride (2.7 mL, 32.2 mmol) and N,N-dimethylformamide (1 drop). After stirring at room temperature for 3 hours, the mixture was concentrated in vacuo to obtain crude 2-(naphthalen-2-yl)acetyl chloride (2.0 g) as a white solid which was used to the following reaction directly.
[1071] Synthesis ofl-bromo-3-(naphthalen-2-yl)propan-2-one. To a solution of 2- (naphthalen-2-yl)acetyl chloride (1.0 g, 4.9 mmol) in acetonitrile (20 mL) was added 2 M solution of (trimethylsilyl)diazomethane in hexanes (2M, 5.4 mL, 10.8 mmol) at 0 °C. The reaction was allowed to warm to room temperature overnight. Then 33% hydrobromic acid, acetic acid solution (2.2 mL, 10.8 mmol) was added slowly at 0 °C. After stirring for 30 minutes, the reaction was diluted with di chloromethane (20 mL) and washed with aqueous solution of sodium bicarbonate, the organic layer was separated, dried and concentrated to yield l-bromo-3- (naphthalen-2-yl)propan-2-one (1.12 g, yield: 86%) as an off-white solid. XH NMR (400 MHz, CDCh) 8 7.84-7.79 (m, 3H), 7.71 (s, 1H), 7.50-7.47 (m, 2H), 7.34 (dd, J= 8.4, 2.0 Hz, 1H), 4.11 (s, 2H), 3.94 (s, 2H).
[1072] Synthesis of8-bronio-2-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyrazine. A mixture of l-bromo-3-(naphthalen-2-yl)propan-2-one (0.6 g, 2.28 mmol) and 3-bromopyrazin-2-amine (0.8 g, 4.56 mmol) in acetonitrile (15 mL) was stirred at reflux for 20 hours. The reaction mixture was concentrated and purified by Prep-TLC (Petro ether:Ethyl acetate= 2:1) to yield 8- bromo-2-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyrazine (0.35 g, yield: 45%) as a yellow oil. ESLMS [M +H]+: 338.0, 340.0. XH NMR (400 MHz, DMSO-t/e) 8 8.56 (d, J= 4.4 Hz, 1H), 8.01 (s, 1H), 7.88-7.86 (m, 3H), 7.83 (s, 1H), 7.67 (d, J= 4.4 Hz, 1H), 7.50-7.47 (m, 3H), 4.32 (s, 2H).
[1073] Synthesis of 5, 7-dimethyl-6-(((2-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyrazin-8- yl)amino)methyl)isoquinolin-l-amine. To a stirred solution of 8-bromo-2-(naphthalen-2- ylmethyl)imidazo[l,2-a]pyrazine (64 mg, 0.19 mmol), (6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine) (46 mg, 0.23 mmol) and cesium carbonate (185 mg, 0.57 mmol) in N,N-dimethylformamide (1.5 mL) was added Pd-PEPPSi (15 mg). The mixture was stirred under microwave irradiation at 120°C for 1 hour. After the completion of reaction, the mixture was diluted with water and filtered. The crude product was purified by Prep-TLC (Di chloromethane : methanol = 10: 1) to give 5,7-dimethyl-6-(((2-(naphthalen-2-ylmethyl)imidazo[l,2-cz]pyrazin-8- yl)amino)methyl)isoquinolin-l -amine (25 mg, yield: 29%) as a yellow solid. ESI-MS [M +H]+: 459.2. 1H NMR (400 MHz, DMSO-fifc) 8 7.99 (s, 1H), 7.83-7.81 (m, 3H), 7.75-7.72 (m, 3H), 7.61 (s, 1H), 7.44 (m, 3H), 7.29 (s, 4H), 7.07-7.06 (m, 1H), 4.81 (s, 2H), 4.17 (s, 2H), 2.56 (s, 6H). Example 526
Synthesis of 5, 7-diniethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-c]pyridin-5-
Figure imgf000599_0001
[1074] Synthesis of6-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde. To a solution of 6- bromo-l/f-pyrrolo[2,3-/>]pyridine (3 g, 15.2 mmol) in acetic acid (10 mL) and water (20 mL) was added urotropine (3.2 g, 22.8 mmol). After the mixture was stirred at 120 °C under reflux for 6 hours, the reaction mixture was concentrated, diluted with saturated sodium bicarbonate solution, extracted by ethyl acetate three times. The combined organic layers were washed by brine, and dried over anhydrous sodium sulfate. Upon removal of the solvent, the residue was purified by silica gel chromatograph (Petroleum ether/Ethyl acetate = 2: 1) to give 6-bromo-lH- pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.5 g, yield: 73%) as a yellow solid. ESI-MS [M +H]+: 222.6
[1075] Synthesis of tert-butyl 6-bromo-3-formyl-lH-pyrrolo[2,3-b]pyridine-l-carboxylate.
