EP4587014A2 - Antagonistes de c5ar1 et leurs utilisations - Google Patents

Antagonistes de c5ar1 et leurs utilisations

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Publication number
EP4587014A2
EP4587014A2 EP23866136.7A EP23866136A EP4587014A2 EP 4587014 A2 EP4587014 A2 EP 4587014A2 EP 23866136 A EP23866136 A EP 23866136A EP 4587014 A2 EP4587014 A2 EP 4587014A2
Authority
EP
European Patent Office
Prior art keywords
compound
optionally substituted
pharmaceutically acceptable
acceptable salt
certain embodiments
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23866136.7A
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German (de)
English (en)
Inventor
Kevin Hunt
Jianbin Zheng
Sida SHEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vanqua Bio Inc
Original Assignee
Vanqua Bio Inc
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Filing date
Publication date
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Publication of EP4587014A2 publication Critical patent/EP4587014A2/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • 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
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • 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

Definitions

  • C5aR1 e.g., IL-12
  • C5AR1 e.g., antagonists
  • These compounds provide new compositions and methods for the treatment of diseases associated with C5AR1 activity.
  • R 1 is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl
  • R 2 is an optionally substituted carbocyclyl or optionally substituted heterocyclyl
  • B 1 is –C(R 4 )t– or –N–, wherein t is 0 or 1 as valency permits
  • B 2 C(R 4 )–, –N–, or –C(O)–
  • Y is –C(R 5 ) 2 – or a bond
  • each R 3 is independently hydrogen
  • compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • methods of treating a disease or disorder in a subject in need thereof comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) to the subject.
  • the disease or disorder is associated with C5aR1 (e.g., C5aR1 activity).
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“ C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“ C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“ C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein.
  • the alkoxyalkyl moiety has 1 to 8 carbon atoms (“C 1-8 alkoxyalkyl”).
  • the alkoxyalkyl moiety has 1 to 6 carbon atoms (“C 1-6 alkoxyalkyl”).
  • the alkoxyalkyl moiety has 1 to 4 carbon atoms (“C 1-4 alkoxyalkyl”).
  • the alkoxyalkyl moiety has 1 to 3 carbon atoms (“C 1-3 alkoxyalkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms (“C 1-2 alkoxyalkyl”).
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group.
  • a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups.
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC 1-20 alkyl.
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkynyl”).
  • the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • the term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C8).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3-14 cycloalkyl.
  • the term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
  • Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole,
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • “Arylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • Heteroarylalkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • the term “unsaturated bond” refers to a double or triple bond.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • the term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • amino refers to the group ⁇ NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb ) 3 and ⁇ N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
  • sulfonyl refers to a group selected from –SO 2 N(R bb ) 2 , –SO 2 R aa , and –SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methyle
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanes
  • Ts p-toluenesulfonamide
  • Mtr 2,
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP
  • R 1 is , wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, -SF5, or –OR A ; and x is 0 or 1.
  • R 1 is , wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, alkyl, haloalkyl, optionally substituted cycloalkyl, -SF 5 , or –OR A ; R A is alkyl or haloalkyl; and x is 0 or 1.
  • R 1 is , wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently -F, -SF5, cyclopropyl, -CH 3 , -CF 3 , - CHF 2 , –CF 2 CH 3 , –CH 2 CF 3 , –CH 2 CHF 2 , -O-cyclopropyl, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CF 3 , – OCH 2 CHF 2 , –OCF 3 , or –OCHF 2 ; and x is 0 or 1.
  • R 1 is , wherein each R 6 is independently -F, -SF 5 , cyclopropyl, -CH 3 , -CF 3 , -CHF 2 , –CF 2 CH 3 , –CH 2 CF 3 , –CH 2 CHF 2 , -O-cyclopropyl, – OCH 3 , –OCH 2 CH 3 , –OCH 2 CF 3 , –OCF 3 , –OCH 2 CHF 2 , or –OCHF 2 ; and x is 0 or 1.
  • each R 6 is independently haloalkyl or optionally substituted cycloalkyl.
  • each R 6 is independently -F, - SF5, cyclopropyl, -CH 3 , -CF 3 , -CHF 2 , –CF 2 CH 3 , –CH 2 CF 3 , –CH 2 CHF 2 , -O-cyclopropyl, – OCH 3 , –OCH 2 CH 3 , –OCH 2 CF 3 , –OCH 2 CHF 2 , –OCF 3 , or –OCHF 2 .
  • R 1 is , wherein each R 6 is independently -F, -SF 5 , -CH 3 , -CF 3 , -CHF 2 , –OCH 2 CF 3 , –OCH 3 , –OCF 3 , or –OCHF 2 ; and x is 0 or 1.
  • R 1 is , wherein each R 6 is independently -F, -SF 5 , cyclopropyl, -CH 3 , -CF 3 , -CHF 2 , –CF 2 CH 3 , –CH 2 CF 3 , –CH 2 CHF 2 , -O-cyclopropyl, – OCH 3 , –OCH 2 CH 3 , –OCH 2 CF 3 , –OCH 2 CHF 2 , –OCF 3 , or –OCHF 2 ; and x is 0 or 1.
  • R 1 is , wherein each R 6 is independently -F, -SF5, -CH 3 , -CF 3 , -CHF 2 , –OCH 2 CF 3 , –OCH 3 , –OCF 3 , or –OCHF 2 ; and x is 0 or 1.
  • R 1 is , wherein each R 6 is independently cyclopropyl, -CF 3 , –CF 2 CH 3 , or –CH 2 CF 3 ; and x is 0 or 1.
  • R 1 is or [00132] In certain embodiments, R 1 is In certain embodimen 1 ts, R is In certain embodiments, R 1 is In certain embodiments, R 1 is [00133] In certain embodiments, R 1 is optionally substituted carbocyclyl. In certain embodiments, R 1 is optionally substituted carbocyclyl, wherein the carbocyclyl is fused with a heteroaryl ring. In certain embodiments, R 1 is optionally substituted C 8-14 carbocyclyl, wherein the carbocyclyl is fused with a heteroaryl ring.
  • R 1 is In certain embodiments, R 1 is [00134] In certain embodiments, R 1 is , , , , , , , [00135] In certain embodiments, R 1 is , , , R 2 [00136] As described herein, R 2 is an optionally substituted carbocyclyl or optionally substituted heterocyclyl. In certain embodiments, R 2 is optionally substituted carbocyclyl. In certain embodiments, R 2 is optionally substituted cycloalkyl. In certain embodiments, R 2 is optionally substituted C 3-8 cycloalkyl. In certain embodiments, R 2 is optionally substituted C 3- 6 cycloalkyl.
  • R 2 is , wherein each R 7 is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • R 2 is , wherein each R 7 is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • R 2 is , wherein each R 7 is independently optionally substituted aryl or optionally substituted heteroaryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • R 2 is , wherein each R 7 is independently optionally substituted aryl or optionally substituted heteroaryl; and y is 1.
  • R 2 is , wherein each R 7 is independently optionally substituted aryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • R 2 is , wherein each R 7 is independently optionally substituted aryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 1 or 2.
  • R 2 is , wherein each R 7 is independently optionally substituted heteroaryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 1 or 2.
  • R 2 is , wherein R 7 is optionally substituted aryl; and y is 1.
  • R 2 is , wherein R 7 is substituted aryl; and y is 1.
  • R 2 is , wherein R 7 is substituted phenyl; and y is 1.
