Multicyclic TLR7 / 8 antagonists and their use in the treatment of immune disorders

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable compositions thereof useful as toll-like receptor 7 / 8 (TLR7 / 8) antagonists.SOLUTION: In Formula (I), ring A is aryl or heteroaryl; ring B is aryl or heteroaryl; and X is C (R4) 2, O, NR4, S, S (R4), or S (R4) 2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 268,765, filed December 17, 2015, and U.S. Provisional Patent Application No. 62 / 353,603, filed June 23, 2016, the contents of which are incorporated herein by reference in their entireties.

[0002] Technical field of the invention The present invention provides compounds of formula (I) as toll-like receptor 7 / 8 (TLR7 / 8) antagonists and their use in the treatment of immune disorders and other diseases associated with TLR7 / 8 overexpression. [Background technology]

[0003] Background of the Invention Toll-like receptors (TLRs) are currently thought to comprise a gene family of 10 receptors with different specificities. These receptors are part of the cellular pathogen pattern recognition system, involved in defense against various infectious diseases (bacterial, viral, and fungal). TLR activation leads to cytokine responses, such as the release of interferon and activation of specific immune cells. The functional expression of selected TLRs varies greatly across tissues. Some of these receptors are located on the cell surface, e.g., TLR4 (stimulated by Escherichia coli lipopolysaccharide (LPS)) on epithelial cells, while TLRs 3, 7, 8, and 9 are located on the endosomal membranes of certain immune cells. All of the latter are activated by nucleic acids, but they recognize various types of nucleic acids. For example, TLR9 is activated by single-stranded DNA containing CpG subsequences, TLRs 7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA.

[0004] TLRs are involved in various autoimmune and inflammatory diseases, the most obvious example being the role that TLR7 plays in the pathology of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223:271-283, 2008). In addition, TLR8 polymorphisms have been associated with rheumatoid arthritis (Enevold et al., J Rheumatol, 37:905-10, 2010). Although various TLR7, TLR8, and TLR9 inhibitors have been described, additional TLR inhibitors are desirable. In particular, polynucleotides containing one or more inhibitory motifs of TLR7, TLR8, and TLR9 are needed to precisely inhibit immune responses in subjects (e.g., patients with autoimmune diseases or inflammatory disorders).

[0005] Over the past few years, significant efforts have been made worldwide to exploit the potent immune activation induced by TLR7, 8, or 9 agonists for cancer treatment. However, cancer immunotherapy has experienced a long history of failure. However, over the past few years, our knowledge of cancer immune surveillance and the resulting functions of immune cell subsets has dramatically improved. TLR7 or TLR9 agonists are in clinical development for cancer monotherapy or combination therapy, or as vaccine adjuvants. The TLR agonist approach for cancer immunotherapy differs from earlier efforts using, for example, cytokines, interferons, or monovalent vaccinations. TLR agonist-mediated immune activation is multifaceted, mediated by specific immune cells (primarily dendritic cells and B cells, followed by other cells), resulting in innate and adaptive immune responses. Furthermore, not only one type of interferon is induced, but rather many different isoforms are induced together, and not only type I (α, β) but also (indirectly) type II (γ, NK cells) are induced. Summary of the Invention

[0006] Summary of the Invention In one aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers thereof: [ka]

[0007] In another aspect, the present invention provides compounds of formula (I) that are dual antagonists of TLR7 and TLR8. In another aspect, the present invention provides compounds of formula (I) that are suitable for the treatment and / or prevention of TLR7 / 8-related disorders. In another aspect, the present invention provides compounds that are able to modify, in particular inhibit, the activity or function of TLR7 / 8 in mammalian, in particular human, pathological conditions.

[0008] According to another aspect of the present invention, a method of treating and / or preventing an autoimmune disorder is provided.

[0009] According to another aspect, the present invention provides compounds of formula (I) that are selective for TLR7 or TLR8.

[0010] According to another aspect, the present invention provides compounds of formula (I) that are selective for TLR7 and TLR8. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description of Specific Embodiments 1. General Description of the Compounds of the Invention In certain aspects, the present invention provides antagonists of TLR7 / 8. In some embodiments, such compounds are of a formula described herein or include pharmaceutically acceptable salts thereof, wherein each variable is as defined or described herein.

[0012] 2. Compounds and Definitions The compounds of the present invention include those generally described above, further exemplified by the classes, subclasses, and genus disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Handbook of Chemistry and Physics, 75th Edition. In addition, general principles of organic chemistry are explained in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Edition, eds. Smith, M.B., and March, J., John Wiley & Sons, New York: 2001, the contents of which are all incorporated herein by reference.

[0013] As used herein, the term "aliphatic" or "aliphatic group" refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, or monocyclic or bicyclic hydrocarbon, that is fully saturated or contains one or more unsaturated units and has a single point of attachment to the rest of the molecule, and that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"). Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, having a single point of attachment to the rest of the molecule. Examples of aliphatic groups are linear or branched, substituted or unsubstituted C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0014] The term "lower alkyl" refers to a C 1-4 It refers to a straight-chain or branched alkyl group. Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0015] The term "lower haloalkyl" refers to a C alkyl group substituted by one or more halogen atoms. 1-4 It refers to a straight or branched chain alkyl group.

[0016] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, or phosphorus (including oxidized forms of nitrogen, sulfur, or phosphorus; quaternized forms of a basic nitrogen; or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl).

[0017] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0018] As used herein, the term "divalent C" 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, as defined herein, that are straight or branched.

[0019] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0020] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0021] The term "halogen" means F, Cl, Br, or I.

[0022] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic and each ring in the ring system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system. Examples of aryl groups are phenyl, biphenyl, naphthyl, anthracyl, and the like, optionally containing one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, are also included within the scope of the term "aryl."

[0023] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 shared pi electrons in a cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocycles, where the radical or point of attachment is on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups are optionally monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0024] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and, as defined above, has one or more, preferably one to four, heteroatoms in addition to carbon atoms. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0025] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. Heterocyclyl groups are optionally monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions are independently optionally substituted.

[0026] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0027] As described herein, certain compounds of the invention contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. "Substituted" applies to one or more hydrogens either explicit or implicit from the structure (e.g., [ka] At least [ka] and, [ka] At least [ka] (refers to "optionally substituted"). Unless otherwise specified, an "optionally substituted" group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituents are either the same or different at each position. Combinations of substituents envisioned in this invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0028] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, deuterium; halogen; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°; optionally substituted by R°, -(CH2) 0-4 Ph; optionally substituted by R°, -(CH2) 0-4 O(CH2) 0-1 Ph; optionally substituted by R°, -CH=CHPh; optionally substituted by R°, -(CH) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°, SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5- or 6-membered heteroaryl ring), or a 5- or 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent occurrences of R° together with their intervening atom(s) form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted as defined below.

[0029] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° with their intervening atoms) are independently deuterium, halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph is independently selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0030] Preferred divalent substituents on a saturated carbon atom of an "optionally substituted" group are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, where each independent R * occurrences of C are substituted as defined below 1-6Aliphatic or unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent R * occurrences of C are hydrogen, optionally substituted as defined below 1-6 It is selected from aliphatic or unsubstituted 5-6-membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] R * Suitable substituents on the aliphatic groups are halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] A preferred substituent on a substitutable nitrogen of an "optionally substituted" group is -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR †2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, optionally substituted C as defined below 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent R † together with their intervening atom(s), form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] In certain embodiments, the terms "optionally substituted," "optionally substituted alkyl," "optionally substituted," "optionally substituted," "optionally substituted alkenyl," "optionally substituted alkynyl," "optionally substituted carbocyclic," "optionally substituted aryl," "optionally substituted heteroaryl," "optionally substituted heterocyclic," and any other optionally substituted group as used herein refer to groups that are substituted or unsubstituted by independent replacement of one, two, three, or more hydrogen atoms thereon with representative substituents, including, but not limited to, the following: -F, -Cl, -Br, -I, deuterium, -OH, protected hydroxy, alkoxy, oxo, thioxo, -NO2, -CN, CF3, N3, -NH, protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocyclic, -dialkylamino, -diarylamino, -diheteroarylamino, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclic, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-carbocyclyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -CONH, -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl, -OCO2-alkyl, -OCO2-alkenyl, -OCO2-alkynyl, -OCO2-carbocyclyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocyclyl, -OCONH2, -OCONH-alkyl, -OCONH-alkenyl, -OCONH-alkynyl, -OCONH-carbocyclyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclyl, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyclyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -NHCO2-alkyl, -NHCO2-alkenyl, -NHCO2-alkynyl, -NHCO2-carbocyclyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocyclyl, -NHC(O)NH2, -NHC(O)NH-alkyl, -NHC(O)NH-alkenyl, -NHC(O)NH-alkenyl, -NHC(O)NH-carbocyclyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclyl, NHC(S)NH2, -NHC(S)NH-alkynyl -NHC(S)NH-alkenyl, -NHC(S)NH-alkynyl, -NHC(S)NH-carbocyclyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclyl, -NHC(NH)NH, -NHC(NH)NH-alkyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)-carbocyclyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocyclyl, -C(NH)NH-alkyl, -C(NH)NH-alkenyl, -C(NH)NH-alkynyl, -C(NH)NH-carbocyclyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclyl, -S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, -S(O)-carbocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclyl, -SONH, -SONH-alkyl, -SONH-alkenyl, -SONH-alkynyl, -SONH-carbocyclyl, -SONH-aryl, -SONH-heteroaryl, -SONH-heterocyclyl, -NHSO2-alkyl, -NHSO2-alkenyl, -NHSO2-alkynyl, -NHSO2-carbocyclyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocyclyl, -CH2NH2, -CH2SO2CH3, mono-, di-, or tri-alkylsilyl, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, -S-heterocyclyl, or methylthiomethyl.

[0035] As used herein, the term "pharmaceutically acceptable salt" refers to such salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, methylpropional ... Examples of the salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0036] Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N+ (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0037] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of that structure; for example, the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0038] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13 C- or 14 Compounds having this structure including replacements with C-enriched carbons are within the scope of this invention. In some embodiments, this group contains one or more deuterium atoms.