To a solution of 6-bromo-U/-pyrrolo[2,3-/>]pyridine-3-carbaldehyde (1.2 g, 5.3 mmol), 4- dimethylaminopyridine (150 mg) and triethylamine (2.7 g,26.5 mmol) in tetrahydrofuran (20 mL) was added di-tert-butyl dicarbonate (1.7 g, 7.9 mmol). After stirring at room temperature overnight, the mixture was concentrated, and purified by silica gel chromatograph (Petroleum ether / Ethyl acetate = 5: 1) to give tert-butyl 6-bromo-3-formyl-U/-pyrrolo[2,3-b]pyridine-l- carboxylate (1.1 g, yield: 65%) as a yellow solid. ESI-MS [M +H]+: 327.0
[1076] Synthesis of tert-butyl 6-bromo-3-(hydroxy(naphthalen-2-yl)methyl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate. To a solution of /cvz-butyl 6-bromo-3 -formyl- \H- pyrrolo[2,3-/>]pyridine-l-carboxylate (1.0 g, 3.1 mmol) in tetrahydrofuran (10 mL) was added (naphthalen-2-ylmethyl)magnesium bromide (12.4 mL, 6.2 mmol) at 0 °C. The mixture was stirred at room temperature overnight, the quenched by ammonium chloride solution, extracted with ethyl acetate for three times. The combined organic layer were washed by brine, dried, concentrated and then purified by silica gel chromatograph (Petroleum ether / Ethyl acetate = 8: 1, UV) to give e/7-butyl 6-bromo-3-(hydroxy(naphthalen-2-yl)methyl)-lH-pyrrolo[2,3- b]pyridine-l -carboxylate (0.95 g, yield: 68%) as a yellow solid. ESI-MS [M +H]+: 455.0
[1077] Synthesis of 6-bromo-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridine. To a solution of /c/7-butyl 6-bromo-3-(hydroxy(naphthalen-2-yl)methyl)-lZ/-pyrrolo[2,3-Z)]pyridine- 1-carboxylate (300 mg, 0.66 mmol) in acetonitrile (5 mL) was added trifluoroacetic acid (1 mL) and tri ethylsilane (1 mL). The mixture was stirred at 80 °C overnight, then concentrated, diluted with saturated sodium bicarbonate solution, and extracted by Ethyl acetate three times. The combined organic layers were washed by brine, and dried. Upon removal of the solvent, the residue was purified by Prep-TLC (Petroleum ether / Ethyl acetate = 1 : 1) to give 6-bromo-3- (naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridine (200 mg, yield: 89%) as a yellow solid. ESIMS [M +H]+: 339.0
[1078] Synthesis of tert-butyl 6-bromo-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3- b]pyridine-l-carboxylate. To a solution of 6-bromo-3-(naphthalen-2-ylmethyl)-l//-pyrrolo[2,3- Z’Jpyridine (300 mg, 0.89 mmol), 4-dimethylaminopyridine (30 mg) and triethylamine (180 mg, 1.78 mmol) in tetrahydrofuran (10 mL) was added di-tert-butyl dicarbonate (385 mg, 1.78 mmol). After the reaction solution was stirred at room temperature overnight, the mixture was concentrated, and purified by Prep-TLC (Petroleum ether / Ethyl acetate = 4: 1) to give / -butyl 6-bromo-3-(naphthalen-2-ylmethyl)-17/-pyrrolo[2,3-b]pyridine-l-carboxylate (260 mg, yield: 67%) as a yellow solid. ESI-MS [M +H]+: 389.1
[1079] Synthesis of (5, 7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3- c]pyridin-5-yl)amino)methyl)isoquinolin-l-amine). To a stirred solution of (/e/7-butyl 5- bromo-3-(naphthalen-2-ylmethyl)-U/-pyrrolo[2,3-c]pyridine-l-carboxylate) (100 mg, 0.23 mmol), (6-(aminomethyl)-5,7-dimethylisoquinolin-l-amine) (55.3 mg, 0.27 mmol) and cesium carbonatein (225.0 mg, 0.69 mmol) in N,N-dimethylformamide (2.0 mL) was added Pd-Peppsi (30.0 mg) under nitrogen atmosphere. The mixture was stirred at 90 °C for 3 hours. After the completion of reaction, the mixture was added water and filtered. The solid crude was purified by Prep-TLC (dichloromethane: methanol = 20:1) to give /erLbutyl 5-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)-3-(naphthalen-2-ylmethyl)-l/f-pyrrolo[2,3-c]pyridine- 1 -carboxylate (15 mg, yield: 14%) as a yellow solid.
[1080] Synthesis of 5, 7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-c]pyridin- 5-yl)amino)methyl)isoqiiinolin-l-amine. Tert-\)vAy\ 5-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-3-(naphthalen-2-ylmethyl)-17/-pyrrolo[2,3-c]pyridine-l -carboxylate (15.0 mg, 0.027 mmol) was dissolved in trifluoroacetic acid / di chloromethane (8 mL). The mixture was stirred at room temperature for 30 minutes. After removing solvent under vacuum, the crude product was purified by Prep-HPLC to afford 5,7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-l/7- pyrrolo[2,3-c]pyridin-5-yl)amino)methyl)isoquinolin-l-amine (12.3 mg, quant.) as a brown solid. ESI-MS [M +H]+: 457.9, 1H NMR (400 MHz, DMSO-cA) 8 13.68 (s, 2H), 11.87 (s, 1H), 9.12 (d, J= 7.6 Hz, 2H), 8.47 (s, 1 H), 8.38 (s, 1H), 7.97 (d, J= 2.8 Hz, 1H), 7.87-7.80 (m, 5H), 7.69 (d, J= 6.8 Hz, 1H), 7.78-7.45 (m, 3H), 7.32-7.27 (m, 2H), 7.11 (s, 1H), 4.60 (s, 2H), 4.22 (s, 2H), 2.65 (s, 3H), 2.57 (s, 3H).
Example 527
Synthesis of 5, 7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridin-5-
Figure imgf000601_0001
[1081] Synthesis of (5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)(naphthalen-2-yl)methanone.
A solution of aluminum trichloride (8.0 g, 60.0 mmol) in 1,2-di chloroethane (150 mL), was added 2-naphthoyl chloride (1) (1.9 g, 10.0 mmol) and stirred at room temperature until the solution became clear. 5-bromo-l 7-pyrrolo[2,3-Z>]pyridine (2) (1.9 g, 10.0 mmol) was added into the above mixture. The result mixture was stirred at room temperature for two hours. The mixture was diluted with methanol, concentrated to give a residue. The residue was dissolved in ethyl acetate, washed with potassium carbonate aqueous solution. The aqueous phase was added 1 M sodium hydroxide aqueous solution, quickly extracted with ethyl acetate. The combined organic phase was concentrated to give (5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)(naphthalen-2- yl) methanone (2.2 g crude, yield: 63%) as a yellow solid. ESI-MS [M +H]+: 353.0
[1082] Synthesis of (5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)(naphth(den-2-yl)methanol.