  • R 2 is , wherein R 7 is optionally substituted heteroaryl; and y is 1. [00148] In certain embodiments, R 2 is , wherein R 7 is substituted heteroaryl; and y is 1. [00149] In certain embodiments, R 2 is , wherein R 7 is substituted pyridine, substituted thiazole, substituted isothiazole, substituted substituted pyrazole, or substituted indazole; and y is 1. [00150] In certain embodiments, R 2 is .
  • R 2 is , wherein two instances of R 7 together with the atoms to which they are attached form a substituted azetidine; and y is 2.
  • R 2 is wherein each R 7 is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • R 2 is wherein R 7 is optionally substituted aryl; and y is 1.
  • each R 3 is independently hydrogen or optionally substituted alkyl. In certain embodiments, each R 3 is independently hydrogen or substituted alkyl. In certain embodiments, each R 3 is independently hydrogen or haloalkyl. In certain embodiments, each R 3 is independently hydrogen, -CHF 2 , -CF 3 , –CH 2 CF 3 , –CF 2 CH 3 , or – CH 2 CF 2 H. In certain embodiments, each R 3 is independently hydrogen or -CHF 2 . In certain embodiments, each R 3 is independently hydrogen or -CF 3 . In certain embodiments, each R 3 is independently hydrogen or –CH 2 CF 3 . In certain embodiments, each R 3 is independently hydrogen or –CF 2 CH 3 .
  • each R 3 is independently hydrogen or – CH 2 CF 2 H.
  • each R 3 is independently hydrogen, –OCH 3 , –OCH 2 CH 3 , - CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 . -CHF 2 , -CF 3 , –CH 2 CF 3 , –CF 2 CH 3 , or –CH 2 CF 2 H.
  • a 1 N–.
  • a 1 C(R 3 )–.
  • a 1 C(R 3 )–; wherein R 3 is independently hydrogen, optionally substituted alkyl, or –OR A .
  • a 4 C(R 3 )–.
  • a 4 C(R 3 )–; wherein R 3 is independently hydrogen, optionally substituted alkyl, or –OR A .
  • a 4 C(R 3 )–; wherein R 3 is independently hydrogen, unsubstituted alkyl, or –OR A ; and R A is unsubstituted alkyl.
  • a 4 C(R 3 )–; wherein R 3 is independently hydrogen, -CH 3 , –OCH 3 , or –OCH 2 CH 3 .
  • a 4 C(R 3 )–; wherein R 3 is hydrogen, –OCH 3 , – OCH 2 CH 3 , -CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 .
  • each occurrence of R A is, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom.
  • each occurrence of R A is, independently, hydrogen, or optionally substituted alkyl.
  • each occurrence of R A is, independently, hydrogen or unsubstituted alkyl.
  • R A is hydrogen.
  • each occurrence of R A is, independently, haloalkyl or unsubstituted alkyl.
  • each occurrence of R A is, independently, haloalkyl.
  • each occurrence of R A is, independently, unsubstituted alkyl. In certain embodiments, each R A is independently C 1-4 haloalkyl or unsubstituted C 1-4 alkyl. In certain embodiments, each R A is independently C 1-4 haloalkyl. In certain embodiments, each R A is independently unsubstituted C 1-4 alkyl. In certain embodiments, each R A is independently -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CH 3 , or -CH 3 . In certain embodiments, each R A is independently -CF 3 . In certain embodiments, each R A is independently -CH 3 .
  • the compound of Formula (I) is of Formula (I-a-8): (I-a-8), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –OR A ; x is 0, 1, 2, or 3; and R 3 and R 4 are as defined herein.
  • Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, or –OR A ; and x is 0, 1, 2, or 3.
  • the compound of Formula (I) is of Formula (I-a-9): (I-a-9), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –OR A ; x is 0, 1, 2, or 3; and R 3 and R 4 are as defined herein.
  • each R 7 is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • the compound of Formula (I) is of Formula (I-a-11): (I-a-11), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –OR A ; x is 0, 1, 2, or 3; each R 7 is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; y is 0, 1, or 2; and R 3 and R 4 are as defined herein.
  • the compound of Formula (I) is of Formula (I-e-1): (I-e-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , Y, R 2 , and R 3 are as defined herein.
  • the compound of Formula (I) is of Formula (I-e-2): (I-e-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , and R 3 are as defined herein.
  • the compound of Formula (I) is of Formula (I-e-4): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –OR A ; x is 0, 1, 2, or 3; R 8 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and R 3 and R 4 are as defined herein.
  • Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, or –OR A ; x is 0, 1, 2, or 3; and R 8 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, or –OR A ; x is 0, 1, 2, or 3; each R 7 is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or – OR A ; x is 0, 1, 2, or 3; each R 7 is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.
  • the compound of Formula (I) is of Formula (I-f): (I-f), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , Y, R 2 , R 3 , and R 4 are as defined herein.
  • the compound of Formula (I) is of Formula (I-g): (I-g), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , Y, R 2 , R 3 , and R 4 are as defined herein.
  • the compound of Formula (I) is of Formula (I-h): (I-h), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , Y, R 2 , R 3 , and R 4 are as defined herein.
  • the compound of Formula (I) is of Formula (I-h-1): (I-h-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , Y, R 2 , and R 3 are as defined herein.
  • the compound of Formula (I) is of Formula (I-a-4): (I-a-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –OR A ; x is 0, 1, 2, or 3; R 8 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and R 3 and R 4 are as defined herein.
  • the compound of Formula (I) is of Formula (I-a-7): (I-a-7), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein each R 7 is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2; and Y, R 1 , R 3 , and R 4 are as defined herein.
  • the compound of Formula (I) is of Formula (I-a-8): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –OR A ; x is 0, 1, 2, or 3; each R 7 is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R 7 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; y is 0, 1, or 2; and R 3 and R 4 are as defined herein.
  • the compound of Formula (I) is of Formula (I-a-9): (I-a-9), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z 1 and Z 2 are each independently CH, CR 6 , or N; each R 6 is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –OR A ; x is 0, 1, 2, or 3; and R 3 and R 4 are as defined herein.
  • the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
  • the provided compounds inhibit C5aR1 with an IC 50 of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
  • compositions comprising a disclosed compound (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable salt e.g., a compound of Formula (I)
  • the pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the effective amount is an amount effective for treating cancer, an infectious disease, an autoimmune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a cerebrovascular disease or disorder, a vasculitis disease or disorder, or a neurodegenerative disease or disorder. In certain embodiments, the effective amount is an amount effective for treating an autoimmune, inflammatory, or neurological disease or disorder. In certain embodiments, the effective amount is an amount effective for treating a neurological disease or disorder in a subject in need thereof.
  • the effective amount is an amount effective for antagonizing C5aR1 in a subject, tissue, biological sample, or cell.
  • the subject being treated or administered a compound described herein is an animal. The animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human.
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) C5aR1 for use in treating a C5aR1-related disease or disorder in a subject in need thereof.
  • the present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., antagonizes) C5aR1 for use in treating a disease or disorder associated with aberrant activity of C5aR1 in a subject in need thereof.
  • the present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., antagonizes) C5aR1 for use in treating a disease or disorder associated with mutated C5aR1 in a subject in need thereof.
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • the therapy employed may achieve a desired effect for the
  • the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • polyoxyethylene sorbitan monolaurate Tween 20
  • polyoxyethylene sorbitan Tween 60
  • polyoxyethylene sorbitan monooleate Tween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene esters e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol
  • sucrose fatty acid esters e.g.