[0039] Furthermore, compounds of Formula I are intended to include their isotopically labeled forms. Isotopically labeled forms of compounds of Formula I are identical to the compounds except for the fact that one or more atoms of the compound have been replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the normally occurring atom. Examples of isotopes that are readily commercially available and can be incorporated into compounds of Formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Compounds of Formula I, their prodrugs, or pharmaceutically acceptable salts, which contain one or more of the aforementioned isotopes and / or other isotopes of other atoms, are intended to be part of the present invention. Isotopically labeled compounds of Formula I can be used in a number of beneficial ways. For example, 3 H or 14 Isotopically labeled compounds of formula I, into which radioactive isotopes such as C are incorporated, are suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes, i.e., tritium ( 3 H) and carbon-14 ( 14 C) is particularly preferred due to its simple preparation and excellent detectability. 2Incorporation of relatively heavy isotopes, such as H, into compounds of formula I offers therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower doses, which under most circumstances will represent a preferred embodiment of the present invention. Isotopically labeled compounds of formula I can generally be prepared by carrying out the procedures set forth in the synthetic schemes and related descriptions, examples and preparations sections of this text, by replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0040] deuterium( 2 H) can also be incorporated into compounds of formula I for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which in turn is caused by a change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually results in a lower ground state energy for the chemical bond, thus causing a decrease in the rate of rate-limiting bond rupture. If bond rupture occurs within or near a saddle point region along the coordinate of a multicomponent reaction, the product distribution ratio will be substantially altered. To explain: if deuterium is attached to a carbon atom at a non-exchangeable position, k M / k D A rate difference of 2 to 7 is common. If this rate difference is successfully applied to a compound of Formula I that is prone to oxidation, the in vivo profile of the compound can be dramatically altered and result in improved pharmacokinetic properties.

[0041] During the discovery and development of therapeutic agents, one skilled in the art can optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information regarding the course of this type of oxidative metabolism, which in turn allows for the rational design of deuterated compounds of Formula I with improved stability through resistance to such oxidative metabolism. This results in significant improvements in the pharmacokinetic profile of compounds of Formula I, which can be seen in in vivo half-life (t / 2), maximum therapeutic concentration (C max ), area under the dose-response curve (AUC), and F; and in terms of reduction in clearance, dosage, and material costs.

[0042] To illustrate the above, the following is intended: A compound of Formula I having multiple potential attack sites for oxidative metabolism, such as benzylic hydrogen atoms and hydrogen atoms attached to nitrogen atoms, is prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms, so that some, most, or all of these hydrogen atoms are replaced with deuterium atoms. Half-life determinations can be made more favorably and accurately to the extent that improved resistance to oxidative metabolism is improved. In this manner, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0043] Deuterium-hydrogen exchange in compounds of Formula I can also be used to achieve favorable modification of the metabolic spectrum of the starting compound to reduce or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises from oxidative carbon-hydrogen (C-H) bond cleavage, it may be reasonable to assume that a deuterated analog will greatly reduce or eliminate the production of the undesired metabolite, even if the specific oxidation is not the rate-limiting step. Further information on the state of the art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry, 33(10) 2927-2937, 1994; and Jarman et al., Carcinogenesis, 16(4), 683-688, 1993.

[0044] The term "modulator" as used herein is defined as a compound that binds to and / or inhibits a target with measurable affinity. In certain embodiments, a modulator is a compound that inhibits binding to and / or inhibits a target with an IC 50 and / or has a binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

[0045] As used herein, the terms "measurable affinity" and "measurably inhibit" refer to a measurable change in TLR7 / 8 activity between a sample containing a compound of the invention, or a composition thereof, and TLR7 / 8 and an equivalent sample containing TLR7 / 8 in the absence of the compound, or a composition thereof.

[0046] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and that maintain their integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0047] The recitation of a list of chemical groups in a definition of a variable herein includes the definition of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or any other embodiment or subcombination thereof.

[0048] 3. Description of illustrative compounds According to one embodiment, the present invention provides compounds of formula I or a pharmaceutically acceptable salt thereof: [ka] (In the formula: Ring A is aryl or heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; Ring B is aryl or heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; R 1 is absent, -H, -CHF2, -CF3, -OMe, or -CN; Each R 2 are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S2R, -SOR, -C(O)R, -C2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R 3are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S2R, -SOR, -C(O)R, -C2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; X is C(R 4 )2, O, NR 4 , S, S(R 4 ), or S(R 4 )2; Each R 4 are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S2R, -SOR, -C(O)R, -C2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R 5 are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S2R, -SOR, -C(O)R, -C2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or Two R groups on the same atom, together with the atom to which they are attached, form a C 3-10 forming an aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; k is 0 or 1; n is 0, 1, or 2; p is 0, 1, or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

[0049] In certain embodiments, [ka] but, [ka] and X is CH2; R 4 is not H, methyl, or hydroxyl.

[0050] In certain embodiments, [ka] but, [ka] and when X is O, R 4 is not -C(O)N(R)2.

[0051] In certain embodiments, R 1 does not exist.

[0052] In certain embodiments, R 1 is -H.

[0053] In certain embodiments, R 1 is -CHF2.

[0054] In certain embodiments, R 1 is -CF3.

[0055] In certain embodiments, R 1 is -OMe.

[0056] In certain embodiments, R 1 is -CN.

[0057] In certain embodiments, Ring A is a C6 aryl or a 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0058] In certain embodiments, Ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; each of which is optionally substituted.

[0059] In certain embodiments, Ring A is phenyl, pyridyl, or pyrimidinyl; each of which is optionally substituted.

[0060] In certain embodiments, ring A is: [ka]

[0061] In certain embodiments, ring A is: [ka]

[0062] In certain embodiments, Ring B is a C6 aryl or a 5-6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0063] In certain embodiments, Ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of which is optionally substituted.

[0064] In certain embodiments, ring B is: [ka]

[0065] In certain embodiments, ring B is: [ka]

[0066] In certain embodiments, each R 2 are independently -H.

[0067] In certain embodiments, each R 2 independently, C 1-6 aliphatic, C 3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0068] In certain embodiments, each R 2 is independently methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl; each of which is optionally substituted.

[0069] In certain embodiments, each R 2are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl thiazolyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted;

[0070] In certain embodiments, each R 2 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0071] In certain embodiments, each R 3 are independently -H.

[0072] In certain embodiments, each R 3 independently, C 1-6 aliphatic, C 3-10aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0073] In certain embodiments, each R 3 is independently methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl; each of which is optionally substituted.

[0074] In certain embodiments, each R 3 is independently methyl.

[0075] In certain embodiments, each R 3are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl thiazolyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted;

[0076] In certain embodiments, each R 3 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0077] In certain embodiments, X is C(R 4 )2 or O.

[0078] In certain embodiments, X is C(R 4 )2. In certain embodiments, X is CH2.

[0079] In certain embodiments, X is O.

[0080] In certain embodiments, each R 4 are independently -H.

[0081] In certain embodiments, each R 4 independently, C 1-6 aliphatic, C 3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0082] In certain embodiments, each R 4 is independently methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl; each of which is optionally substituted.

[0083] In certain embodiments, each R 4are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl thiazolyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted;

[0084] In certain embodiments, each R 4 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0085] In certain embodiments, each R 4 are independently -H, C 1-6 aliphatic, -OR, -C(O)R, -COR, -C(O)N(R), -NRc(O)R, -NRc(O)N(R), -NRSOR, or -N(R); each of which is optionally substituted.

[0086] In certain embodiments, each R 4are independently -H, C 1-6 aliphatic, -C(O)N(R)2, -NR C(O)R, or -N(R)2; each of which is optionally substituted.

[0087] In certain embodiments, each R 4 are, independently: [ka] [ka] [ka] [ka]

[0088] In certain embodiments, each R 4 are, independently: [ka]

[0089] In certain embodiments, each R 5 are independently -H.

[0090] In certain embodiments, each R 5 independently, C 1-6 aliphatic, C 3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0091] In certain embodiments, each R 5is independently methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl; each of which is optionally substituted.

[0092] In certain embodiments, each R 5are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl nyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted;

[0093] In certain embodiments, each R 5 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0094] In certain embodiments, each R 5 is independently methyl, cyclopropyl, —F, or —CF 3 .

[0095] In certain embodiments, each R 5 are independently: [ka] -F or -CF3.

[0096] In certain embodiments, X, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , k, m, n, p, r, and t are each as defined above and described singly or in combination in the embodiments, classes and subclasses above and herein.

[0097] In certain embodiments, the present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0098] In certain embodiments, the present invention provides a compound of formula Ib, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0099] In certain embodiments, the present invention provides a compound of formula Ic, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0100] In certain embodiments, the present invention provides a compound of formula Id, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0101] In certain embodiments, the present invention provides a compound of formula Ie, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0102] In certain embodiments, the present invention provides a compound of formula If, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, ring B, R 1 , R 2 , R3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0103] In certain embodiments, the present invention provides a compound of formula Ig, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, ring B, R 2 , R 3 , R 4 , R 5 , n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0104] In certain embodiments, the present invention provides a compound of formula Ih, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, R 1 , R 2 , R 3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0105] In certain embodiments, the present invention provides a compound of formula Ij, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, R 2 , R 3 , R 4 , R 5, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0106] In certain embodiments, the present invention provides a compound of formula Im, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, R 2 , R 3 , R 4 , R 5 , n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0107] In certain embodiments, the present invention provides a compound of formula In, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, R 1 , R 2 , R 3 , R 4 , R 5 , k, n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0108] In certain embodiments, the present invention provides a compound of formula Ip, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X, R 2 , R 3 , R 4 , R 5 , n, p, r, and t are as defined above and described singly or in combination in the embodiments, classes and subclasses herein).