To a solution of (5-bromo-l//-pyrrolo[2,3-Z>]pyridin-3-yl)(naphthalen-2-yl)methanone (2.2 g, 6.2 mmol) in ethanol (300mL), was added sodium borohydride (3.5 g, 93.3 mmol) slowly. The mixture was stirred at room temperature for one and a half hour. The resulting mixture was concentrated and diluted with water, extracted with ethyl acetate for three times. The organic phases were washed with water, brine, dried over magnesium, and concentrated to afford (5- bromo-l//-pyrrolo[2,3-Z>]pyridin-3-yl) (naphthalen-2-yl)methanol (1.7 g, yield: 77%) as a yellow solid. ESI-MS [M +H]+: 353.1
[1083] Synthesis of 5-bromo-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridine. To a solution of (5-bromo-l//-pyrrolo[2,3-Z>]pyridin-3-yl)(naphthalen-2-yl)methanol (1.7 g, 4.8 mmol) in acetonitrile (200 m ) was added triethylsilane (5.6 g, 48.0 mmol), trifluoroacetic acid (5 ml). After stirring at room temperature for two hours, the resulting mixture was diluted with water and ethyl acetate. Separated the aqueous phase, neutralized with sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phases were washed with water, brine, dried over magnesium sulfate, and concentrated to give a crude of 5-bromo-3- (naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridine (1.7 g, crude) as a yellow solid. ESI-MS [M +H]+: 339.0
[1084] Synthesis of tert-butyl 5-bromo-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b] pyridine-l-carboxylate. To a solution of 5-bromo-3-(naphthalen-2-ylmethyl)-17/-pyrrolo[2,3- />]pyridine (1.6 g, 4.7mmol) in tetrahydrofuran (100 m ) was aded di-tert-butyl dicarbonate (1.5 g, 7.1mmol), triethylamine (0.95 g, 9.4 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol). The mixture was stirred at room temperature for one hour. The mixture was concentrated and purified by a silica gel column chromatography (light petrol : ethyl acetate = 30: 1) to afford tert- butyl 5-bromo-3-(naphthalen-2-ylmethyl)-l//-pyrrolo[2,3-Z>]pyridine-l -carboxylate (6) (460 mg, yield: 38%) as a yellow solid. ESI-MS [M +H]+: 437.1
[1085] Synthesis of tert-butyl 5-(((l-anuno-5, 7-dimethylisoquinolin-6-yl)niethyl) amino)-3- (naphthalen-2-ylniethyl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate. A solution of tert-butyl 5- bromo-3-(naphthalen-2-ylmethyl)- 17/-pyrrolo[2,3-b]pyridine-l-carboxylate (130mg, 0.29 mmol), 6-(aminomethyl)-5,7-dimethylisoquinolin-l -amine (7) (59mg, 0.29mmol) and cesium carbonate (189 mg, 0.58mmol) in N,N-dimethylformamide (2 mL) was degassed with nitrogen for five minutes. Catalyst Pd-peppsi (15 mg, 0.02 mmol) was added. The result mixture was heated to 110 °C for one and a half hour in a microwave reactor. The mixture was diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water, brine, and concentrated to give a residue which was purified by Prep-TLC (dichloromethane : methanol = 20: 1, ammonia) to get tert-butyl 5-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl) amino)-3-(naphthalen-2-ylmethyl)-l/7-pyrrolo[2,3-/>]pyridine- 1-carboxylate (30 mg, 19%) as a yellow solid. ESLMS [M +H]+: 559.3
[1086] Synthesis of 5, 7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridin- 5-yl)amino)methyl)isoquinolin-l-amine. To a solution of tert-butyl 5-(((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)amino)- 3-(naphthalen-2-ylmethyl)-17/-pyrrolo[2,3-Z>]pyridine- 1-carboxylate (30 mg, 0.05 mmol) in methanol (2 mL) was added a solution of hydrogen chloride in ether (5 mL) After stirring at room temperature for one hour, the reaction mixture was concentrated in vacuo and the residue was dissolved in sodium bicarbonate aqueous solution. The aqueous solution was extracted with ethyl acetate. The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to give the crude which was purified by Prep-TLC (dichloromethane : methanol = 10:1, ammonia) to afford 5,7-dimethyl-6- (((3-(naphthalen-2-ylmethyl)-l//-pyrrolo[2,3-Z>]pyridin-5-yl) amino)methyl)isoquinolin-l -amine (8 mg, 33%) as a yellow solid. ESLMS [M +H]+: 458.2 ’H NMR (400 MHz, DMSO-fifo) 5 10.96 (s, 1H), 7.91 (s, 1H), 7.83-7.80 (m, 5H), 7.75 (d, J= 6.0 Hz, 1H), 7.47-7.44 (m, 3H), 7.15 (d, J = 2.4 Hz, 2H), 6.99 (d, J= 3.6 Hz, 2H), 6.72 (m, 2H), 5.20 (s, 1H), 4.21 (d, J= 4.0 Hz, 2H), 4.16 (s, 2H), 2.50 (s, 3H), 2.43 (s, 3H). Example 528
Synthesis of 5, 7-diniethyl-6-(((l-(quinolin-6-ylnwthyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)isoquinolin-l-amine (1-528)
Figure imgf000604_0001
[1087] Synthesis of 6-bromoimidazo[l ,2-a]pyrazine-3-carbaldehyde. To a solution of 5- bromopyrazin-2-amine (15 g, 0.086 mol) in acetonitrile (200 mL) was added 2- bromomalonaldehyde (15.6 g, 0.10 mol). The mixture was stirred at refluxfor 4 hours under nitrogen atmosphere and then concentrated. The solid crude was washed by water, and purified by silica gel chromatograph (Petroleum ether : Ethyl acetate = 5: 1) to give 6-bromoimidazo[l,2- a]pyrazine-3-carbaldehyde (2.3 g, yield 12.5%) as a yellow solid. ESI-MS [M +H]+: 227.9