  • CremophorTM polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • polyoxyethylene ethers e.g. polyoxyethylene lauryl ether (Brij 30)
  • poly(vinyl-pyrrolidone) diethylene glycol monolaurate
  • triethanolamine oleate sodium oleate
  • potassium oleate ethyl oleate
  • oleic acid ethyl laurate
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • an effective amount of a compound of the disclosure may be administered to a patient at risk for myocardial infarction or thrombosis (i.e., a patient who has one or more recognized risk factor for myocardial infarction or thrombosis, such as, but not limited to, obesity, smoking, high blood pressure, hypercholesterolemia, previous or genetic history of myocardial infarction or thrombosis) in order reduce the risk of myocardial infarction or thrombosis.
  • the compounds of the present disclosure are useful in the treatment of cisplatin induced nephrotoxicity.
  • the disease or disorder is selected from the group consisting of neutropenia, neutrophilia, C3-glomerulopathy, C3-glomerulonephritis, dense deposit disease, membranoproliferative glomerulonephritis, Kawasaki disease, sepsis, septic shock, Hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS), Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, chronic obstructive pulmonary disorder, inflammation associated with burns, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, Uveitis, tissue graft rejection, hyperacute rejection of transplanted organs, myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, polypoidal
  • the disease or disorder is selected from the group consisting of melanoma, lung cancer, lymphoma, sarcoma, carcinoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma
  • the disease or disorder is selected from the group consisting of glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymus neo
  • the application provides a method of treating cancer, an infectious disease, an autoimmune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a cerebrovascular disease or disorder, a vasculitis disease or disorder, or a neurodegenerative disease or disorder.
  • the application provides a method of treating an autoimmune, inflammatory, or neurological disease or disorder.
  • the application provides a method of treating a neurological disease or disorder.
  • the present disclosure provides a method of antagonizing C5aR1.
  • the present disclosure provides a method of decreasing the activity of C5aR1.
  • Step 1 tert-butyl 4-(5-((3-methoxypyrazin-2-yl)methyl)-8-methyl-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1- carboxylate 140 mg, 0.406 mmol, 1 equiv
  • 2-(bromomethyl)-3-methoxypyrazine 98 mg, 0.487 mmol
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-5,6- dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 100 mg, 0.303 mmol, 1 equiv) and 1-(bromomethyl)-2-(2,2,2-trifluoroethoxy)benzene (89.5 mg, 0.333 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((3-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)-5,6-dihydro
  • Step 3 5-(2-fluorobenzyl)-8-methyl-7-(1-(2-(trifluoromethyl)phenyl)piperidin-4- yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 5-(2-fluorobenzyl)- 8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one 70 mg, 0.199 mmol, 1 equiv
  • 1-bromo-2-(trifluoromethyl)benzene 53.6 mg, 0.239 mmol, 1.2 equiv
  • Step 1 tert-butyl 4-(6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6- oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 210 mg, 0.636 mmol, 1 equiv) and 1-(bromomethyl)-2-(trifluoromethyl)benzene (229 mg, 0.954 mmol, 1.5 equiv) as the starting materials to
  • Step 1 tert-butyl 4-(5-(2-fluorobenzyl)-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 210 mg, 0.636 mmol, 1 equiv
  • 1-(bromomethyl)-2-fluorobenzene 180 mg, 0.954 mmol, 1.5 equiv
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 45 mg, 0.136 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (49.2 mg, 0.204
  • Step 2 tert-butyl 4-(6-oxo-5-((2-(trifluoromethyl)pyridin-3-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 100 mg, 0.302 mmol, 1 equiv) and 3-(chloromethyl)-2-(trifluoromethyl)pyridine (88.8 mg, 0.453 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((2- (trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydr
  • Step 2 7-(piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((5- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one(60 mg, 0.154 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (32 mg, 0.169 mmol, 1.1 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-((5-(trifluoromethyl)pyridin-2-yl)
  • Step 1 tert-butyl 4-(6-oxo-5-((4-(trifluoromethyl)pyridin-3-yl)methyl)-5,6- dihydropyrido[2,3-b] pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b] pyrazine-7-yl)piperidine-1-carboxylate 100 mg, 0.303 mmol, 1 equiv) and (4-(trifluoromethyl)pyridin-3-yl)methanol (58.9 mg
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-4-yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-((3-(trifluoromethyl) pyridin-4-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (50 mg, 0.128 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (29.1 mg, 0.154 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyri
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 50 mg, 0.151 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrogen bromide (48.5 mg, 0.151
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)me-thyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)me-thyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoromethyl)phenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)me-thyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoromethyl)phenyl)piperidin-4-y
  • Step 5 8-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 8-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 8-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • tert-butyl 4- (8-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl
  • Step 2 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate 60 mg, 0.181 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (65.4 mg, 0.271 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)-5,6-di
  • Step 3 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate 100 mg, 0.290 mmol, 1 equiv
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 (5-(trifluoromethyl)pyrazin-2-yl)methanol:
  • 2-chloro-5-(trifluoromethyl)pyrazine 500 mg, 2.73 mmol, 1 equiv
  • (tributylstannyl)methanol 1055 mg, 3.28 mmol, 1.2 equiv
  • MS m/z 179 [M+H] + .
  • Step 2 (5-(trifluoromethyl)pyrazin-2-yl)methyl methanesulfonate:
  • 5-(trifluoromethyl)pyrazin-2-yl)methanol 100 mg, 0.561 mmol, 1 equiv
  • MsCl 96.4 mg, 0.842 mmol, 1.5 equiv
  • MS m/z 257 [M+H] + .
  • Step 4 7-(piperidin-4-yl)-5-((5-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 4 7-(piperidin-4-yl)-5-((5-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 4 7-(piperidin-4-yl)-5-((5-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((5- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 7-(piperidin-4-yl)-5-((5-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((5- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((5-(trifluoromethyl)pyrazin-2-yl
  • Step 1 tert-butyl 4-(7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1- carboxylate:
  • tert-butyl 4-(2-methoxy-2- oxoethyl)piperidine-1-carboxylate 752 mg, 2.92 mmol, 1.2 equiv
  • 4-aminopyrimidine-5- carbaldehyde 300 mg, 2.43 mmol, 1 equiv
  • Step 3 6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one:
  • Step 3 6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one:
  • Step 3 6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 4 6-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • 6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- d]pyrimidin-7(8H)-one (30 mg, 0.091 mmol, 1 equiv) and 2-bromo-1-fluoro-3- methylbenzene (32.8 mg, 0.137 mmol, 1.5 equiv) as the starting materials to give 6-(1-(2- fluoro-6-methylphenyl)piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2- yl)methyl
  • Step 1 tert-butyl 4-(5-(2-fluorobenzyl)-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 60 mg, 0.182 mmol, 1 equiv
  • 1-(bromomethyl)-2-fluorobenzene (51.4 mg, 0.273 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(5-(2-fluorobenzyl)-6-oxo-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate (70 mg, 87%) as a light yellow solid
  • Step 2 5-(2-fluorobenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 5-(2-fluorobenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 5-(2-fluorobenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 5-(2-fluorobenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(2- fluorobenzyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(2- fluorobenzyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(2- fluorobenzyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)quinazoline-2,4(1H,3H)- dione:
  • 2-amino-N-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)benzamide 70 mg, 0.214 mmol, 1 equiv
  • 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)quinazoline-2,4(1H,3H)-dione 60 mg, 79%) as a yellow oil.