[0109] In certain embodiments, the present invention provides a compound selected from Table 1: Table 1

[0110] [Table 1-1]

[0111] [Table 1-2]

[0112] [Table 1-3]

[0113] [Table 1-4]

[0114] [Table 1-5]

[0115] [Table 1-6]

[0116] [Table 1-7]

[0117] [Table 1-8]

[0118] [Table 1-9]

[0119] Table 1-10

[0120] Table 1-11

[0121] Table 1-12

[0122] Table 1-13

[0123] Table 1-14

[0124] Table 1-15

[0125] Table 1-16

[0126] Table 1-17

[0127] Table 1-18

[0128] Table 1-19

[0129] Table 1-20

[0130] Table 1-21

[0131] Table 1-22

[0132] Table 1-23

[0133] Table 1-24

[0134] Table 1-25

[0135] Table 1-26

[0136] Table 1-27

[0137] Table 1-28

[0138] Table 1-29

[0139] Table 1-30

[0140] Table 1-31

[0141] Table 1-32

[0142] Table 1-33

[0143] Table 1-34

[0144] Table 1-35

[0145] Table 1-36

[0146] Table 1-37

[0147] Table 1-38

[0148] Table 1-39

[0149] Table 1-40

[0150] Table 1-41

[0151] Table 1-42

[0152] Table 1-43

[0153] Table 1-44

[0154] Table 1-45

[0155] Table 1-46

[0156] Table 1-47

[0157] Table 1-48

[0158] Table 1-49

[0159] Table 1-50

[0160] Table 1-51

[0161] Table 1-52

[0162] Table 1-53

[0163] Table 1-54

[0164] Table 1-55

[0165] Table 1-56

[0166] Table 1-57

[0167] Table 1-58

[0168] Table 1-59

[0169] Table 1-60

[0170] Table 1-61

[0171] Table 1-62

[0172] Table 1-63

[0173] Table 1-64

[0174] Table 1-65

[0175] Table 1-66

[0176] Table 1-67

[0177] Table 1-68

[0178] Table 1-69

[0179] Table 1-70

[0180] Table 1-71

[0181] Table 1-72

[0182] Table 1-73

[0183] Table 1-74

[0184] Table 1-75

[0185] Table 1-76

[0186] Table 1-77

[0187] Table 1-78

[0188] Table 1-79

[0189] Table 1-80

[0190] Table 1-81

[0191] Table 1-82

[0192] Table 1-83

[0193] Table 1-84

[0194] Table 1-85

[0195] Table 1-86

[0196] Table 1-87

[0197] Table 1-88

[0198] Table 1-89

[0199]

Table 1-90

[0200] Table 1-91

[0201] Table 1-92

[0202] Table 1-93

[0203] Table 1-94

[0204] Table 1-95

[0205] Table 1-96

[0206] Table 1-97

[0207] Table 1-98

[0208] Table 1-99

[0209]

Table 1-100

[0210] In some embodiments, the present invention provides a compound selected from those depicted above, or a pharmaceutically acceptable salt thereof.

[0211] Various structural depictions may show heteroatoms without attached groups, radicals, charges, or counterions. Those skilled in the art will appreciate that such depictions may indicate heteroatoms bonded to hydrogens (e.g., [ka] teeth, [ka] I know that this means that the

[0212] In certain embodiments, compounds of the present invention were synthesized according to the schemes provided in the examples below.

[0213] 4. Uses, Formulation and Administration Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is such that it is effective to measurably inhibit TLR7 / 8, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in the composition of the present invention is such that it is effective to measurably inhibit TLR7 / 8, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition.

[0214] The terms "patient" or "subject," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0215] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0216] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof.

[0217] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention include aqueous or oily suspensions. These suspensions are formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as a solution of 1,3-butanediol. Among the acceptable vehicles and solvents employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0218] For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in injectable preparations, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens and Spans, as well as other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0219] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form.Examples of oral dosage forms are capsules, tablets, aqueous suspensions or liquids.For tablets for oral use, commonly used carriers are lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavors or coloring agents are also optionally added.

[0220] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the substance with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0221] Pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0222] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.

[0223] For external application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Examples of carriers for external administration of the present compound include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0224] The pharmaceutically acceptable compositions of the present invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and are prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0225] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered together with or separately from food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered separately from food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered together with food.

[0226] The amount of the compounds of the present invention that are optionally combined with a carrier material to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, the compositions provided should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0227] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, excretion rate, concomitant medications, and the judgment of the attending physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will depend on the particular compound in the composition.

[0228] Uses of the Compounds and Pharmaceutically Acceptable Compositions The present invention further relates to a method of treating a subject suffering from a TLR7 / 8-associated disorder, comprising administering to the subject an effective amount of a compound of Formula I and related formulae.

[0229] The compounds of the present invention are useful as anti-cancer agents for cancers that respond to TLR7 activation. In certain embodiments, these cancers include, but are not limited to, cancers of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testicle, stomach, skin, ureter, vagina, and vulva; hereditary cancers, retinoblastoma, and Wilms' tumor; leukemia, lymphoma, non-Hodgkin's lymphoma, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, multiple myeloma, and T-cell lymphoma; myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndrome, cancer of unknown primary site, and AIDS-related malignancies.

[0230] In certain embodiments, the compounds of the present invention are used to treat cancers of the skin or kidney.The susceptibility of a given cancer to activating TLR7 can be assessed by, but is not limited to, measuring a reduction (minimal, partial or complete regression) in primary or metastatic tumor burden, changes in blood picture, altered hormone or cytokine blood levels, inhibition of further increase in tumor burden, stabilization of disease in patients, evaluation of disease-related biomarkers or surrogate markers, prolonged overall patient survival, prolonged time to disease progression in patients, prolonged progression-free survival in patients, prolonged disease-free survival in patients, improved quality of life in patients, or changes in co-morbidities (for example, but not limited to, pain, cachexia, mobilization, hospitalization, altered blood picture, weight loss, wound healing, fever, etc.).

[0231] The compounds of the present invention are further useful as immune response modifiers, modifying the immune response in a number of different ways, making them useful in the treatment of a variety of disorders.

[0232] Provided herein are methods for inhibiting an immune response in an individual, comprising administering to the individual an effective amount of an inhibitor of TLR7 and / or TLR8 (e.g., a TLR inhibitor) using a compound described herein. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits both TLR7-dependent and TLR8-dependent immune responses. In some variations, the TLR inhibitor inhibits TLR7-dependent, TLR8-dependent, and other TLR-dependent immune responses. Unless otherwise noted, the term TLR inhibitor refers to any one of the TLR inhibitors disclosed herein. In some preferred embodiments, the individual is a human patient.

[0233] Immunomodulatory methods are provided by the present disclosure and include those that suppress and / or inhibit immune responses, including, but not limited to, immune responses. The present disclosure also provides methods for ameliorating symptoms associated with unwanted immune activation, including, but not limited to, symptoms associated with autoimmunity. Immunosuppression and / or inhibition by the methods described herein may be practiced in individuals, including those suffering from disorders associated with unwanted activation of the immune response. The present disclosure also provides methods for inhibiting TLR7- and / or TLR8-induced responses (e.g., in vitro or in vivo). In some variations, cells are contacted with a TLR inhibitor in an amount effective to inhibit responses from cells that contribute to the immune response.

[0234] Inhibition of TLR7 and / or TLR8 is useful for the treatment and / or prevention of various diseases or disorders that respond to cytokines. Conditions for which TLR7 and / or TLR8 inhibitors can be used as treatments include, but are not limited to, autoimmune diseases and inflammatory disorders. Provided herein are methods for treating or preventing a disease or disorder in an individual, comprising administering to the individual an effective amount of a TLR7 and / or TLR8 inhibitor. Also provided are methods for ameliorating symptoms associated with a disease or disorder, comprising administering to an individual having the disease or disorder an effective amount of a TLR7 and / or TLR8 inhibitor. Also provided herein are methods for preventing or delaying the onset of a disease or disorder, comprising administering to an individual having the disease or disorder an effective amount of one or more inhibitors of TLR7 and / or TLR8. In certain embodiments, the inhibitor is a compound described herein.

[0235] Provided herein are methods of inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor disclosed herein in an amount effective to inhibit an immune response in the individual. In some variations, the immune response is associated with an autoimmune disease. In further embodiments, inhibiting the immune response therein ameliorates one or more symptoms of the autoimmune disease. In even further embodiments, inhibiting the immune response therein treats the autoimmune disease. In still further embodiments, inhibiting the immune response therein prevents or delays the onset of the autoimmune disease. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits both TLR7- and TLR8-dependent immune responses. In some embodiments, at least one TLR inhibitor is administered in an amount effective to inhibit an immune response in the individual.

[0236] Also provided herein is a method for treating or preventing an autoimmune disease in an individual, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor to the individual. In some embodiments, the autoimmune disease is characterized by joint pain, positive antinuclear antibodies, malar rash, or discoid rash. In some embodiments, the autoimmune disease is associated with skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is not evidenced in the individual by symptoms of skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases include, but are not limited to, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type 1 diabetes, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic-onset arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases may also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold fever.

[0237] In some embodiments, the autoimmune disease is selected from the group consisting of arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholipid syndrome (APS), systemic onset arthritis, and irritable bowel syndrome.

[0238] In other embodiments, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin diseases, and multiple sclerosis.

[0239] In other embodiments, the autoimmune disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelitis, sclerosing cholangitis, and type 1 diabetes. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is autoimmune pancreatitis (AIP). In some embodiments, the autoimmune disease is glomerulonephritis. In some embodiments, the autoimmune disease is pyelitis. In some embodiments, the autoimmune disease is sclerosing cholangitis. In some embodiments, the autoimmune disease is psoriasis. In some embodiments, the autoimmune disease is a rheumatic disease or disorder. In some embodiments, the rheumatic disease or disorder is rheumatoid arthritis. In some embodiments, the disease is diabetes and / or diabetes-related diseases or disorders. In some embodiments, the autoimmune disease is associated with RNA-containing immune complexes. In some embodiments, the autoimmune disease is Sjogren's disease.

[0240] Provided herein are methods for inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is associated with an inflammatory disorder. As used herein, the term "inflammatory disorder" encompasses autoimmune diseases as well as inflammatory conditions without a known autoimmune component (e.g., atherosclerosis, asthma, etc.). In further embodiments, inhibiting the immune response ameliorates one or more symptoms of the inflammatory disorder. In even further embodiments, inhibiting the immune response treats the inflammatory disorder. In still further embodiments, inhibiting the immune response prevents or delays the onset of the inflammatory disorder. In some embodiments, the inflammatory disorder is selected from the group consisting of non-rheumatoid arthritis, renal fibrosis, and hepatic fibrosis. In some embodiments, the inflammatory disorder is border dermatitis. In some further embodiments, the border dermatitis is selected from the group consisting of lichen planus, lichenoid eruption, lichen planus-like keratosis, linear lichen, chronic lichenoid keratosis, erythema multiforme, fixed drug eruption, pityriasis lichenoides, phototoxic dermatitis, radiation dermatitis, viral rash, dermatomyositis, secondary syphilis, lichen sclerosus et atrophicus, mycosis fungoides, bullous pemphigoid, lichen xanthoides, porokeratosis, acrodermatitis chronica atrophica, and regressing melanoma. In some embodiments, the inflammatory condition is a skin disorder such as atopic dermatitis (eczema). In some embodiments, the inflammatory disorder is a sterile inflammatory condition such as drug-induced liver and / or pancreatic inflammation. In some further embodiments, the inflammatory disease is an inflammatory liver disorder. In some other further embodiments, the inflammatory disease is an inflammatory pancreatic disorder.