[1088] Synthesis of (6-bromoimidazo[l,2-a]pyrazin-3-yl)(naphthalen-2-yl)methanoi. To a solution of 6-bromoimidazo[l,2-a]pyrazine-3-carbaldehyde (2.2 g, 9.7 mmol) in tetrahydrofuran (20 mL) was added naphthalen-2-ylmagnesium bromide (19.5 mL, 9.7 mmol) under nitrogen atmosphere. The mixture was stirred at 50 °C overnight, then quenched by ammonium chloride solution, extracted with Ethyl acetate three times. The combined organic layer were washed with brine and dried. Upon removal of the solvent, the residue was purified by silica gel chromatograph (Petroleum ether : Ethyl acetate = 1 : 1) to give (6-bromoimidazo[l,2-cz]pyrazin-3- yl)(naphthalen-2-yl)methanol (1.3 g, yield 38%) as a yellow solid. ESI-MS [M +H]+: 355.9
[1089] Synthesis of 6-bromo-3-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyrazine. To a solution of (6-bromoimidazo[l,2-a]pyrazin-3-yl)(naphthalen-2-yl)methanol (1.3 g, 2.8 mmol) in acetonitrile (10 mL) was added tri ethylsilane (3 mL) and trifluoroacetic acid (3 mL) slowly. After stirring at 80 °C overnight, the reaction mixture was concentrated and diluted with sodium bicarbonate solution, extracted with ethyl acetate three times. The combined organic layers were washed with brine, and dried. Upon removal of the solvent, the residue was purified by silica gel chromatograph (Petroleum ether/Ethyl acetate = 1 : 1) to get 6-bromo-3 -(naphthal en-2- ylmethyl)imidazo[l,2-rz]pyrazine (220 mg, yield: 23%) as a yellow solid. ESI-MS [M +H]+: 339.9 ’H NMR (400 MHz, DMSO-t76) 8 8.93(s, 1 H), 8.80 (s, 1H), 7.89-7.83 (m, 3H), 7.79(s, 1H), 7.75 (s, 1H), 7.48-7.41 (m, 3H), 4.54 (s, 2H).
[1090] Synthesis of 5, 7-dimethyl-6-(((l-(quinolin-6-ylmethyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)isoquinolin-l-amine. To a solution of 6-bromo-3-(naphthalen-2- ylmethyl)imidazo[l,2-a]pyrazine (200 mg, 0.59 mmol) and 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (142 mg, 0.71 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (384 mg, 1.18 mmol). Then Pd-Peppsi (70 mg) was added to reaction solution under nitrogen atmosphere. The mixture was stirred under microwave irradiation at 110 °C for 3 hours. The reaction mixture was quenched by water, extracted with ethyl acetate three times. The combined organic layers were washed with brine, and dried. Upon removal of the solvent, the residue was purified by Prep-TLC (dichloromethane: methanol = 10: 1) to give 5,7- dimethyl-6-(((l-(quinolin-6-ylmethyl)-lH-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)isoquinolin- 1 -amine (50 mg, yield: 19%) as a yellow solid. ESI-MS [M +H]+: 459.1, ’H NMR (400 MHz, DMSO-t ) 8 8.76(s, 1H), 7.98-7.85 (d, J= 1.2 Hz, 1H), 7.87-7.81 (m, 3H), 7.79 (d, J= 4.0 Hz, 1H), 7.76-7.74 (d, J= 8.0 Hz, 1H), 7.58-7.57 (d, J= 4.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.03 (s, 3H), 5.95 (s, 1H), 4.44-4.38 (m, 4H), 2.34-2.31 (m, 6H).
Example 529
Synthesis of 6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4- yl)amino)methyl)-5, 7-diniethylisoquinolin-l-amine (1-529)
Figure imgf000605_0001
[1091] Synthesis of (6-chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methanol. NaBH-i (62.4 mg, 1.7 mmol) was added portion wise to a stirred solution of (6- chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanone (450 mg, 1.5 mol) (synthesis described in Example 404) in MeOH (10 mL) at 0 °C and stirred at 0 °C for 5 min. The reaction was then allowed to warm to room temperature and stirred for 30 min. The reaction was quenched with NH4Q (sat. aq., 10 mL) and extracted with EtOAc (3 x 15 mL). The combined organics were dried over MgSCU then concentrated in vacuo to give the title compound (450 mg) which was carried forward to the next step without further purification. 'H NMR (400 MHz, CDCh) 5 8.89 (d, J=1.0 Hz, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.90 (dd, J=1.8, 9.3 Hz, 1H), 6.00 (s, 1H), 5.49 - 5.49 (m, 1H), 0.97 - 0.91 (m, 2H), 0.66 - 0.60 (m, 2H).
[1092] Synthesis of 2-((6-chloropyrimidin-4-yl)fluoromethyl)-6-cyclopropylimidazo[l,2- ajpyridine. DAST (290 mg, 1.8 mmol) was added dropwise to a stirred solution of (6- chloropyrimidin-4-yl)(6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methanol (450 mg, 1.5 mmol) in DCM (5.0 mL) and the reaction was stirred at room temperature for 18 h. The reaction was poured over ice water (20 mL) and extracted with DCM (3 x 15 mL). The combined organics were dried over MgSOi then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-100 % EtOAc in cyclohexane to give the title compound (205 mg, 45%). ESLMS [M+H]+: 303, 'H NMR (400 MHz, CDCh) 5 8.92 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.64 (d, J=3.0 Hz, 1H), 7.49 (d, J=9.3 Hz, 1H), 6.96 (dd, J=1.8, 9.3 Hz, 1H), 6.61 (d, >47.1 Hz, 1H), 1.57 - 1.49 (m, 1H), 1.00 - 0.94 (m, 2H), 0.69 - 0.64 (m, 2H).