  • Step 4 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-1-((3- (trifluoromethyl)pyridin-2-yl)methyl)quinazoline-2,4(1H,3H)-dione:
  • 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)quinazoline-2,4(1H,3H)- dione 60 mg, 0.17 mmol, 1 equiv
  • 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrobromide 59.9 mg, 0.187 mmol, 1.1 equiv) as the starting materials to give 3-(1-(2- fluoro-6-methylphenyl)piperidin-4-yl)-1-((3-(trifluoromethyl)pyridin-2- yl)methyl)quinazoline-2,4(1H,3H)-dione (21.9 mg
  • Step 2 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)pteridine-2,4(1H,3H)-dione
  • Step 2 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)pteridine-2,4(1H,3H)-dione
  • 3-amino-N-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)pyrazine-2-carboxamide 100 mg, 0.304 mmol, 1 equiv) as the starting material to give 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)pteridine-2,4(1H,3H)- dione (40 mg, 37%) as a white solid.
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 tert-butyl 4-(6-oxo-5-(5,6,7,8-tetrahydroquinolin-8-yl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 300 mg, 0.908 mmol, 1 equiv) and 8-chloro-5,6,7,8-tetrahydroquinoline (197 mg, 1.18 mmol, 1.3 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-(5,6,7,8-tetrahydroquinolin-8- yl)-5,6-dihydropyr
  • Step 1 tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one 35 mg, 0.087 mmol, 1 equiv
  • 3-bromo-5- fluoro-2-methylpyridine (19.6 mg, 0.104 mmol, 1.2
  • Step 1 3-amino-N-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)pyrazine-2- carboxamide:
  • 3-aminopyrazine-2-carboxylic acid 100 mg, 0.719 mmol, 1 equiv
  • 1-(2-fluoro-6-methylphenyl)piperidin-4-amine hydrochloride 176 mg, 0.719 mmol, 1 equiv
  • 3-amino-N-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)pyrazine-2-carboxamide 140 mg, 59%) as a yellow oil
  • Step 2 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)pteridine-2,4(1H,3H)-dione:
  • 2-amino-N-(1-(2-fluoro-6-methylphenyl)piperidin-4- yl)benzamide 140 mg, 0.425 mmol, 1.00 equiv
  • the crude product 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)pteridine-2,4(1H,3H)-dione (60 mg, 39%) as a yellow oil.
  • Step 3 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-1-((3- (trifluoromethyl)pyridin-2-yl)methyl)pteridine-2,4(1H,3H)-dione:
  • 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)pteridine-2,4(1H,3H)-dione 60 mg, 0.169 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrobromide (59.6 mg, 0.186 mmol, 1.1 equiv) as the starting materials to give 3-(1-(2- fluoro-6-methylphenyl)piperidin-4-yl)-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)pteridine- 2,4(
  • Step 2 tert-butyl 4-(6-oxo-5-(5,6,7,8-tetrahydroquinoxalin-5-yl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • 5-bromo-5,6,7,8-tetrahydroquinoxaline 300 mg, 0.908 mmol, 1 equiv
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 232 mg, 1.09 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-(5,6,7,8- tetrahydroquinoxalin-5-yl)-5,6-
  • Step 4 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(5,6,7,8- tetrahydroquinoxalin-5-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinoxalin-5-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 2-bromo-1-fluoro-3-methylbenzene 156 mg, 0.828 mmol, 1.5 equiv
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 60 mg, 0.182 mmol, 1 equiv) and 2-(bromomethyl)-3
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one 50 mg, 0.128 mmol, 1 equiv) and 3-bromo-5-fluoro-2-methylpyridine (26.7 mg, 0.141 mmol, 1.1 equiv) as the starting materials to give 7-(1-(5-fluoro-2- methylpyridin-3-yl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 3-amino-N-methoxy-N-methylpyrazine-2-carboxamide:
  • 3-aminopyrazine-2-carboxylic acid 300 mg, 2.15 mmol, 1 equiv
  • N,O-dimethylhydroxylamine 197 mg, 3.23 mmol, 1.5 equiv
  • 3-amino-N-methoxy-N-methylpyrazine-2-carboxamide 320 mg, 81.4%) as an off- white solid.
  • Step 3 tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate:
  • tert-butyl 4-(2-methoxy-2- oxoethyl)piperidine-1-carboxylate 501 mg, 1.94 mmol, 1.2 equiv
  • 3-amino-5- methylpyrazine-2-carbaldehyde 200 mg, 1.62 mmol, 1 equiv
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 300 mg, 55%) as a light brown solid.
  • Step 4 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 90 mg, 0.272 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (98.4 mg, 0.408 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-
  • Step 6 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 6 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 6 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 3-bromo-5- fluoro-2-methylpyridine (26.2 mg, 0.138
  • Step 1 benzyl 4-(4-(2-(difluoromethoxy)benzyl)-3-oxo-3,4-dihydropyrazino[2,3- b]pyrazin-2-yl)piperidine-1-carboxylate:
  • benzyl 4-(3- oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)piperidine-1-carboxylate 120 mg, 0.328 mmol, 1 equiv
  • 1-(bromomethyl)-2-(difluoromethoxy)benzene 116 mg, 0.492 mmol, 1.5 equiv
  • Step 1 tert-butyl 4-(2-methyl-7-oxo-8-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)piperidine-1-carboxylate 80 mg, 0.232 mmol, 1 equiv) and 2-(bromomethyl)-3- (trifluoromethyl)pyrazine (61.5 mg, 0.255 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(2-methyl-7-oxo-8-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-7,8- dihydropyrido[2,3
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 tert-butyl 3-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)azetidine-1-carboxylate:
  • Step 2 tert-butyl 3-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)azetidine-1-carboxylate:
  • 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrobromide (234 mg, 0.728 mmol, 1 equiv) as the starting material to give tert-butyl 3-(6-oxo-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)-5,6-dihydropyrido[2,3-b
  • Step 4 7-(1-(2-fluoro-6-methylphenyl)azetidin-3-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(azetidin-3-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • 2-bromo-1-fluoro-3-methylbenzene (43.9 mg, 0.233 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)azetidin-3-yl)-5-((3-(trifluoromethyl)
  • Step 4 7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinolin-5-yl)pyrido[2,3-b]pyrazin- 6(5H)-one:
  • Step 4 7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinolin-5-yl)pyrido[2,3-b]pyrazin- 6(5H)-one:
  • Step 4 7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinolin-5-yl)pyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (470 mg, 1.01 mmol, 1 equiv) as the starting material to give the crude product 7-(piperidin-4-yl)- 5-(5,6,7,8-tetrahydroquinolin-5-yl)pyrido[2,3-b]pyrazin-6(5
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(5,6,7,8- tetrahydroquinolin-5-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(5,6,7,8- tetrahydroquinolin-5-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 2-bromo-1-fluoro-3-methylbenzene 94.1 mg, 0.498 mmol, 1.5 equiv
  • Step 2 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-7-methylpteridine- 2,4(1H,3H)-dione:
  • 3-amino-N-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-methylpyrazine-2-carboxamide 150 mg, 0.437 mmol, 1 equiv
  • the crude product 3-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-7-methylpteridine-2,4(1H,3H)-dione (40 mg) as a white solid.