[0241] Provided herein are methods for inhibiting an immune response in an individual, comprising administering to the individual at least one TLR inhibitor as disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is associated with chronic pathogen stimulation. In some variations, the immune response is associated with infection with HIV. In further embodiments, inhibiting the immune response therein ameliorates one or more symptoms of a viral disease or disorder resulting from infection with HIV. In even further embodiments, inhibiting the immune response therein treats a viral disease or disorder resulting from infection with HIV. In still further embodiments, inhibiting the immune response therein prevents or delays the onset of a viral disease or disorder resulting from infection with HIV. Another variation provided herein relates to immunosuppressive therapy of an individual exposed to or infected with HIV. Administration of a TLR inhibitor to an individual exposed to or infected with HIV results in suppression of HIV-induced cytokine production. In some embodiments, the at least one TLR inhibitor is administered in an amount effective to suppress HIV-induced cytokine production in an individual exposed to or infected with HIV.

[0242]

[0010] Provided herein are methods for inhibiting a TLR7- and / or TLR8-dependent immune response in an individual, the methods comprising administering to the individual an amount of a TLR inhibitor effective to inhibit the immune response in the individual. In some variations, the immune response is associated with an autoimmune disease. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of rheumatoid arthritis. In some embodiments, the autoimmune disease is multiple sclerosis. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of multiple sclerosis. In some embodiments, the autoimmune disease is lupus. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of lupus. In some embodiments, the autoimmune disease is pancreatitis. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of pancreatitis. In some embodiments, the autoimmune disease is diabetes. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of diabetes. In some embodiments, the disease is Sjogren's disease. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of Sjogren's disease. In some variations, the immune response is associated with an inflammatory disorder. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of an inflammatory disorder. In some variations, the immune response is associated with chronic pathogen stimulation. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of chronic pathogen stimulation. In some variations, the immune response is associated with a viral disease resulting from HIV infection. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of a viral disease resulting from HIV infection. In any variation, the TLR inhibitor is a polynucleotide comprising one or more inhibitory motifs of TLR7, TLR8, and TLR9.

[0243] In some embodiments of any method involving administration of a TLR inhibitor to an individual (e.g., methods for inhibiting an immune response, treating or preventing an autoimmune disease or inflammatory disorder, etc.), the TLR inhibitor has a therapeutically acceptable safety profile. The TLR inhibitor can have a therapeutically acceptable histological profile, including, for example, acceptably low, if any, toxicity to the liver, kidney, pancreas, or other organs. In some cases, the polynucleotide is associated with toxicity to specific organs, such as the liver, kidney, and pancreas. In some embodiments, the TLR inhibitor has an unexpectedly advantageous safety profile. In some embodiments, the safety profile includes assessment of toxicity, histological profile, and / or necrosis (e.g., liver, kidney, and / or heart). In some embodiments, the TLR inhibitor has a therapeutically acceptable level of toxicity. In some embodiments, the TLR inhibitor has a reduced level of toxicity compared to another TLR inhibitor. In some embodiments, the TLR inhibitor includes a therapeutically acceptable reduction in body weight compared to the treated individual's initial body weight. In some embodiments, the TLR inhibitor induces a decrease of less than 5%, 7.5%, 10%, 12.5, or 15% of total body weight. In some embodiments, the TLR inhibitor has a therapeutically acceptable histological profile. In some embodiments, the TLR inhibitor has a better histological profile (e.g., lower severity score), e.g., compared to a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a better histological profile (e.g., lower severity score), e.g., when evaluating the liver, kidney, and / or heart. In some embodiments, the TLR inhibitor has a therapeutically acceptable necrosis score. In some embodiments, the TLR inhibitor has reduced necrosis and / or a better (e.g., lower) necrosis score, e.g., compared to a reference TLR inhibitor. In some embodiments, the TLR inhibitor has reduced renal and / or hepatocellular necrosis and / or a better renal and / or hepatocellular necrosis score, eg, compared to a reference TLR inhibitor.

[0244] Accordingly, the present invention provides methods for activating TLR7 in animals, particularly mammals, preferably humans, comprising administering to the animal an effective amount of a compound of Formula I. As with all compositions for inhibiting an immune response, the effective amount and method of administration of a particular TLR inhibitor formulation can vary based on the individual, the condition being treated, and other factors apparent to one of skill in the art. While an effective amount of the compound will vary according to factors known in the art, it is expected that the dosage will be about 0.1-10 mg / kg, 0.5-10 mg / kg, 1-10 mg / kg, 0.1-20 mg / kg, 0.1-20 mg / kg, or 1-20 mg / kg.

[0245] The present invention also provides a method for treating a viral infection in an animal, comprising administering to the animal an effective amount of a compound of Formula I. An effective amount for treating or inhibiting a viral infection is an amount that causes a decrease in one or more symptoms of the viral infection, such as viral foci, viral load, viral production rate, and mortality, compared to untreated control animals. The exact amount will vary according to known factors, but is expected to be a dose as set forth above for activating TLR7, or from about 100 ng / kg to about 50 mg / kg, preferably from about 10 μg / kg to about 5 mg / kg.

[0246] In various embodiments, compounds of Formula (I) and related formulae exhibit an IC50 for binding to TLR7 / 8 of less than about 5 μM, preferably less than about 1 μM, and even more preferably less than about 0.100 μM.

[0247] The methods of the present invention can be carried out either in vitro or in vivo. The susceptibility of a particular cell to treatment with a compound of the present invention, whether in a research process or for clinical application, can be determined particularly by in vitro testing. Typically, a culture of cells is combined with various concentrations of a compound of the present invention for a period of time sufficient for the active substance to inhibit TLR7 / 8 activity, usually between about one hour and one week. In vitro treatment can be carried out using cultured cells from a biopsy sample or a cell line.

[0248] The host or patient can belong to any mammalian species, such as a primate species, particularly humans; rodents, including mice, rats, and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental studies, providing models for the treatment of human diseases.

[0249] To identify signal transduction pathways and detect interactions between various signal transduction pathways, various scientists have developed suitable models or model systems, such as cell culture models and transgenic animal models. To determine the specific stage of the signal transduction cascade, interacting compounds can be used to modify the signal. The compounds of the present invention can also be used as reagents for studying TLR7 / 8-dependent signal transduction pathways in animal and / or cell culture models or in the clinical diseases mentioned in this application.

[0250] Furthermore, the remainder of this specification relating to the use of compounds of formula (I) and derivatives thereof for the manufacture of medicaments for prophylactic or therapeutic treatment and / or monitoring is deemed to be illustrative and applicable, even for convenience, and is not limited to the use of the compounds for the inhibition of TLR7 / 8 activity.

[0251] The present invention also relates to the use of compounds of formula (I) and / or physiologically acceptable salts thereof for the preventive or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or propagated by TLR7 / 8 activity. Furthermore, the present invention relates to the use of compounds of formula (I) and / or physiologically acceptable salts thereof for the manufacture of a medicament for the preventive or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or propagated by TLR7 / 8 activity. In a particular embodiment, the present invention provides the use of compounds of formula I or physiologically acceptable salts thereof for the manufacture of a medicament for the preventive or therapeutic treatment of TLR7 / 8-mediated disorders.

[0252] The compounds of formula (I) and / or their physiologically acceptable salts can further be used as intermediates for the preparation of further active pharmaceutical ingredients, which are preferably prepared by non-chemical methods, for example by combining the active ingredient with at least one solid, liquid and / or semi-liquid carrier or excipient, and optionally in combination with one or more other active substances, in a suitable dosage form.

[0253] The compounds of formula (I) of the present invention can be administered once or several times before or after the onset of a disease to serve as a treatment. The aforementioned compounds and medicinal products in the inventive use are particularly used for therapeutic treatment. A therapeutically relevant effect is to alleviate one or more symptoms of a disorder to some extent, or to restore one or more physiological or biochemical parameters related to the cause of a disease or pathological condition, either partially or completely, to normal. Monitoring is considered a type of treatment when these compounds are administered at separate intervals, for example, to enhance the response and completely eradicate pathogens and / or disease symptoms. Either the same compound or different compounds can be applied. The methods of the present invention can also be used to reduce the probability of developing a disorder, or even prevent the onset of a disorder related to TLR7 / 8 activity, or to treat existing and ongoing symptoms.

[0254] In the sense of the present invention, prophylactic treatment is indicated when the subject has a prerequisite for any of the aforementioned physiological or pathological conditions, such as a familial predisposition, a genetic defect, or a previously suffered disease.

[0255] The present invention further relates to pharmaceutical preparations containing at least one compound of the invention and / or its pharmaceutically useful derivatives, salts, solvates and stereoisomers, including mixtures thereof in all ratios. In certain embodiments, the present invention relates to pharmaceutical preparations containing at least one compound of the invention and / or its physiologically acceptable salts.

[0256] A "medicine" in the sense of the present invention is any substance in the field of medicines, comprising one or more compounds of formula (I) or their preparations (e.g. pharmaceutical compositions or pharmaceutical formulations), and which can be used for the prevention, treatment, follow-up or convalescent health care of patients suffering from diseases associated with TLR7 / 8 activity, so that a pathogenic modification of the patient's general condition or of the condition in a specific area of ​​the organism is established, at least temporarily.

[0257] In various embodiments, the active ingredient may be administered alone or in combination with other treatments. Synergistic effects may be achieved by the use of two or more compounds in a pharmaceutical composition, i.e., a compound of formula (I) is combined with at least another substance as the active ingredient, either another compound of formula (I) or a compound of a different structural framework. These active ingredients may be used either simultaneously or sequentially.

[0258] The TLR inhibitors of the present disclosure can be administered in combination with one or more additional therapeutic agents. As described herein, the TLR inhibitors can be combined with a physiologically acceptable carrier. The methods described herein can be practiced in combination with other therapies that constitute standard treatment for the disorder, such as the administration of anti-inflammatory drugs.

[0259] In some embodiments, the TLR inhibitors described herein are administered in combination with a corticosteroid. In some embodiments, the corticosteroid is a glucocorticosteroid. In some embodiments, the corticosteroid is a mineralocorticoid. Corticosteroids include corticosterone and its derivatives, prodrugs, isomers, and analogs, cortisone and its derivatives, prodrugs, isomers, and analogs (i.e., Cortone), aldosterone and its derivatives, prodrugs, isomers, and analogs, dexamethasone and its derivatives, prodrugs, isomers, and analogs (i.e., Decadron), prednisone and their derivatives, prodrugs, isomers, and analogs (i.e., Prelon), fludrocortisone and its derivatives, prodrugs, isomers, and analogs, hydrocortisone and their derivatives, prodrugs, isomers, and analogs (i.e., Cortisol or Cortef), hydroxycortisone and and derivatives, prodrugs, isomers, and analogs thereof, betamethasone and its derivatives, prodrugs, isomers, and analogs (i.e., Celestone), budesonide and its derivatives, prodrugs, isomers, and analogs (i.e., Entocort EC), methylprednisolone and its derivatives, prodrugs, isomers, and analogs (i.e., Melodol), prednisolone and its derivatives, prodrugs, isomers, and analogs (i.e., Deltasone, Crtan, Methycortene, Orasone, or Stellapred), triamcinolone and its derivatives, prodrugs, isomers, and analogs (i.e., Kenacort or Kenalog), and the like. In some embodiments, the corticosteroid is fludrocortisone or a derivative, prodrug, isomer, or analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone or a derivative, prodrug, isomer, or analog thereof. In some embodiments, the corticosteroid is hydroxycortisone.