[1093] Synthesis of 6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-5,7-diniethylisoquinolin-l-amine. DIPEA (0.053 mL, 0.41 mmol) was added to a stirred solution of 2-((6-chloropyrimidin-4- yl)fluoromethyl)-6-cyclopropylimidazo[l,2-rz]pyridine (49 mg, 0.11 mmol) and 6- (aminomethyl)-5,7-dimethylisoquinolin-l-amine (36 mg, 0.18 mmol) in zPrOH (1.0 mL) and stirred at 80 °C for 18 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (33 mg, 44%). ESI-MS [M+H]+: 468, 'H NMR (400 MHz, DMSO) 8 8.55 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 8.01 (d, J=3.0 Hz, 1H), 7.90 (d, J=6.3 Hz, 1H), 7.78 (dd, J=4.0, 4.0 Hz, 1H), 7.54 (d, J=9.3 Hz, 1H), 7.17 - 7.12 (m, 2H), 6.91 (s, 1H), 6.81 (s, 2H), 6.53 (d, J=46.6 Hz, 1H), 4.80 (d, J=2.0 Hz, 2H), 2.68 (s, 3H), 2.10 - 2.01 (m, 1H), 1.08 - 1.02 (m, 2H), 0.83 - 0.77 (m, 2H), 3H obscured by DMSO peak.
Example 530
Synthesis of 6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-4-yl)amino)methyl)-5, 7- dimethylisoquinolin-l-amine (1-530)
Figure imgf000607_0001
[1094] Synthesis of (4-((lH-pyrazol-l-yl)methyl)phenyl)methanol. A mixture of 4-
(chloromethyl)benzyl alcohol (10.0 g, 63.9 mmol), pyrazole (5.42 g, 79.7 mmol), potassium carbonate (22.1 g, 160 mmol), and benzyltrimethylammonium iodide (1.78 g, 6.40 mmol) in acetonitrile (200 mL) was heated under reflux for 15.5 h. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (4 x 50 mL). The extracts were washed with a solution of copper sulphate pentahydrate (5 g in 20 mL water), 10% aqueous ammonia (20 mL), and brine (20 mL). The resulting organic solution was dried (MgSCh), filtered, and concentrated under reduced pressure. The residue was dissolved three times in dry dioxane (10 mL) and evaporated to remove residual water to give the title compound, which was used without further purification (9.47 g, 79%). ESI-MS [M-pyrazolyl]+: 121, ‘HNMR (400 MHz, (CDCh) 5 7.54 (d, J=1 Hz, 1H), 7.37 (d, J=2 Hz, 1H), 7.34 (d, J=8 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 6.28 (m, 1H), 5.31 (s, 2H), 4.68 (s, 2H).
[1095] Synthesis of 5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-3-chloropyridazine and 3-
((4-((lH-pyrazol-l-yl)niethyl)benzyl)oxy)-5-chloropyridazine. A solution of (4-(( 17/-pyrazol- l - yl)methyl)phenyl)methanol (4.49 g, 23.9 mmol) in anhydrous tetrahydrofuran (8 mL) was added via syringe over 20 min to a stirred suspension of sodium hydride (1.06 g, 60% oil dispersion, 26.5 mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogen with cooling using a cold water bath. After 15 min, 3,5-dichloropyridazine (4.46 g, 30.2 mmol) was added as a solid in portions over 10 min with ice-bath cooling. The mixture was stirred in the ice bath for 10 min and then warmed to room temperature. The mixture was stirred for 1.5 h at room temperature and quenched by the addition of aqueous citric acid (0.1 M) until pH 5 was reached. The tetrahydrofuran was removed under reduced pressure and the residue was partitioned between water (40 mL) and ethyl acetate (3 x 60 mL). The combined organic extracts were washed with water (50 mL). The organic phase was dried (MgSCL), fdtered, and concentrated under reduced pressure. The two regio-isomers were purified by column chromatography on silica gel eluting with a gradient of 45-66% ethyl acetate in heptane to afford 5-((4-((lH-pyrazol-l- yl)methyl)benzyl)oxy)-3-chloropyridazine as a pale yellow solid (1.984 g, 28%). TLC ethyl acetate: heptane = 2: 1 Rf = 0.24; 'HNMR (400 MHz, CDCh, ppm) 5 8.85 (d, J=2.4 Hz, 1H), 7.54 (d, J=1 Hz, 1H), 7.40 (d, 2 Hz, 1H), 7.35 (d, 8 Hz, 2H), 7.23 (d, 8 Hz, 2H), 6.95 (d, J=2.4 Hz, 1H), 6.28 (m, 1H), 5.34 (s, 2H), 5.12 (s, 2H).
[1096] 3-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-5-chloropyridazine was re-purified by column chromatography eluting with a gradient 0-5% methyl tert-butyl ether in dichloromethane over 10 column volumes (100 mL/min) to give two batches. One batch was isolated as a colourless solid (0.207 g, 3%) and the second as a pale yellow solid (0.470 g, 7%). TLC ethyl acetate: heptane = 2: 1 Rf = 0.44; 1H NMR (400 MHz, CDCh) 6 8.81 (d, J=2.4 Hz, 1H), 7.53 (br s, 1H), 7.43 (d, J=8 Hz, 2H), 7.37 (d, J=1.6 Hz, 1H), 7.21 (d, J=8 Hz, 2H), 7.02 (d, J=2 Hz, 1H), 6.27 (m, 1H), 5.54 (s, 2H), 5.32 (s, 2H).