  • Step 2 tert-butyl 4-(2-ethoxy-7-oxo-8-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-ethoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)piperidine-1-carboxylate 90 mg, 0.240 mmol, 1 equiv) and 2-(bromomethyl)-3- (trifluoromethyl)pyrazine (63.7 mg, 0.264 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(2-ethoxy-7-oxo-8-((3-(trifluoromethyl)pyra
  • Step 4 2-ethoxy-6-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-((3- (trifluoromethyl) pyrazin-2-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • 2-ethoxy-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one 50 mg, 0.106 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (22 mg, 0.117 mmol, 1.1 equiv) as the starting materials to give 2- ethoxy-6-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-((3-
  • Step 2 3-amino-5-methylpyrazine-2-carbaldehyde:
  • 3-amino-N-methoxy-N,5-dimethylpyrazine-2-carboxamide (320 mg, 1.63 mmol, 1 equiv) as the starting material to give 3-amino-5-methylpyrazine-2-carbaldehyde (200 mg, 89%) as a yellow solid.
  • Step 3 tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-methoxy-2- oxoethyl)piperazine-1-carboxylate (452 mg, 1.75 mmol, 1.2 equiv) and 3-amino-5- methylpyrazine-2-carbaldehyde (200 mg, 1.45 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (320 mg, 63%) as a light brown solid.
  • Step 5 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 6 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one
  • Step 6 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one
  • 3-bromo-5-fluoro-2-methylpyridine (25.3 mg, 0.133 mmol, 1.2 equiv) as the starting materials to give 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5
  • Step 1 tert-butyl4-(6-oxo-5-(1,2,3,4-tetrahydronaphthalen-1-yl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl) piperidine-1-carboxylate:
  • Step 2 7-(piperidin-4-yl)-5-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-(1,2,3,4-t
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(1,2,3,4- tetrahydronaphthalen-1-yl) pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 2-bromo-1-fluoro-3-methylbenzene (74.2 mg, 0.392 mmol, 1.20 equiv) as the starting materials to give the crude product 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-(1,2,3,4-tetrahydronaphthalen
  • Step 2 3-amino-5-methoxypyrazine-2-carbaldehyde:
  • 3-amino-N,5-dimethoxy-N-methylpyrazine-2-carboxamide(245 mg, 1.15 mmol, 1 equiv) as the starting material to give 3-amino-5-methoxypyrazine-2-carbaldehyde (132 mg, 74%) as a yellow solid.
  • Step 3 tert-butyl 4-(3-methoxy-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate:
  • 3-amino-5- methoxypyrazine-2-carbaldehyde 132 mg, 0.862 mmol, 1 equiv
  • tert-butyl 4-(2- methoxy-2-oxoethyl)piperidine-1-carboxylate (266 mg, 1.03 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1- carboxylate (80 mg, 26%) as a yellow solid.
  • Step 4 tert-butyl 4-(3-methoxy-6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • Step 5 3-methoxy-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 3-methoxy-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 3-methoxy-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 6 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methoxy-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 6 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methoxy-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 6 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methoxy-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(2-bromo-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-methoxy-2- oxoethyl)piperidine-1-carboxylate (382 mg, 1.48 mmol, 1.5 equiv) and 3-amino-6- bromopyrazine-2-carbaldehyde (200 mg, 0.99 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(2-bromo-6-oxo-5,6-
  • Step 2 tert-butyl 4-(2-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-bromo-6- oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 40 mg, 0.098 mmol, 1 equiv
  • methylboronic acid 8.78 mg, 0.147 mmol, 1.5 equiv
  • Step 3 tert-butyl 4-(2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (30 mg, 0.087 mmol, 1 equiv) and 1-(bromomethyl)-2-(trifluoromethyl)benzene (22.9 mg, 0.096 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(2-methyl-6- oxo-5-(2-(trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3-
  • Step 4 2-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one hydrochloride:
  • 2-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one hydrochloride followsed general procedure F using tert-butyl 4-(2- methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine- 1-carboxylate (30 mg, 0.06 mmol, 1 equiv) as the starting material to give the crude product 2-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-2-methyl-5-(2- (trifluoromethyl)-benzyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 2-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)-pyrido[2,3-b]pyrazin-6(5H)- one (20 mg, 0.05 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (10.3 mg, 0.055 mmol, 1.1 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4- yl)-2-methyl-5-(2-(trifluoromethyl)benzyl)pyrido-[2,3-b]
  • Step 1 tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one hydrochloride:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one hydrochloride:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one hydrochloride:
  • Step 3 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)-pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)-pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one hydrochloride (30 mg, 0.074 mmol, 1 equiv) and 3-bromo-5-fluoro-2-methylpyridine (15.5 mg, 0.081 mmol, 1.1 equiv) as the starting materials to give 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)
  • Step 1 tert-butyl 4-(8-methyl-6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate 100 mg, 0.29 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrobro
  • Step 1 tert-butyl 4-(3-methoxy-6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • Step 2 tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate:
  • Step 3 3-methyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 3-methyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperazine-1-carboxylate (70 mg, 0.139 mmol, 1 equiv) as the starting material to give the crude product 3-methyl-7-(piperazin-1-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyr
  • Step 4 7-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-1-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-1-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(5-fluoro-2-methylpyridin-3-yl)piperazin-1-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 200 mg, 0.605 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine (145 mg,
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-
  • Step 3 5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-7-(1-(4- (trifluoromethyl)pyridin-3-yl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-7-(1-(4- (trifluoromethyl)pyridin-3-yl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-7-(1-(4- (trifluoromethyl)pyridin-3-yl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 5-((3-(trifluoromethyl)pyridin-2-y
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinoxalin-5- yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinoxalin-5- yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinoxalin-5- yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(5,6,7,8-tetrahydroquinoxalin-5- yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methyl-5-(5,6,7,8- tetrahydroquinoxalin-5-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methyl-5-(5,6,7,8- tetrahydroquinoxalin-5-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methyl-5-(5,6,7,8- tetrahydroquinoxalin-5-yl)pyrido[2,3-b]pyrazin- 6(5H)-one (110 mg, 0.292 mmol, 1 equiv) and 2-bromo-1-flu
  • Step 2 (3-(difluoromethoxy)pyridin-2-yl)methanol:
  • 3-(difluoromethoxy)picolinate 180 mg, 0.829 mmol, 1 equiv
  • 3-(difluoromethoxy)pyridin-2-yl)methanol 100 mg, 68%) as a colorless oil.