[0260] In some embodiments, the corticosteroid is administered at about 0.001 mg to 1 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 120 mg, 120 mg to 200 mg, 200 mg to 500 mg, or 500 mg to 1000 mg per day. In some embodiments, the corticosteroid is administered at about 0.1 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 2 mg / kg to 5 mg / kg, 5 mg / kg to 10 mg / kg, 10 mg / kg to 15 mg / kg, 15 mg / kg to 20 mg / kg, 20 mg / kg to 25 mg / kg, 25 mg / kg to 35 mg / kg, or 35 mg / kg to 50 mg / kg per day.

[0261] In some embodiments, the TLR inhibitor used in the combination therapy may be delivered in an amount of TLR inhibitor ranging from, for example, about 0.1 to 10 mg / kg, 0.5 to 10 mg / kg, 1 to 10 mg / kg, 0.1 to 20 mg / kg, 0.1 to 20 mg / kg, or 1 to 20 mg / kg.

[0262] In some embodiments, the TLR inhibitor is administered simultaneously with one or more additional therapeutic agents (coadministration), including but not limited to, corticosteroids. In some embodiments, the TLR inhibitor is administered sequentially with the additional therapeutic agent (sequential administration), including but not limited to, corticosteroids. In some embodiments, sequential administration includes administering the TLR inhibitor or the additional therapeutic agent within any of about 1 minute, 5 minutes, 30 minutes, 1 hour, 5 hours, 24 hours, 48 ​​hours, or 1 week. In some embodiments, the TLR inhibitor is administered by the same route of administration as the additional therapeutic agent. In some embodiments, the TLR inhibitor is administered by a different route of administration than the additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered parenterally (e.g., central venous line, intraarterial, intravenous, intramuscular, intraperitoneal, intradermal, or subcutaneous injection), orally, intragastrointestinal, topically, nasopharyngeal, and pulmonary (e.g., inhalation or intranasal). In some embodiments, the additional therapeutic agent is a corticosteroid.

[0263] The disclosed compounds of Formula I can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any substance administered to a cancer patient for the purpose of treating the cancer.

[0264] The anti-cancer treatments defined above may be applied as monotherapy or may involve, in addition to the compounds of formula I disclosed herein, conventional surgery or radiation therapy or drug therapy. Such drug therapy, such as chemotherapy or targeted therapy, may include one or more, but preferably one, of the following anti-tumor agents: Alkylating agents: Altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-302 4 , VAL-083 4 etc; platinum compound : Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin, etc.; DNA modifying agents : Amrubicin, Bisantrene, Decitabine, Mitoxantrone, Procarbazine, Trabectedin, Clofarabine; Amsacrine, Brostallicin, Pixantrone, Laromustine 1,3 etc; Topoisomerase inhibitors : Etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin, etc.; Microtubule-active drugs : Cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabine, tesetaxel, etc.; Antimetabolites : Asparaginase 3 , azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacitarabine, raltitrexed, sapacitabine, tegafur 2,3, trimetrexate, etc.; anticancer antibiotics : Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin; aclarubicin, peplomycin, pirarubicin, etc.; Hormones / antagonists Abarelix, abiraterone, bicalutamide, buserelin, calcitriol, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyroid-stimulating hormone alpha, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide 1,3 etc; Aromatase inhibitors : Aminoglutethimide, Anastrozole, Exemestane, Fadrozole, Letrozole, Testolactone; Formestane, etc.; Small molecule kinase inhibitorsCrizotinib, Dasatinib, Erlotinib, Imatinib, Lapatinib, Nilotinib, Pazopanib, Regorafenib, Ruxolitinib, Sorafenib, Sunitinib, Vandetanib, Vemurafenib, Bosutinib, Gefitinib, Axitinib; Afatinib, Alisertib, Dabrafenib, Dacomitinib, Dinaciclib, Dovitinib, Enzastaurin, Nintedanib, Lenvatinib, Linifanib, Linsitinib, Mafia Citinib, Midostaurin, Motesanib, Neratinib, Orantinib, Perifosine, Ponatinib, Radotinib, Rigosertib, Tipifarnib, Tivantinib, Tivozanib, Trametinib, Pimasertib, Brivanib, Alaninate, Cediranib, Apatinib 4 , Cabozantinib S-Malate 1,3 , ibrutinib 1,3 , icotinib 4 , Buparisib 2 , cifatinib 4 , cobimetinib 1,3 , idelalisib 1,3 , fedratinib 1 , XL-647 4 etc; Photosensitizers :Methoxsalen 3 ;porfimer sodium, talaporfin, temoporfin, etc.; antibody : Alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3 Catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocalatuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab 1,2,3 , onartuzumab 1,3 , Lakotsumobab1 , tabalumab 1,3 , EMD-525797 4 , nivolumab 1,3 etc; cytokines : Aldesleukin, interferon alpha 2 , interferon alpha 2a 3 , interferon α2b 2,3 ; Celmoleukin, tasonermin, teseleukin, oprelvekin 1,3 , recombinant interferon beta-1a 4 etc; Drug conjugates : Denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; syntredequin besudotox, edotreotide, inotuzumab ozogamicin, naptumovab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab 1,3 , Bintaferid 1,3 etc; vaccine :Sipuleucel 3 ;Vitespen 3 , emepepimut-S 3 , oncoVAX 4 , Rindopepimut 3 , troVax 4 , MGN-1601 4 , MGN-1703 4 etc.; and Others: alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronate, pegaspargase, pentostatin, sipuleucel 3, sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxyl, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazole, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, travedelsen, ubenimex, valspodar, gendicine 4 , Picibanil 4 , leolysin 4 , retaspimycin hydrochloride 1,3 , trebananib 2,3 , virurisin 4 , carfilzomib 1,3 , endostatin 4 , Imcotel 4 , belinstat 3 , MGN-1703 4 . ( 1 Prop. INN (Proposed International Nonproprietary Name); 2 Rec. INN (Recommended International Nonproprietary Name); 3 USAN (United States Adopted Name); 4 Non-INN).

[0265] In some embodiments, the combination of a TLR inhibitor with one or more additional therapeutic agents reduces the effective amount (including, but not limited to, dose volume, dose concentration, and / or total drug dose) of the TLR inhibitor and / or one or more additional therapeutic agents to achieve the same result compared to the effective amount administered when the TLR inhibitor or additional therapeutic agent is administered alone. In some embodiments, the combination of a TLR inhibitor with a corticosteroid reduces the effective amount of the corticosteroid administered compared to the corticosteroid administered alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the frequency of administration of the therapeutic agent compared to administration of the additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the total duration of treatment compared to administration of the additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces side effects associated with administration of the additional therapeutic agent alone. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is fludrocortisone or a derivative, prodrug, isomer, or analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the combination of an effective amount of a TLR inhibitor with an additional therapeutic agent is more potent than an effective amount of either the TLR inhibitor or the additional therapeutic agent alone.

[0266] TLR inhibitors are also useful as vaccine adjuvants for use with any substance that alters either the humoral and / or cellular immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoan, organism-derived, fungal, or bacterial immunogens, toxoids, toxins; autoantigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides. In some embodiments, combination therapies, including but not limited to, TLR inhibitors and vaccines, are used in the treatment of autoimmune diseases or inflammatory disorders. In some embodiments, combination therapies, including but not limited to, TLR inhibitors and vaccines, are used in the treatment of infectious diseases.

[0267] In some embodiments, the combination therapy, including but not limited to the combination of TLR inhibitor and corticosteroid, is used to treat autoimmune disease or inflammatory disorders.In some embodiments, the autoimmune disease is selected from, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, autoimmune skin disease, multiple sclerosis, pancreatitis, glomerulonephritis, pyelitis, sclerosing cholangitis and type 1 diabetes.In some embodiments, the autoimmune disease is Sjogren's disease.

[0268] Also provided herein are kits containing the TLR inhibitors provided herein and instructions for use in methods of inhibiting TLR7- and / or TLR8-dependent immune responses.

[0269] The kit may include one or more containers containing a TLR inhibitor (or a formulation containing a TLR inhibitor) described herein, as well as a set of package inserts, typically written, but also acceptable electronic storage media (e.g., magnetic or optical disks) containing the package inserts, regarding the use and dosage of the TLR inhibitor or formulation for the intended treatment (e.g., suppressing responses to TLR7 and / or TLR8 agonists, suppressing TLR7 and / or TLR8-dependent immune responses, ameliorating one or more symptoms of an autoimmune disease, ameliorating symptoms of a chronic inflammatory disease, reducing cytokine production in response to a virus, and / or treating and / or preventing one or more symptoms of a disease or disorder mediated by TLR7 and / or TLR8). The package insert included in the kit typically includes information regarding the dosage, dosing schedule, and route of administration for the intended treatment. The containers for the TLR inhibitor (or formulation containing a TLR inhibitor) may be unit doses, bulk packages (e.g., multi-dose packages), or sub-unit doses. The kit further includes a container containing an adjuvant.

[0270] In another aspect, the present invention provides a kit consisting of separate packs containing effective amounts of the compounds of the present invention and / or their pharmaceutically acceptable salts, derivatives, solvates, and stereoisomers, including any ratio of mixtures thereof, and, optionally, effective amounts of additional active ingredients. The kit comprises suitable containers such as boxes, separate bottles, bags, or ampoules. The kit may, for example, contain separate ampoules, each containing an effective amount of the compounds of the present invention and / or their pharmaceutically acceptable salts, derivatives, solvates, and stereoisomers, including any ratio of mixtures thereof, and an effective amount of the additional active ingredient in dissolved or lyophilized form.

[0271] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered asymptomatically. For example, treatment is administered to a susceptible individual before the onset of symptoms (e.g., taking into account medical history and / or genetic or other susceptibility factors). Treatment is also continued after symptoms have ameliorated, e.g., to prevent or delay their recurrence.