[1097] Synthesis of 6-(((6-((4-((lH-pyrazoi-l-yl)methyl)benzyl)oxy)pyridazin-4- yl)amino)methyl)-5, 7-dimethylisoquinolin-l -amine. 3 -((4-(( 1 H-PyrazoL 1 - yl)methyl)benzyl)oxy)-5-chloropyridazine (121 mg, 0.400 mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (106 mg, 0.530 mmol), Pd-PEPPSI2Me-IPentcl (16.6 mg, 0.019 mmol), cesium carbonate (389 mg, 1.19 mmol), and 3,5-di-tert-butyl-4-hydroxytoluene (91 mg, 0.41 mmol) were placed in a vial and suspended in anhydrous dimethylformamide (0.4 mL). After bubbling nitrogen through the mixture for 2 min, the vial was sealed, and the mixture was heated at 75 °C for 90 min. The mixture was cooled to room temperature and suspended in 20: 1 di chloromethane: methanol + 1% acetic acid (1 mL) and passed through a silica gel plug, eluting with 5-20% methanol in dichloromethane + 1% acetic acid. The fractions were concentrated under reduced pressure and the residue treated with concentrated aqueous ammonia until pH 10. The solid was purified by reversed phase column chromatography eluting with a 30-65% acetonitrile in water containing 0.1% ammonia gradient to give the title compound, 6-(((6-((4- ((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-4-yl)amino)methyl)-5, 7-dimethylisoquinolin-l- amine as a colourless solid (35 mg, 19%). ESI-MS [M+H]+: 466, ’H NMR (400 MHz, DMSO) 8 8.35 (s, 1H), 7.94 (s, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.78 (d, J=6 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.23 (d, J=8 Hz, 2H), 7.00 (m, 2H), 6.65 (br s, 2H), 6.27 (m, 1H), 6.24 (d, J=1.6 Hz, 1H), 5.40 (s, 2H), 5.34 (s, 2H), 4.31 (d, J=3.6 Hz, 2H), 2.49 (s, 3H), 2.43 (s, 3H).
Example 531
[1098] Synthesis of 6-(((l-((3-chloroquinolin-6-yl)methyl)-lH- pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5, 7-dimethylisoquinolin-l -amine (J-531)
Figure imgf000609_0001
[1099] Synthesis of methyl 3-chloroquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (4.5g, 24.0mmol) and N-chlorosuccinimide (12.9 g, 96.0mmol) was dissolved in N,N-dimethylformamide (100 mL). Then the solution was heated to 120 °C with stirring overnight. After cooling, the reaction was quenched by water (100 mL) and extracted with ethyl acetate (50 mL x 4). The organic layer was washed with water (50 mL x 4), dried over anhydrous sodium sulphate, and evaporated under vacuum. The residue was purified by a silica gel column chromatography using light petrol: ethyl acetate (10: 1) as eluant to give the title compound as a yellow solid (2.3 g, 43%). ESLMS [M+H]+: 222.
[1100] Synthesis of (3-chloroquinolin-6-yl)methanol. To a cooled (0 °C) solution of methyl
3-chloroquinoline-6-carboxylate (1.0 g, 4.5 mmol) in tetrahydrofuran (20 mL) was added lithium aluminumhydride (1.8 mL, 2.5 N in THF, 4.5 mmol) slowly. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with sodium sulfate decahydrate. After stirring at room temperature for 30 minutes, the mixture was fdtered through a celite pad. The filtrate was concentrated, and the residue was purified by silica gel column chromatography using light petrol: ethyl acetate (3: 1) as eluant to give the title compound as a white solid (740 mg, 84%). ESI-MS [M+H]+: 194.
[1101] Synthesis of 3-chloro-6-(chloromethyl) quinoline. A solution of (3-chloroquinolin-6- yl)methanol (740 mg, 7.9 mmol) in thionyl chloride (5 mL) was stirred at room temperature for one hour. The resultant mixture was concentrated and the residue was diluted with dichloromethane (20 mL) washed with aqueous sodium bicarbonate. The organic phase was concentrated and purified by Prep-TLC (light petrol : ethyl acetate = 3 : 1) to give the title compound as a yellow solid (458 mg, 56%). ES MS [M+H]+: 212.
[1102] Synthesis of 6-((6-bronio-lH-pyrrolo[3,2-c]pyridin-l-yl)methyl)-3-chloroquinoline. A solution of 6-bromo-lH-pyrrolo[3,2-c]pyridine (500mg, 2.5 mmol) in N,N- dimethylformamide (10 mL), was added potassium carbonate (1.05 g, 7.6 mmol) slowly. After the mixture was stirred at room temperature for 30 minutes, 3-chloro-6-(chloromethyl)quinoline (538 mg, 2.5 mmol) was added. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with water and filtered. The solid was recrystallized from di chloromethane to give the title compound as a gray solid (800 mg, 84%). ESLMS [M+H]+: 372.
[1103] Synthesis of 6-(((l-((3-chloroquinolin-6-yl)methyl)-lH- pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5,7-diniethylisoquinolin-l-annne. A solution of 6-((6-bromo-lH-pyrrolo[3,2- c]pyridin-l-yl)methyl)-3 -chloroquinoline (100 mg, 0.27mmol), 6-(aminomethyl)-5,7- dimethylisoquinolin-1 -amine (54 mg, 0.27mmol), and cesium carbonate (264 mg, 0.81mmol) in N,N-dimethylformamide (2 mL) was degassed with nitrogen for five minutes. Pd-peppsi (30 mg, 0.03mmol) was then added. The resultant mixture was heated to 90 °C and stirred under nitrogen atmosphere for three hours. After cooling, the mixture was diluted with ethyl acetate, washed with water (x4), and then concentrated. The residue was purified by Prep-TLC (di chloromethane : methanol = 10: 1, ammonia) to give the title compound as a yellow solid (6.5 mg, 4.8%). ESI-MS [M+H]+: 493, 1H NMR (400 MHz, CD3OD) 6 8.78-8.77 (m, 1H), 8.39 (s, 1H), 8.30 (m, 1H), 8.03-7.99 (m, 2H), 7.62-7.56 (m, 3H), 7.29-7.27 (m, 2H), 6.62 (s, 2H), 5.54 (s, 2H), 4.59 (s, 2H), 2.61 (s, 3H), 2.56 (s, 3H).