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3,8-dimethyl-5-((3- (trifluoromethyl) pyrazine-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3,8-dimethyl-5-((3- (trifluoromethyl) pyrazine-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3,8-dimethyl-5-((3- (trifluoromethyl) pyrazine-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 5-(2-(difluoromethoxy)benzyl)-3-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-(2-(difluoromethoxy)benzyl)-3-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-(2-(difluoromethoxy)benzyl)-3-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-(2-(difluoromethoxy)benzyl)-3-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-(2-(difluoromethoxy)benzyl)-3-methyl-7-(piperidin-4-y
  • Step 3 5-(2-(difluoromethoxy)benzyl)-7-(1-(2-fluoro-6-methylphenyl)piperidin-4- yl)-3-methylpyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 5-(2-(difluoromethoxy)benzyl)-7-(1-(2-fluoro-6-methylphenyl)piperidin-4- yl)-3-methylpyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 5-(2-(difluoromethoxy)benzyl)-7-(1-(2-fluoro-6-methylphenyl)piperidin-4- yl)-3-methylpyrido[2,3-b]pyrazin-6(5H)-one:
  • 2-bromo-1-fluoro-3-methylbenzene 56.7 mg, 0.3 mmol, 1.2 equiv
  • Step 2 3,8-dimethyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3,8-dimethyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3,8-dimethyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3,8-dimethyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3,8-dimethyl-5-((3- (trifluoromethyl) pyridine-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3,8-dimethyl-5-((3- (trifluoromethyl) pyridine-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3,8-dimethyl-5-((3- (trifluoromethyl) pyridine-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(3-methoxy-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(3-methoxy-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 80 mg, 0.222 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoro
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methoxy-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methoxy-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (45 mg, 0.107 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (30.3 mg, 0.161 mmol, 1.5 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-
  • Step 2 2-(chloromethyl)-3-fluoropyrazine:
  • 3- fluoropyrazin-2-yl)methanol 80 mg, 0.625 mmol, 1 equiv
  • MS m/z 147 [M+H] + .
  • Step 3 tert-butyl 4-(5-((3-fluoropyrazin-2-yl)methyl)-8-methyl-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • Step 4 5-((3-fluoropyrazin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 4 5-((3-fluoropyrazin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 4 5-((3-fluoropyrazin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 5-((3-fluoropyrazin-2-yl)methyl)-8-methyl-7-(1-(2- (trifluoromethyl)phenyl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 5-((3-fluoropyrazin-2-yl)methyl)-8-methyl-7-(1-(2- (trifluoromethyl)phenyl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 5-((3-fluoropyrazin-2-yl)methyl)-8-methyl-7-(1-(2- (trifluoromethyl)phenyl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethoxy)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethoxy)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethoxy)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethoxy)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 90 mg, 0.272 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrobromid
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5
  • Step 3 7-(1-(2-fluoro-4-methoxypyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methoxypyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methoxypyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate 100 mg, 0.29 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoro
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methoxypyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methoxypyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 3-bromo-2- fluoro-4-methoxypyridine 36.6 mg, 0.178 mmol, 1.2 equiv
  • Step 1 tert-butyl 4-(2-methyl-7-oxo-8-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-methyl-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-6- yl)piperidine-1-carboxylate 80 mg, 0.232 mmol, 1 equiv) and (2-(bromomethyl)-3- (trifluoromethyl)pyridine hydrobromide (82 mg, 0.255 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(2-methyl-7-oxo-8-((3-(trifluoromethyl)pyridin-2-yl) methyl)- 7,8-dihydropyri
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d] pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d] pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d] pyrimidin-7(8H)-one:
  • Step 3 6-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-2-methyl-8-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one 60 mg, 0.149 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (33.7 mg, 0.179 mmol, 1.2 equiv) as the starting materials to give 6- (1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-2-methyl-8-((3-(trifluoromethyl) pyr
  • Step 1 tert-butyl 4-((5-aminopyrimidin-4-yl)ethynyl)piperidine-1-carboxylate:
  • 4-iodopyrimidin-5-amine 200 mg, 0.905 mmol, 1 equiv
  • tert-butyl 4-ethynylpiperidine-1-carboxylate 284 mg, 1.35 mmol, 1.5 equiv
  • tert-butyl 4-[2-(5-aminopyrimidin-4-yl)ethynyl]piperidine-1- carboxylate 200 mg, 73%) as a white solid.
  • Step 2 tert-butyl 4-(6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1- carboxylate:
  • tert-butyl 4-((5-aminopyrimidin-4- yl)ethynyl)piperidine-1-carboxylate 150 mg, 0.496 mmol, 1 equiv) and sodium 2-chloro-2,2- difluoroacetate (151 mg, 0.992 mmol, 2 equiv) as the starting materials to give tert-butyl 4- (6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (50 mg, 30%) as a white solid.
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate:
  • 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrobromide 86.7 mg, 0.272 mmol, 1 equiv
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1- carboxylate 90 mg, 0.272 mmol, 1.5 equiv
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[3,2-d]pyrimidin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[3,2-d]pyrimidin-6(5H)-one (40 mg, 0.102 mmol, 1 equiv) and 2-bromo-1-fluoro-3- methylbenzene (23.2 mg, 0.123 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2- fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)
  • Step 2 5-((3-fluoropyridin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-((3-fluoropyridin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-((3-fluoropyridin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 5-((3-fluoropyridin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethoxy)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 9 mg, 0.276 mmol, 1 equiv) and 2-(chloromethyl)-3-(trifluoromethoxy)pyridine (58.2 mg,
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-yl)-5-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 7-(piperidin-4-y
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethoxy)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethoxy)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethoxy)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3
  • Step 1 tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperazine-1-carboxylate:
  • tert-butyl 4-(2-ethoxy-2- oxoethyl)piperazine-1-carboxylate 200 mg, 0.735 mmol, 1 equiv
  • 1-(3-aminopyrazin-2- yl)ethan-1-one 121 mg, 0.882 mmol, 1.2 equiv
  • Step 2 tert-butyl 4-(8-methyl-6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate:
  • tert-butyl 4-(3-methoxy-6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate 70 mg, 0.202 mmol, 1 equiv
  • 2-(bromomethyl)- 3-(trifluoromethyl)pyridine (65.1 mg, 0.202 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(8-methyl-6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 5,6-dihydro
  • Step 3 8-methyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 8-methyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 8-methyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-8-methyl-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-8-methyl-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • 8-methyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (58 mg, 0.143 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (25.2 mg, 0.134 mmol, 1.5
  • Step 1 7-(4-(2-Fluoro-6-methylphenyl)piperidin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one (89) [00680]
  • Step 1 7-(4-(2-fluoro-6-methylphenyl)piperidin-1-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 7-(4-(2-fluoro-6-methylphenyl)piperidin-1-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 7-(4-(2-fluoro-6-methylphenyl)piperidin
  • Step 1 methyl 3-amino-5-methylpicolinate:
  • 2-bromo-5-methylpyridin-3-amine 1.5 g, 8.02 mmol, 1 equiv
  • MS m/z 167 [M+H] + .
  • Step 2 3-amino-5-methylpicolinaldehyde:
  • methyl 3-amino-5-methylpicolinate 410 mg, 2.48 mmol, 1 equiv
  • DIBAL-H 526 mg, 3.7 mmol, 1.5 equiv
  • MS m/z 137 [M+H] + .
  • Step 4 tert-butyl 4-(7-methyl-2-oxo-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1,2-dihydro-1,5-naphthyridin-3-yl)piperidine-1-carboxylate:
  • Step 6 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-7-methyl-1-((3- (trifluoromethyl) pyridin-2-yl)methyl)-1,5-naphthyridin-2(1H)-one:
  • Step 6 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-7-methyl-1-((3- (trifluoromethyl) pyridin-2-yl)methyl)-1,5-naphthyridin-2(1H)-one:
  • Step 6 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-7-methyl-1-((3- (trifluoromethyl)pyridin-2-yl)methyl)-1,5-naphthyridin-2(1H)-one:
  • Step 6 3-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-7-methyl-1
  • Step 1 benzyl 4-(2-fluoro-6-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate:
  • Step 2 benzyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2 g, 5.82 mmol, 1 equiv) and 2- bromo-1-fluoro-3-methylbenzene (1.32 g, 6.99 mmol, 1.2 equiv) as the starting materials to give benzyl 4-(2-fluoro-6-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.6 g, 84%) as a colorless oil.