[0272] The compounds and compositions of the present invention may be administered in any amount and via any route of administration effective for treating or reducing the severity of the disorders described above. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific substance, its mode of administration, and the like. The compounds of the present invention are preferably formulated in a unit dosage form with uniform dosages for ease of administration. As used herein, the term "unit dosage form" refers to a physically discrete unit of material appropriate for the patient being treated. However, it will be understood that the total daily dosage of the compounds or compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will vary depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general condition, sex, and diet of the patient; the time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concurrently with the specific compound used, and similar factors well known in the medical field.

[0273] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), buccally, or by oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention are administered orally or parenterally at a dosage level of about 0.01 mg to about 100 mg, and preferably about 1 mg to about 50 mg, per kg of subject body weight per day, one or more times per day to achieve the desired therapeutic effect.

[0274] In certain embodiments, the therapeutically effective amount of compounds of Formula (I) and related formulae, as well as other active ingredients, will depend on numerous factors, including, for example, the age and weight of the animal, the exact condition and severity of the disease requiring treatment, the nature of the formulation and method of administration, and will ultimately be determined by the attending physician or a skilled practitioner. However, an effective amount of a compound will generally be in the range of 0.1 to 100 mg per kg of recipient (mammal) body weight per day, with a more typical range being 1 to 10 mg per kg of body weight per day. Thus, the actual daily amount for an adult mammal weighing 70 kg will usually be 70 to 700 mg, administered as individual doses per day or as a series of partial doses (e.g., 2, 3, 4, 5, or 6 times per day) so that the total daily dose is the same. The effective amount of a salt or solvate or physiologically functional derivative thereof can be determined as a fraction of the effective amount of the compound itself.

[0275] In certain embodiments, pharmaceutical preparations can be administered in unit dosage forms, each containing a predetermined amount of active ingredient. Such units can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg of the compound of the present invention, depending on the disease state to be treated, the method of administration, and the age, weight, and condition of the patient. Alternatively, pharmaceutical preparations can be administered in unit dosage forms, each containing a predetermined amount of active ingredient. Preferred unit dosage formulations are those containing the daily dose or partial dose, as indicated above, or a corresponding fraction thereof, of the active ingredient. Furthermore, such pharmaceutical preparations can be prepared using processes generally known in the pharmaceutical arts.

[0276] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms optionally contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also contain auxiliary substances, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and perfuming agents.

[0277] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, are formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations are also sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0278] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0279] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This is accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a compound therefore depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0280] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0281] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or calcium hydrogen phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum acacia; c) humectants, such as glycerol; d) agar-agar, calcium carbonate, potato starch, and the like. or disintegrating agents such as tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form also optionally contains a buffering agent.

[0282] Solid compositions of a similar type are also used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. These can optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type are also used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0283] The active compound may also be in microencapsulated form with one or more excipients as noted above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, for example, magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, these dosage forms also optionally contain buffering agents. They may also optionally contain opacifying agents and be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0284] Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0285] According to one embodiment, the present invention relates to a method of inhibiting TLR7 / 8 activity in a biological sample comprising contacting said biological sample with a compound of the present invention or a composition containing said compound.

[0286] According to another embodiment, the present invention relates to a method for inhibiting the activity of TLR7 / 8 or a mutant thereof in a biological sample in a positive manner, comprising the step of contacting said biological sample with a compound of the present invention, or a composition containing said compound.

[0287] The compounds of the present invention are useful in vitro as unique tools for understanding the biological role of TLR7 / 8, including assessing the many factors that influence and are influenced by TLR7 / 8 generation and TLR7 / 8 interaction. Because the compounds provide important structure-activity relationship (SAR) information that facilitates development, the compounds are also useful in the development of other compounds that interact with TLR7 / 8. Compounds of the present invention that bind to TLR7 / 8 can be used as reagents to detect TLR7 / 8 in live cells, fixed cells, biological fluids, tissue homogenates, purified natural biological materials, and the like, for example, by labeling such compounds to identify cells expressing TLR7 / 8. Additionally, based on their ability to bind to TLR7 / 8, the compounds of the present invention can be used in in situ staining, FACS (fluorescence-activated cell sorting), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA (enzyme-linked immunosorbent assay), and other enzyme purification methods, or in the purification of TLR7 / 8-expressing cells inside permeabilized cells. The compounds of the present invention may also be utilized as commercial research reagents for a variety of medical research and diagnostic applications.Such uses may include, but are not limited to, use as calibration standards to quantify the activity of candidate TLR7 / 8 inhibitors in various functional assays; use as blocking reagents in random compound screens, i.e., in the search for new families of TLR7 / 8 ligands, these compounds can be used to block the recovery of the presently claimed TLR7 / 8 compounds; use in co-crystallization with TLR7 / 8, i.e., compounds of the invention can form crystals of the compound bound to TLR7 / 8, allowing the determination of the enzyme / compound structure by X-ray crystallography; other research and diagnostic applications, where TLR7 / 8 is preferably activated, or such activation is conveniently calibrated against known amounts of, e.g., TLR7 / 8 inhibitors; use in assays as probes to determine the expression of TLR7 / 8 in cells; and use in the development of assays to detect compounds that bind to the same site as TLR7 / 8-binding ligands.

[0288] The compounds of the present invention can be applied either by themselves and / or in combination with physical measurements for diagnosing therapeutic efficacy. Pharmaceutical compositions containing the compounds and their use for treating TLR7 / 8-mediated conditions are promising new approaches for broad-spectrum therapy that cause direct and immediate improvement in health status in either humans or animals. The orally bioavailable and active novel chemical entities of the present invention improve patient convenience and physician compliance.

[0289] The compounds of formula (I), their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and / or metabolites are characterized by high specificity and stability, low production costs and convenient handling. These characteristics form the basis for reproducible action, including the lack of cross-reactivity, for reliable and safe interaction with target structures.

[0290] As used herein, a "biological sample" includes, but is not limited to, a cell culture or an extract thereof; a biopsy obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0291] Altering the activity of TLR7 / 8 or their variants in biological samples is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays. [Example]

[0292] As shown in the Examples below, in certain illustrative embodiments, compounds are prepared according to the following general procedures. While the general methods refer to the synthesis of specific compounds of the invention, it will be understood that the following general methods, and other methods known to those skilled in the art, are applicable to all compounds and subclasses and classes of these compounds, as described herein.

[0293] The symbols and conventions used in the description of the processes, schemes, and examples that follow are consistent with those used in contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0294] Unless otherwise specified, all temperatures are expressed in degrees Celsius.

[0295] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen. Flash column chromatography was generally performed using silica gel 60 (particle size 0.035-0.070 mm).

[0296] All NMR experiments were recorded either on a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR, or on a Bruker Mercury Plus 300 NMR spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR, or on a Bruker Avance III 400 NMR spectrometer equipped with a Bruker PABBO BB-1H / DZ GRD probe at 400 MHz for proton NMR. Most deuterated solvents typically contained 0.03%-0.05% v / v tetramethylsilane, which provides the reference signal ( 1 H and 13 The d was used as the reference signal (set to 0.00 for both C and C). When the deuterated solvent did not contain tetramethylsilane, the peak of the residual undeuterated solvent was used as the reference signal according to published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997).

[0297] LC-MS analysis was performed on one of two instruments:

[0298] The Shimadzu LC-MS system consisted of a UFLC 20-AD system and an LCMS 2020 MS detector. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. A linear gradient was applied, starting from 95% A (A: 0.05% TFA in water) over 2.2 min and ending at 100% B (B: 0.05% TFA in acetonitrile), for a total run time of 3.6 min. The column temperature was 40 °C, and the flow rate was 1.0 mL / min. The diode array detector scanned from 200 to 400 nm. The mass analyzer was equipped with an electrospray ionizer (ES) operated in positive or negative mode. The mass analyzer scanned from m / z 90 to 900 with a scan time of 0.6 s.

[0299] Agilent Technologies Agilent 1200 Series mass spectrometer using either atmospheric pressure ionization (APCI) or electrospray ionization (ESI). The diode array detector scanned from 200 to 400 nm. The mass spectrometer scanned from m / z 90 to 900 with a scan time of 0.6 seconds. Column: XBridge C8, 3.5 μm, 4.6 x 50 mm; Solvent A: water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow rate: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B, or LC / MS Waters ZMD (ESI).

[0300] HPLC data were obtained from either a SHIMAZU LC-MS instrument or an Agilent 1100 Series HPLC from Agilent Technologies using a column (XBridge C8, 3.5 μm, 4.6 × 50 mm) and two mobile phases (Mobile Phase A: water + 0.1% TFA; Mobile Phase B: ACN + 0.1% TFA). The flow rate was 2 ml / min. The gradient method was 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B, unless otherwise specified.

[0301] In general, compounds of Formula (I) and related formulae of the present invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they may be prepared by standard synthetic techniques. Generally, the synthetic route to any individual compound of Formula (I) and related formulae will depend on the specific substituents of each molecule, factors understood by those skilled in the art. The following general methods and procedures, illustrated below in the Examples, can be used to prepare compounds of Formula (I) and related formulae. Reaction conditions depicted in the following schemes, such as temperature, solvent, or co-reagent, are provided by way of example only and are not limiting. Where typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvent, etc.) are given, it will be understood that other experimental conditions can also be used unless otherwise specified. Optimum reaction conditions will vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures. For complete protection and deprotection methods, see Philip J. Kocienski, "Protecting Groups," Georg Thieme Verlag Stuttgart, New York, 1994, and Theodora W. Greene and Peter G. M. Wuts, "Protective Groups in Organic Synthesis," Wiley Interscience, 3rd Edition, 1999. Intermediate 1: 8-chloropyrido[2,3-b]pyrazine [ka]

[0302] Method A 8-Chloropyrido[2,3-b]pyrazineTo a solution of 4-chloropyridine-2,3-diamine (1.90 g, 13.20 mmol) in THF (100 mL) was added oxyaldehyde (1.00 g, 17.20 mmol) at room temperature. The resulting solution was then stirred at room temperature for 6 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to yield 8-chloropyrido[2,3-b]pyrazine as a yellow solid (2.10 g, 91%). MS: m / z=166.1 [M+H] + . Intermediate 2: 4-chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridine [ka]

[0303] Method B 4-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.85 g, 18.68 mmol) in DCM (100 mL) was added benzenesulfonyl chloride (4.95 g, 28.02 mmol), 4-dimethylaminopyridine (228 mg, 1.87 mmol), and triethylamine (5.67 g, 56.04 mmol) at room temperature. The resulting solution was then stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to yield 1-(benzenesulfonyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine as a white solid (4.98 g, 91%). MS: m / z = 292.9 [M+H] + .