Example 532
[1104] Synthesis of 6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)niethoxy)pyridin-4- yl)amino)methyi)-5, 7-dimethylisoquinolin-l-amine (1-532)
Figure imgf000611_0001
[1105] The title compound was prepared using a simillar method to that described for the synthesis of ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (see Example 274) starting from (6-cy cl opropylimidazo[l,2-a]pyri din-2 -yl)methanol and 4-chloro-2-fluoropyridine. ESI-MS [M+H]+: 456, 'H NMR (400 MHz, DMSO) 5 8.34 (s, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.79-7.76 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 2H), 6.73 (s, 1H), 6.51 (s, 1H), 6.37 (d, J = 4.0, 1H), 6.03 (s, 1H), 5.33 (s, 2H), 4.30 (d, J = 4.0 Hz, 2H), 2.50-2.45 (m, 6H), 1.95-1.91 (m, 1H), 0.95-0.90 (m, 2H), 0.70 - 0.66 (m, 2H).
Example 541
[1106] Inhibitory Activity of Exemplary Compounds against Plasma Kallikrein.
[1107] Compounds were evaluated for inhibition of the human activated kallikrein enzyme in two formats of an assay employing a fluorogenic peptide substrate. In one assay format, the concentrations of reagents were as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 500 pM activated kallikrein enzyme, 300 pM Pro- Phe-Arg-7-amido-4-methylcoumarin (PFR-AMC) substrate. Prior to reaction initiation with substrate, enzyme and inhibitors were preincubated for 30 min at room temperature. After initiation with substrate, reactions were incubated for 10 min at room temperature and fluorescence emission at 460 nm from 380 nm excitation measured with a microplate reader. In another assay format, the concentrations of reagents were as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 5 pM activated kallikrein enzyme, 300 uM PFR-AMC substrate. Prior to reaction initiation with substrate, enzyme and inhibitors were preincubated for 30 min at room temperature. After initiation with substrate, reactions were incubated for 18 hr at room temperature and fluorescence emission at 460 nm from 380 nm excitation measured with a microplate reader.
[1108] Table 35 provides the results of the assay in the format with 500 pM activated kallikrein assay. For the compounds listed in Table 35, the ECso values are reported according to the following ranges: A < 1.0 nM; 1.0 nM < B < 10 nM; 10 nM < C < 100 nM; 100 nM < D < 1000 nM; 1000 nM < E.
Table 35
Figure imgf000612_0001
Figure imgf000613_0001
Figure imgf000614_0001
Figure imgf000615_0001
Figure imgf000616_0001
Figure imgf000617_0001
Example 542
Neat human and rat plasma assay (Anorogenic peptide).
[1109] To analyze inhibition of plasma kallikrein in an ex vivo setting, the potency of compounds was measure in contact pathway-activated plasma assays. In a fluorogenic peptide substrate assay, test compounds dissolved in DMSO were added to sodium citrate collected human or rat plasma in a 96-well microplate. Alternatively, citrated plasma was collected from rats administered the compounds orally or by IV. 10 nM of human FXIIa (Enzyme Research Laboratories) diluted in PKa buffer (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 0.1% PEG-8000, and 0.1% Triton X-100) was added to the plasma, followed by the 100 pM of the profluorescent, synthetic plasma kallikrein substrate PFR-AMC (also diluted in PKa buffer). Final plasma concentration in the reaction was 78%. Fluorescence was immediately monitored by excitation/emission wavelengths of 360 nm/480 nm respectively over a period of 5 minutes in a microplate reader. The resulting linear increase in fluorescence emission (reflecting PKa proteolysis of PFR-AMC substrate) was fit to extract a proteolytic rate (fluorescent units over time), and this rate was subsequently plotted against compound inhibitor concentration. Resulting plots were fit to a standard 4-parameter IC50/IC90 equation to determine min/max values, IC50/90, and slope. All experimental steps were performed at room temperature. Table 36 provides results of the assay.
[1110] For the compounds listed in Table 36, the IC90 values are reported according to the following ranges: A < 1000 nM; 1000 nM < B < 5000 nM; 5000 nM < C.
Table 36
Figure imgf000618_0001
Figure imgf000619_0001
[HU] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of examples.

Claims

1. A compound of F ormul a (I) :
CyB_ L'— cy A— [_— Cyc
(I) or a pharmaceutically acceptable salt thereof, wherein:
CyA is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyA is substituted with 0-4 -RA groups; each RA is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, - SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur; each R is independently hydrogen or an optionally substituted C1-6 aliphatic group;
L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each Rz is independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group;
Figure imgf000620_0001
wherein: each of RB1 and RB2 is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;
RB3 is hydrogen or Ci-6 aliphatic;
RB4 is -N(RX)2; each Rx is independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic. wherein no more than one of RB1 or RB2 is hydrogen; or
Figure imgf000621_0001
wherein:
RB5 is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of RB6 and RB7 is independently hydrogen or an optionally substituted Ci-6 aliphatic;
L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
Cyc is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cyc is substituted with 0-6 -Lc-Rc groups; each Lc is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each Rc is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(0)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
2. The compound of claim 1, wherein the compound is of Formula (Il-a):
Figure imgf000622_0001
or a pharmaceutically acceptable salt thereof.
3. The compound of any one of claims claim 1-2, wherein the compound is of Formula (III- a), (Ill-b), (III-c), or (Ill-d):
Figure imgf000622_0002
or a pharmaceutically acceptable salt thereof.
4. The compound of any one of claims 1-2, wherein the compound is of Formula (III-a-1),
Figure imgf000623_0001
(III-a-3) or a pharmaceutically acceptable salt thereof.
5. The compound of any one of claims 1-3, wherein the compound is of Formula (III-b-1), (III-b-2), or (III-b-3):
Figure imgf000623_0002
(III-b-3) or a pharmaceutically acceptable salt thereof.
6. The compound of any one of claims 1-3, wherein the compound is of Formula (IV), (IV- a), (IV-b), or (IV-c):
Figure imgf000624_0001
(IV-b) (IV-c) or a pharmaceutically acceptable salt thereof
7. The compound of any one of claims 1-6, wherein the compound is of Formula (V-a), (V- b), or (V-c):
Figure imgf000624_0002
(V-c) or a pharmaceutically acceptable salt thereof
8. The compound of any one of claims 1-6, wherein the compound is of Formula (Vl-a), (Vl-b), or (VI-c):
Figure imgf000624_0003
(Vl-a) (Vl-b)
Figure imgf000625_0001
or a pharmaceutically acceptable salt thereof.