  • Step 2 4-(2-fluoro-6-methylphenyl)piperidine:
  • Step 2 4-(2-fluoro-6-methylphenyl)piperidine:
  • benzyl 4-(2-fluoro-6-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.07 mmol, 1 equiv) as the starting material to give the crude product 4-(2-fluoro-6- methylphenyl)piperidine (550 mg) as a light yellow oil.
  • Step 3 ethyl 2-(4-(2-fluoro-6-methylphenyl)piperidin-1-yl)acetate:
  • 4-(2-fluoro-6-methylphenyl)piperidine 550 mg, 2.84 mmol, 1 equiv
  • ethyl 2-bromoacetate 570 mg, 3.41 mmol, 1.2 equiv
  • MS m/z 280 [M+H] + .
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperidin-1-yl)pyrido[2,3-b]pyrazin-6(5H)- one:
  • 3-aminopyrazine-2-carbaldehyde 105 mg, 0.859 mmol, 1.2 equiv
  • ethyl 2-(4-(2-fluoro-6-methylphenyl)piperidin-1-yl)acetate 200 mg, 0.716 mmol, 1 equiv
  • 7-(4-(2-fluoro-6- methylphenyl)piperidin-1-yl)pyrido[2,3-b]pyrazin-6(5H)-one 60 mg, 24%) as a yellow solid.
  • Step 5 7-(4-(2-fluoro-6-methylphenyl)piperidin-1-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one:
  • 7-(4-(2-fluoro-6-methylphenyl)piperidin-1-yl)pyrido[2,3-b]pyrazin-6(5H)- one 60 mg, 0.177 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrobromide (62.6 mg, 0.195 mmol, 1.1 equiv) as the starting materials to give 7-(4-(2- fluoro-6-methylphenyl)piperidin-1-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl
  • Step 1 tert-butyl 4-((5-amino-6-methoxypyrimidin-4-yl)ethynyl)piperidine-1- carboxylate:
  • 4-chloro-6-methoxypyrimidin-5-amine 200 mg, 1.253 mmol, 1 equiv
  • tert-butyl 4-ethynylpiperidine-1-carboxylate 314 mg, 1.504 mmol, 1.2 equiv) as the starting materials
  • XPhos 60.7 mg, 0.125 mmol, 0.1 equiv
  • XPhos Pd G3 106 mg, 0.125 mmol,
  • Step 2 tert-butyl 4-(4-methoxy-6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7- yl)piperidine-1-carboxylate:
  • tert-butyl 4-((5-amino-6- methoxypyrimidin-4-yl)ethynyl)piperidine-1-carboxylate 200 mg, 0.602 mmol, 1 equiv
  • sodium 2-chloro-2,2-difluoroacetate 275 mg, 1.806 mmol, 3 equiv
  • tert-butyl 4-(4-methoxy-6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1- carboxylate 70 mg, 32%) as a light yellow solid.
  • Step 3 tert-butyl 4-(4-methoxy-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 5,6-dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(4-methoxy-6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7- yl)piperidine-1-carboxylate 70 mg, 0.194 mmol, 1 equiv
  • 2-(bromomethyl)-3- (trifluoromethyl)pyrazine 70 mg, 0.291 mmol, 1.5 equiv
  • Step 4 4-methoxy-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[3,2-d]pyrimidin-6(5H)-one:
  • Step 4 4-methoxy-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[3,2-d]pyrimidin-6(5H)-one:
  • Step 4 4-methoxy-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[3,2- d]pyrimidin-7-yl)piperidine-1-carboxylate (60 mg, 0.115 mmol, 1 equiv) as the starting material to give the crude product 4-methoxy-7-(piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-y
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-4-methoxy-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[3,2-d]pyrimidin-6(5H)-one:
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-4-methoxy-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[3,2-d]pyrimidin-6(5H)-one:
  • Step 5 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-4-methoxy-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[3,2-d]pyrimidin-6(5H)-one:
  • Step 1 2-amino-N-methoxy-N,6-dimethylnicotinamide:
  • 2-amino-6-methylnicotinic acid 600 mg, 3.94 mmol, 1 equiv
  • N,O- dimethylhydroxylamine 361 mg, 5.91 mmol, 1.5 equiv
  • 2- amino-N-methoxy-N,6-dimethylnicotinamide 530 mg, 68%) as a yellow solid.
  • Step 2 2-amino-6-methylnicotinaldehyde:
  • 2-amino-6-methylnicotinaldehyde followsed general procedure B using 2- amino-N-methoxy-N,6-dimethylnicotinamide (380 mg, 1.94 mmol, 1 equiv) as the starting material to give 2-amino-6-methylnicotinaldehyde (240 mg, 90%) as a yellow oil.
  • Step 3 tert-butyl 4-(7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)piperidine- 1-carboxylate:
  • 2-amino-6-methylnicotinaldehyde 240 mg, 1.76 mmol, 1 equiv
  • tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1- carboxylate(680 mg,2.64 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(7- methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)piperidine-1-carboxylate (90 mg, 14%) as a yellow oil.
  • Step 5 7-methyl-3-(piperidin-4-yl)-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1,8-naphthyridin-2(1H)-one:
  • Step 5 7-methyl-3-(piperidin-4-yl)-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1,8-naphthyridin-2(1H)-one:
  • Step 5 7-methyl-3-(piperidin-4-yl)-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1,8-naphthyridin-2(1H)-one:
  • Step 5 7-methyl-3-(piperidin-4-yl)-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1,8-naphthyridin-2(1H)-one:
  • Step 1 tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1- carboxylate:
  • 3-aminopyrazine-2-carbaldehyde 180 mg, 1.47 mmol, 2 equiv
  • tert -butyl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate 200 mg, 0.73 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(6-
  • Step 2 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate 130 mg, 0.392 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrogen bromide (138 mg, 0.431 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(6- oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5
  • Step 3 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-8-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-8-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-8-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl
  • Step 2 (2-(trifluoromethoxy)pyridin-3-yl)methanol:
  • (2-(trifluoromethoxy)pyridin-3-yl)methanol was followeded general procedure I using methyl 2-(trifluoromethoxy)nicotinate (120 mg, 0.543 mmol, 1 equiv) as the starting material to give (2-(trifluoromethoxy)pyridin-3-yl)methanol (70 mg, 66%) as a colorless oil.