[0304] Method C 4-chloro-2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]To a solution of 1-(benzenesulfonyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (1.86 g, 6.40 mmol) in THF (35 mL) at −78° C., n-BuLi solution (2.5 M in THF, 5 mL, 12.80 mmol) was added dropwise over 5 minutes. The resulting solution was stirred at −78° C. for 1 hour, after which iodoethane (2.20 g, 14.10 mmol) was slowly added. The reaction mixture was then slowly warmed from −78° C. to 0° C. over 3 hours with stirring. Upon completion of the reaction, it was quenched by the addition of saturated NH4Cl solution (20 mL), and the resulting mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 5% gradient) to give 1-(benzenesulfonyl)-4-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine as a white solid (591 mg, 29%). MS: m / z=320.8 [M+H] + .

[0305] Method D 4-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine To a solution of 1-(benzenesulfonyl)-4-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine (575 mg, 1.80 mmol) in MeOH (20 mL) was added potassium carbonate (592 mg, 4.30 mmol) at room temperature. The resulting mixture was then stirred at 50° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (50 mL). The insoluble solid in the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (443 mg, crude). MS: m / z=180.9 [M+H] + .

[0306] Method E 4-chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridineTo a solution of 4-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine (443 mg, crude) in acetonitrile (23 mL) was added CsCO (1.40 g, 4.30 mmol) and iodoethane (676 mg, 4.30 mmol) at room temperature. The resulting mixture was then stirred at 40 °C for 3.5 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (30 mL). The insoluble solids in the mixture were filtered, and the filtrate was concentrated under reduced pressure to give 4-chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridine as a yellow oil (333 mg, 89% for two steps). MS: m / z = 209.0 [M+H] + . Intermediate 3: 4-Chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine [ka]

[0307] Method F 4-chloro-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b] To a solution of 1-(benzenesulfonyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.85 mmol) in tetrahydrofuran (30 mL) at −78° C., LDA solution (2 M in THF, 3.4 mL, 6.85 mmol) was added dropwise. The resulting solution was stirred at −78° C. for 1 hour, and then iodomethane (0.97 g, 6.85 mmol) was slowly added. The resulting mixture was then stirred at −78° C. for 5 hours. Upon completion of the reaction, it was quenched with HO (30 mL), and the resulting mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure to give 1-(benzenesulfonyl)-4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine as a brown oil (2.50 g, crude).

[0308] 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine4-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine was prepared from 4-chloro-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine using Method D. The crude product was purified by flash chromatography eluting with MeOH in DCM (0% to 10% gradient) to give 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (900 mg, 79% for two steps). MS: m / z=166.9 [M+H] + .

[0309] Method G 4-Chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine To a solution of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (338 mg, 2.03 mmol) in N,N-dimethylformamide (10 mL) at −10° C., sodium hydroxide (240 mg, 6.00 mmol) was added. Iodomethane (284 mg, 2.00 mmol) was then added, and the resulting mixture was stirred at −10° C. for 4 hours. Upon completion of the reaction, the reaction mixture was diluted with DCM (100 mL), and the resulting mixture was washed with water (30 mL × 3). The organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 10% gradient) to yield 4-chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (300 mg, 82%). MS: m / z = 181.0 [M+H] + . Intermediate 4: tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate [ka]

[0310] tert-Butyl 5-methylpyridin-3-ylcarbamateTo a solution of 5-methylpyridin-3-amine (9.50 g, 88.0 mmol) in tetrahydrofuran (150 mL) at room temperature, NaHMDS solution (2 M in THF, 110 mL, 220.0 mmol) was added dropwise over 10 minutes. The resulting solution was stirred at room temperature for 1 hour. Then, BocO (21.14 g, 92.4 mmol) was added. The reaction mixture was stirred at room temperature for an additional 2 hours. When the reaction was complete, it was quenched by the addition of saturated NHCl solution (100 mL). The resulting mixture was extracted with ethyl acetate (150 mL x 3), and the organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 35% gradient) to give tert-butyl N-(5-methylpyridin-3-yl)carbamate as a yellow solid (15.18 g, 83%). MS: m / z=209.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.49 (s, 1 H), 8.38 (d, J = 2.4 Hz, 1 H), 8.05-7.97 (m, 1 H), 7.73 (s, 1 H), 2.24 (s, 3 H), 1.47 (s, 9 H).

[0311] tert-Butyl 5-methylpiperidin-3-ylcarbamateIn a 500 mL pressure tank reactor, tert-butyl N-(5-methylpyridin-3-yl)carbamate (14.22 g, 68.43 mmol), PtO (2.50 g, 11.01 mmol), and Rh / C (5%, 2.50 g, 1.21 mmol) were mixed in AcOH (250 mL) at room temperature. The mixture was hydrogenated under 15 atm hydrogen pressure at 70° C. for 24 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature. The insoluble solids in the reaction mixture were filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (100 mL), and the pH of the mixture was adjusted to 12 with sodium hydroxide solution (20%). The resulting mixture was extracted with DCM (100 mL × 3), and the organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure to give tert-butyl N-(5-methylpiperidin-3-yl)carbamate as a light brown solid (14.19, 97%). MS: m / z=215.2 [M+H] + .

[0312] tert-Butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate To a solution of tert-butyl N-(5-methylpiperidin-3-yl)carbamate (11.70 g, 54.60 mmol) in acetone (200 mL) was added a solution of (2R,3R)-2,3-bis[(4-methoxyphenyl)carbonyloxy]butanedioic acid (28.95 g, 69.19 mmol) in isopropanol (13 mL) at room temperature. The resulting mixture was stirred at room temperature for 24 hours, and precipitation occurred. Upon completion of the reaction, the precipitate was collected by filtration to produce a white solid, which was added in small portions to a solution of potassium carbonate (29.06 g, 210.27 mmol) in water (15 mL) at 0° C. The resulting mixture was then mixed with dichloromethane (100 mL) at 0° C. and stirred at room temperature for 2.5 hours. The mixture was then extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate as a white solid (2.93 g, 25%). MS: m / z=215.2 [M+H] + . Intermediate 5: 8-Chloroquinoxaline-5-carbonitrile [ka]

[0313] 4-Chloro-2,3-dinitrobenzoic acid At room temperature, HNO3 (14.4 mol / L, 16 mL, 0.23 mol) was added dropwise over 30 minutes to a solution of 4-chloro-2-nitrobenzoic acid (19.00 g, 94.52 mmol) in H2SO4 (80 mL). The resulting solution was then stirred at 130 °C for 1 hour. After cooling to room temperature, the reaction mixture was poured into ice water (300 mL). The pH value of the resulting mixture was adjusted to 7 with sodium hydroxide solution (6 M). The mixture was then concentrated under reduced pressure, and the insoluble solid was filtered from the remaining mixture. The pH value of the filtrate was then adjusted to 3 with hydrochloric acid solution (6 M), causing precipitation. The precipitate was collected by filtration and dried in a vacuum oven to give 4-chloro-2,3-dinitrobenzoic acid as a light yellow solid (4.8 g, crude). MS: m / z = 247.0 [M+H] + .

[0314] 2,3-Diamino-4-chlorobenzoic acid To a solution of 4-chloro-2,3-dinitrobenzoic acid (4.80 g, crude) in AcOH (80 mL) was added iron powder (1000 mg, 3.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The insoluble solids in the reaction mixture were filtered, and the filtrate was concentrated under reduced pressure to give 2,3-diamino-4-chlorobenzoic acid as a black oil (3.12 g, crude). MS: m / z=186.9 [M+H] + .

[0315] 8-Chloroquinoxaline-5-carboxylic acidTo a solution of 2,3-diamino-4-chlorobenzoic acid (3.12 g, crude) in ethanol (40 mL) was added a solution of oxyaldehyde (40%, 14.4 mol / L, 20 mL, 0.29 mol) in HO at room temperature. The resulting solution was stirred at 75 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with HO (50 mL), and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure to give 8-chloroquinoxaline-5-carboxylic acid as a yellow oil (1.70 g, crude). MS: m / z = 208.9 [M+H] + .

[0316] 8-Chloroquinoxaline-5-carboxylic acid 8-Chloroquinoxaline-5-carboxylic acid (1.70 g, crude) was added to thionyl chloride (30 mL, 0.39 mol) at room temperature. The resulting solution was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (30 mL). The resulting solution was cooled to 0 °C, and NH OH solution (28%, 14.8 mol / L, 20 mL, 0.30 mol) was added dropwise over 5 minutes. The resulting mixture was then stirred at room temperature for 1 hour. Upon completion of the reaction, the reaction mixture was diluted with 20 mL H O and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with brine, and dried over Na SO . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to give 8-chloroquinoxaline-5-carboxamide as a yellow oil (1.20 g, 6% for 4 steps). MS: m / z=208.1 [M+H] + .

[0317] 8-Chloroquinoxaline-5-carbonitrileTo a solution of 8-chloroquinoxaline-5-carboxamide (0.78 g, 3.77 mmol) in N,N-dimethylformamide (10 mL) was added POCl (4.00 g, 22.88 mmol) at room temperature. The resulting solution was stirred at 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with brine, and dried over Na SO . The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 2% gradient) to give 8-chloroquinoxaline-5-carbonitrile as an off-white solid (555 mg, 78%). MS: m / z = 189.9 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.24 (s, 2H), 8.48 (d, J = 8.1 Hz, 1H), 8.23 ​​(d, J = 8.1 Hz, 1H). Intermediate 6: 8-Bromoquinoxaline-5-carbonitrile [ka]

[0318] 5-Bromo-8-methylquinoxaline To a solution of 5-methylquinoxaline (9.50 g, 65.97 mmol) in CHCN (80 mL) was added 1-bromopyrrolidine-2,5-dione (27.00 g, 151.74 mmol) at room temperature. The resulting solution was stirred at 60° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (500 mL). The insoluble solid in this mixture was filtered, and the filtrate was washed with brine and dried over NaSO. The solvent was removed under reduced pressure to give 5-bromo-8-methylquinoxaline as a brown solid (6.00 g, 41%). MS: m / z=222.9 [M+H] + .

[0319] 5-Bromo-8-(dibromomethyl)quinoxalineTo a solution of 5-bromo-8-methylquinoxaline (6.00 g, 27.02 mmol) in CCl4 (200 mL) was added NBS (19.23 g, 108.08 mmol) and AIBN (0.71 g, 4.32 mmol) at room temperature. The resulting solution was then stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (500 mL). The insoluble solid in this mixture was filtered, and the filtrate was then washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 5% gradient) to give 5-bromo-8-(dibromomethyl)quinoxaline as a light yellow solid (7.15 g, 70%). MS: m / z = 378.7 [M+H] + .