9. The compound of any one of claims 1-6, wherein the compound is of Formula (Vll-a), (Vn-b), or (VII-c):
Figure imgf000625_0002
or a pharmaceutically acceptable salt thereof.
10. The compound of any one of claims 1-6, wherein the compound is of Formula (Vlll-a),
(Vlll-b
Figure imgf000625_0003
(VIILa) (Vlll-b)
Figure imgf000626_0001
(VIII-c) or a pharmaceutically acceptable salt thereof.
11. The compound of any one of claims 1-6, wherein the compound is of Formula (IX-a),
Figure imgf000626_0002
(IX-c) or a pharmaceutically acceptable salt thereof.
12. The compound of any one of claims 1-6, wherein the compound is of Formula (X-a), (X- b), or (X-c):
Figure imgf000626_0003
or a pharmaceutically acceptable salt thereof.
13. The compound of any one of claims 1-6, wherein the compound is of Formula (Xl-a), (XLb), or (XI-c):
Figure imgf000627_0001
(XI-c) or a pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 1-6, wherein the compound is of Formula (Xll-a),
Figure imgf000627_0002
or a pharmaceutically acceptable salt thereof.
15. The compound of any one of claims 1-6, wherein the compound is of Formula (XIILa), (XIILb), or (XIII-c):
Figure imgf000627_0003
(XIILa) (Xlll-b)
Figure imgf000628_0001
or a pharmaceutically acceptable salt thereof.
16. The compound of any one of claims 1-6, wherein the compound is of Formula (XlV-a),
(XlV-b), or (XIV-c):
Figure imgf000628_0002
(XIV-c) or a pharmaceutically acceptable salt thereof.
17. The compound of any one of claims 1-6, wherein the compound is of Formula (XV-a), (XV-b), or (XV-c):
Figure imgf000628_0003
(XV-a)
Figure imgf000629_0001
(XV-c) or a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1-6, wherein the compound is of Formula (XVI-a),
(XVI-b), or (XVI-c):
Figure imgf000629_0002
(XVI-c) or a pharmaceutically acceptable salt thereof.
19. The compound of any one of claims 1-3, 5, or 7-18, wherein RB1 is hydrogen or Ci-6 aliphatic.
20. The compound of any one of claims 1-4 or 7-19, wherein RB2 is hydrogen, methyl, ethyl, ■CF. or .
21. The compound of any one of claims 1-3, 6, or 19-20, wherein RB3 is hydrogen or methyl.
22. The compound of any one of claims 1-6 or 19-20, wherein each Rx is hydrogen.
23. The compound of any one of claims 1-6 or 19-20, wherein one Rx is hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.
24. The compound of claim 1 or 2, wherein CyB is selected from the group consisting of:
Figure imgf000630_0001
25. The compound of claim 1, wherein the compound is of Formula (Il-b):
Figure imgf000631_0001
(Il-b) or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 or 25, wherein RB5 is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl.
27. The compound of any one of claims 1 or 25-26, wherein RB6 is an optionally substituted Ci-6 aliphatic.
28. The compound of any one of claims 1 or 25-27, wherein RB7 is Ci-6 aliphatic.
29. The compound of any one of claims 1-6 or 10-28, wherein CyAis selected from the group consisting of
Figure imgf000631_0002
Figure imgf000632_0001
wherein * represents the point of attachment to L’.
30. The compound of any one of claims 1-29, wherein each RAis independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.
31. The compound of any one of claims 1-9 or 12-30, wherein L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
32. The compound of any one of claims 1-9 or 12-31, wherein L’ is selected from the group consisting of:
Figure imgf000633_0001
and O , wherein # represents the point of attachment to CyB.
33. The compound of any one of claims 1-11 or 14-32, wherein L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, or -S-.
34. The compound of any one of claims 1-11 or 14-32, wherein L is selected from the group consisting of:
Figure imgf000633_0002
Figure imgf000634_0001
35. The compound of any one of claims 1-13, or 19-34, wherein Cyc is selected from the group consisting of:
Figure imgf000634_0002
36. The compound of any one of claims 1-13 or 19-34, wherein Cyc is selected from the group consisting of:
Figure imgf000634_0003
Figure imgf000635_0001
37. The compound of any one of claims 1-13 or 19-34, wherein Cyc is
Figure imgf000635_0002
38. The compound of any one of claims 1-37, wherein Lc is selected from the group consisting of: *-NH-, *-NCH3-, *-O-, *-CH2-, *-CH2C(CH3)2-, *-CH2CH2-, <CH2C(O)N(CH3)-, *-CH2C(O)N(CH3)CH2-, *-CF2-, *-CH(CH3)-, *-OCH2-, *-OCF2-, *-OC(CH3)2-, *-CH2C(O)-, *-OCH2C(O)-, *-CH2C(O)NH-,*-CH2C(O)NHCH2-,*-N(CH3)C(O)-, *-C(CH2CH3)-, *- C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cyc.
39. The compound of any one of claims 1-38, wherein each Rc is independently selected from oxo, halogen, -CN, -C(0)2R, -C(0)N(R)2, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
40. The compound of any one of the preceding claims, wherein the compound is selected from compounds 1-1 through 1-540, or a pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition comprising a compound of any one of the preceding claims.
42. The pharmaceutical composition comprising a compound of any one of the preceding claims, further comprising a pharmaceutically acceptable excipient.
43. A method of treating a plasma kallikrein-mediated disease or disorder using a compound or composition of any one of the preceding claims.
44. A method of treating hereditary angioedema comprising administering to a patient in need thereof a compound or composition of any one of the preceding claims.
45. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding claims.
PCT/US2023/032723 2022-09-15 2023-09-14 N-((isoquinolin-6-yl)methyl)-1h-pyrazole-4-carboxamid derivatives as plasma kallikrein inhibitors for the treatment of hereditary angioedema Ceased WO2024059186A1 (en)

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