  • Step 3 3-(chloromethyl)-2-(trifluoromethoxy)pyridine:
  • (2-(trifluoromethoxy)pyridin-3-yl)methanol 100 mg, 0.474 mmol, 1 equiv
  • Step 5 3-methyl-7-(piperidin-4-yl)-5-((2-(trifluoromethoxy)pyridin-3- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 3-methyl-7-(piperidin-4-yl)-5-((2-(trifluoromethoxy)pyridin-3- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 3-methyl-7-(piperidin-4-yl)-5-((2-(trifluoromethoxy)pyridin-3- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethoxy)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethoxy)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperidin-4-yl)-8-((3-(trifluoromethoxy)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 1 tert-butyl 4-(3,8-dimethyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-methoxy-2- oxoethyl)piperidine-1-carboxylate 200 mg, 0.775 mmol, 1.00 equiv
  • 1-(3-amino-5- methylpyrazin-2-yl)ethan-1-one 141 mg, 0.93 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(3,
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-3-methyl-5-((3- methylpyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-3-methyl-5-((3- methylpyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-3-methyl-5-((3-methylpyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-3-methyl-5-((3-methylpyrazin-2-
  • Step 1 tert-butyl 4-(8-((3-(difluoromethoxy)pyridin-2-yl)methyl)-2-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate 75 mg, 0.218 mmol, 1 equiv) and 2-(chloromethyl)-3- (difluorometh
  • Step 2 8-((3-(difluoromethoxy)pyridin-2-yl)methyl)-2-methyl-6-(piperidin-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 8-((3-(difluoromethoxy)pyridin-2-yl)methyl)-2-methyl-6-(piperidin-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 8-((3-(difluoromethoxy)pyridin-2-yl)methyl)-2-methyl-6-(piperidin-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 8-((3-(difluoromethoxy)pyridin-2-yl)methyl)-2-methyl-6-(piperidin-4- yl)pyrido[2,3-d]pyrimidin-7(8H
  • Step 2 3-methyl-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methyl-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 6-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-2-methyl-8-((3- methylpyrazin-2-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • 2-methyl-8-((3-methylpyrazin-2-yl)methyl)-6-(piperidin-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 50 mg, 0.043 mmol, 1 equiv
  • 2-bromo-1-fluoro-3- methylbenzene (12.2 mg, 0.065 mmol, 1.5 equiv) as the starting materials to give 6-(1-(2- fluoro-6-methylphenyl)piperidin-4-yl)-2-methyl-8-((3-methylpyrazin-2- yl)methyl)pyrido[
  • Step 3 tert-butyl 4-(2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)piperazine-1-carboxylate:
  • tert-butyl 4-(2- (methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperazine-1-carboxylate 300 mg, 0.733 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(2-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperazine-1-carboxylate (100 mg, 39%) as a yellow solid.
  • Step 1 7-(1-(2-(Difluoromethoxy)phenyl)piperidin-4-yl)-5-((3-methylpyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (111) [00759] Step 1: 7-(1-(2-(difluoromethoxy)phenyl)piperidin-4-yl)-5-((3-methylpyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 7-(1-(2-(difluoromethoxy)phenyl)piperidin-4-yl)-5-((3-methylpyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 7-(1-(2-(difluoromethoxy)phenyl)piperidin-4-yl)-5-((3
  • Step 2 3-methoxy-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methoxy-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methoxy-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methoxy-5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 3-methoxy-5-((3-methylpyrazin-2-yl)methyl
  • Step 3 7-(piperidin-4-yl)-5-((4-(trifluoromethyl)pyrimidin-5-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-((4-(trifluoromethyl)pyrimidin-5-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-((4-(trifluoromethyl)pyrimidin-5-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-((4-(trifluoromethyl)pyrimidin-5-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(piperidin-4-yl)-5-(
  • Step 4 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((4- (trifluoromethyl)pyrimidin-5-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((4- (trifluoromethyl)pyrimidin-5-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((4- (trifluoromethyl)pyrimidin-5-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 4 7-(piperidin-4-yl)-5-((4-(trifluoromethyl)pyrimidin-5- yl)
  • Step 3 8-((3-(difluoromethoxy)pyridin-2-yl)methyl)-6-(4-(2-fluoro-6- methylphenyl)piperazin-1-yl)-2-methylpyrido[2,3-d]pyrimidin-7(8H)-one:
  • 2-methyl-6-(piperazin-1-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one 40 mg, 0.1 mmol, 1 equiv
  • 2-bromo-1- fluoro-3-methylbenzene (20.7 mg, 0.11 mmol, 1.5 equiv) as the starting materials to give 8- ((3-(difluoromethoxy)pyridin-2-yl)methyl)-6-(4-(2-fluoro-6-methyl
  • Step 3 3,8-dimethyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 3,8-dimethyl-7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 3,8-dimethyl-6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperazine-1-carboxylat (45 mg, 0.087 mmol, 1 equiv) as the starting material to give the crude product 3,8-dimethyl-7-(piperazin-1-yl)-5-((3-
  • Step 1 tert-butyl 4-(2-methyl-7-oxo-8-((3-(trifluoromethyl)pyridin-2-yl)methyl)- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperazine-1-carboxylate:
  • tert-butyl 4-(2-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)piperazine-1-carboxylate 100 mg, 0.29 mmol, 1 equiv) and 2-(chloromethyl)-3- (trifluoromethyl)pyridine (85 mg, 0.435 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(2-methyl-7-oxo-8-((3-(trifluoromethyl)pyridin-2-yl)methyl)-7,8- dihydropyrido[2,3-d]
  • Step 2 2-methyl-6-(piperazin-1-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperazin-1-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 2 2-methyl-6-(piperazin-1-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • Step 3 6-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-2-methyl-8-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • 2-methyl-6-(piperazin-1-yl)-8-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one 45 mg, 0.11 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (31.6 mg, 0.17 mmol, 1.5 equiv) as the starting materials to give 6- (4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-2-methyl-8-((3-(trifluoromethyl)pyridin
  • Step 2 2-(bromomethyl)-3-(difluoromethyl)pyrazine:
  • 2-(difluoromethyl)-3-methylpyrazine 100 mg, 0.694 mmol, 1 equiv
  • Step 5 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-3-methylpyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-3-methylpyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 5 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-3-methylpyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 1 tert-butyl 4-(5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 100 mg, 0.303 mmol, 1 equiv) and 2-(bromomethyl)-3-(difluoromethyl)pyrazine (67.2 mg, 0.303 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(5-((3-(difluoromethyl)pyrazin-2- yl)methyl)-6-oxo-5,6-dihydropyrido[2,3-b]pyr
  • Step 2 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 2 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 5-((3-(difluoromethyl)pyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin- 6(5H)-one
  • 2-bromo-1-fluoro-3-methylbenzene 37.9 mg, 0.201 mmol, 1.5 equiv
  • Step 1 tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethoxy)pyridin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate:
  • tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate 150 mg, 0.434 mmol, 1 equiv) and 2-(chloromethyl)-3- (trifluoromethoxy)pyr
  • Step 1 tert-butyl 4-(5-((3-methoxypyrazin-2-yl)methyl)-3-methyl-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate:
  • tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1- carboxylate 140 mg, 0.405 mmol, 1 equiv
  • 2-(bromomethyl)-3-methoxypyrazine 123 mg, 0.608 mmol, 1.5
  • Step 1 tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate:
  • tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate 200 mg, 0.604 mmol, 1.0 equiv.
  • Step 3 7-(1-(2-fluoro-4-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one
  • 3-bromo-2-fluoro-4- methylpyridine 103 mg, 0.540 m
  • Step 3 7-(1-(2-fluoro-4-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methylpyridin-3-yl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one:
  • Step 3 7-(1-(2-fluoro-4-methylpyridin-3-yl

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés qui modulent (par exemple, antagonisent) le récepteur 1 du composant 5a du complément (C5aR1), un récepteur couplé à une protéine g pour C5a qui est associé à des troubles auto-immuns, inflammatoires et neurodégénératifs. L'invention concerne également des compositions pharmaceutiques et des kits comprenant les composés, et des méthodes de traitement de maladies et de troubles liés à C5aR1 avec les composés chez un sujet, par administration des composés et/ou des compositions décrits ici.
EP23866136.7A 2022-09-14 2023-09-13 Antagonistes de c5ar1 et leurs utilisations Pending EP4587014A2 (fr)

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