[0320] 8-Bromoquinoxaline-5-carbaldehyde To a solution of 5-bromo-8-(dibromomethyl)quinoxaline (13.50 g, 35.71 mmol) in ethanol (290 mL) was added dropwise a solution of AgNO3 (24.27 g, 142.86 mmol) in water (90 mL) at room temperature. The resulting mixture was then stirred at room temperature for 1 hour. Upon completion of the reaction, the reaction mixture was diluted with CH3CN (300 mL), resulting in the formation of a precipitate. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to give 8-bromoquinoxaline-5-carbaldehyde as a yellow solid (10.00 g, crude). MS: m / z = 236.8 [M+H] + .

[0321] (E)-8-Bromoquinoxaline-5-carbaldehyde oximeTo a solution of 8-bromoquinoxaline-5-carbaldehyde (10 g, crude) in ethanol (100 mL) were added NaOAc (6.34 g, 73.42 mmol) and NHOH HCl (3.12 g, 42.65 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 3 hours. Upon completion of the reaction, the insoluble solid in the reaction mixture was filtered at 70 °C, and the filtrate was then cooled to 0 °C, resulting in a precipitate. The precipitate was collected by filtration and dried in an oven to give (E)-N-[(8-bromoquinoxalin-5-yl)methylidene]hydroxylamine as a yellow solid (2.96 g, 33% for two steps). MS: m / z = 253.9 [M+H] + .

[0322] 8-Bromoquinoxaline-5-carbonitrile To a solution of (E)-N-[(8-bromoquinoxalin-5-yl)methylidene]hydroxylamine (3.47 g, 13.82 mmol) in acetonitrile (20 mL) was added Cu(OAc) (577 mg, 3.18 mmol) and acetic acid (1.24 g, 20.73 mmol) at room temperature. The resulting mixture was stirred at 88 °C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with acetonitrile (10 mL). The insoluble solid in the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 15% gradient) to give 8-bromoquinoxaline-5-carbonitrile as a yellow solid (1.22 g, 38%). MS: m / z = 235.8 [M+H] + . Intermediate 7: 5-Bromoquinazoline-8-carbonitrile [ka]

[0323] 8-Methyl-3H-quinazolin-4-one2-Amino-3-methylbenzoic acid (125 g, 0.820 mol), formamidine acetate (257 g, 2.46 mol), and formamide (32.5 mL, 0.8200 mol) were mixed in a 2 L reaction vessel (RB) equipped with a mechanical stirrer. The reaction mixture was heated at 180 °C for 3 h. Completion of the reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled to RT and diluted with 2 N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reaction mixture was neutralized with 1.5 N HCl solution. The precipitated solid was filtered, washed with ice-cold water, and dried under vacuum to yield 8-methyl-3H-quinazolin-4-one (125 g, 94%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 12.2 (bs, 1H), 8.1 (s, 1H), 8.0 (d, J = 7.8 Hz, 1H), 7.7 (d, J = 7.2 Hz, 1H), 7.4 (t, J = 7.6 Hz, 1H), 2.5 (s, 3H); LC / MS(ESI) 161 (M+H).

[0324] 4-chloro-8-methylquinazoline Phosphorus oxychloride (800 mL) was placed in a 2 L round-bottom flask under nitrogen. To this was added 8-methylquinazolin-4(3H)-one (125 g) in small portions. The reaction mixture was refluxed at 120° C. for 12 hours. Completion of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The resulting residue was dissolved in DCM (500 mL) and slowly quenched into an ice-cold solution of saturated KCO with constant stirring. The organic layer was then separated, washed with brine solution, dried over sodium sulfate, and concentrated under vacuum to afford 4-chloro-8-methylquinazoline (120 g, 86%) as a yellow solid, which was used in the next step without further purification. MS: m / z=179 / 181 [M+H] + .

[0325] 8-MethylquinazolineTo a stirred solution of 4-chloro-8-methylquinazoline (120 g, 0.674 mol) in DCM (700 mL) under nitrogen, p-toluenesulfonyl hydrazide (175.7 g, 0.943 mol) was added portionwise. The reaction mixture was heated at 45° C. for 12 h. Completion of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was cooled to RT, the solvent was evaporated to dryness, and the resulting residue was dissolved in EtOH (500 mL), 5N NaOH solution (500 mL) was added, and the mixture was refluxed for 6 h. Completion of the reaction was monitored by LCMS. After completion, the reaction mixture was cooled to RT and extracted with MTBE (3×600 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by chromatography using neutralized silica gel (60-120 mesh) and eluting with petroleum ether / ethyl acetate to give 8-methylquinazoline (60 g, 61%) as a low-melting yellow solid. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.54 (s, 1H), 9.31 (s, 1H), 7.96 (dd, J = 8.8, 8.1 Hz, 1H), 7.87-7.84 (m, 1H), 7.64 (d, J = 15.2 Hz, 1H), 2.67 (s, 3H).

[0326] 5-Bromo-8-methylquinazolineTo a stirred solution of silver sulfate (151.5 g, 0.486 mol) in concentrated sulfuric acid (700 mL) was added 8-methylquinazoline (50 g, 0.347 mol) in small portions at 0° C. Bromine (21.3 mL, 0.382 mol) was added dropwise, and the reaction mixture was stirred at RT for 16 h. The reaction was monitored by LCMS at regular intervals. After 16 h, LCMS showed 40% starting material, 7% isomer, 10% dibromo compound, and 40% product. The reaction mixture was quenched with ice, filtered, and made basic with ammonium hydroxide solution. The aqueous layer was extracted with MTBE (4×500 mL) and washed with water and brine solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography using neutralized silica gel (60-120 mesh) and eluting with petroleum ether / ethyl acetate to give 5-bromo-8-methylquinazoline (16 g, 20%) as a white solid. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.59 (s, 1H), 9.39 (s, 1H), 7.92 (d, J = 7.72 Hz, 1H), 7.76 (d, J = 7.72 Hz, 1H), 2.62 (s, 3H);MS:m / z= 223 / 225 [M+H] + .

[0327] 5-Bromo-8-dibromomethylquinazoline To a stirred solution of 5-bromo-8-methylquinazoline (53 g, 0.237 mol) in CCl4 (800 mL) under nitrogen was added N-bromosuccinimide (94.1 g, 0.522 mol) followed by AIBN (7.8 g, 0.048 mol) at RT. The reaction mixture was heated at 90°C for 12 h. After completion, the reaction mixture was cooled to RT, filtered, and washed with CCl4. The filtrate was concentrated and recrystallized to give 5-bromo-8-dibromomethylquinazoline (61 g, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.73 (s, 1H), 9.53 (s, 1H), 8.44 (d, J = 8.04 Hz, 1H), 8.21 (d, J = 8.04 Hz, 1H), 8.02 (s, 1H).

[0328] 5-Bromoquinazoline-8-carbaldehyde To a stirred solution of 5-bromo-8-dibromomethylquinazoline (110 g, crude mixture) in acetone (1 L) and water (200 mL) was added silver nitrate (110 g) in small portions at 0° C. The reaction mixture was stirred at RT for 2 h. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered, and the filtrate was washed with 10% NaHCO3 solution and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with water and brine. The solvent was dried over sodium sulfate and concentrated in vacuo to provide 5-bromoquinazoline-8-carbaldehyde, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 11.14 (s, 1H), 9.80 (s, 1H), 9.58 (s, 1H), 8.29 (d, J = 12.3 Hz, 2H);MS:m / z=237 / 239 [M+H] + .

[0329] 5-Bromoquinazoline-8-carbonitrile To a stirred solution of 5-bromoquinazoline-8-carbaldehyde (25 g, 0.105 mol) in DMF (125 mL) was added hydroxylamine (7.3 g, 0.105 mol), triethylamine (89 mL, 0.633 mol), and T3P (100 mL, 0.158 mol). The reaction mixture was heated at 100° C. for 3 hours. 1The reaction mixture was monitored by H NMR. After completion, the reaction mixture was cooled to RT and quenched with ice. The reaction mixture was filtered, and the filtrate was made basic with sodium bicarbonate and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give 5-bromoquinazoline-8-carbonitrile (8 g, 32%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.80 (s, 1H), 9.58 (s, 1H), 8.55 (d, J = 7.9 Hz, 2H), 8.27(d, J = 7.8 Hz, 2H);MS:m / z=232 / 234 [M+H] + . Intermediate 8: 5-Bromo-quinoline-8-carbonitrile [ka]

[0330] 5-Bromo-quinoline-8-carbaldehyde oxime Sodium acetate (1.9 g; 23.3 mmol), 5-bromoquinoline-8-carbaldehyde (5.0 g; 21.2 mmol), and hydroxylamine hydrochloride (1.6 g; 23.3 mmol) were added to absolute ethanol (50 mL). The beige suspension was heated at 70° C. for 3 hours, and the reaction mixture was cooled to room temperature. After adding water (25 mL), the beige suspension was concentrated under reduced pressure to ∼30 mL. Water (25 mL), tert-butyl methyl ether (12 mL), and heptane (12 mL) were added to the beige slurry, and the mixture was stirred for 5 minutes and concentrated under reduced pressure to ∼30 mL. Water (25 mL) was added to the beige slurry, and the mixture was cooled to 0° C., and 1N aqueous sodium hydroxide solution (2 mL) was added. The beige suspension was stirred at 0° C. for 10 minutes and filtered. The solid was washed with water and dried under vacuum to afford 5-bromo-quinoline-8-carbaldehyde oxime (5.20 g; 94%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.16 (s, 1H), 9.03 (dd, J = 4.2, 1.7 Hz, 1H), 8.54 (dd, J = 8.6, 1.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.75 (dd, J = 8.6, 4.2 Hz, 1H);MS:m / z=251 [M+H] + .

[0331] 5-Bromo-quinoline-8-carbonitrile To a mixture of 5-bromo-quinoline-8-carbaldehyde oxime (5.1 g; 20.3 mmol) and copper(II) acetate monohydrate (81.1 mg; 0.41 mmol) in anhydrous acetonitrile (40 mL) was added acetic acid (1.4 mL; 24.4 mmol), and the reaction mixture was heated at reflux for 1 day. The brown solution was cooled, and water (40 mL) was added. The beige suspension was concentrated under reduced pressure, and water (30 mL) was added to the beige slurry. The mixture was cooled to 0°C, and 1N aqueous sodium hydroxide solution (25 mL) was added. The beige suspension was stirred at 0°C for 10 minutes and filtered. The brown solid was purified by recrystallization in chloroform and hexane to give 5-bromo-quinoline-8-carbonitrile (1.22 g; 26%) as a cream-colored solid. 1 H NMR (400 MHz, CDCl3) δ 9.13 (dd, J = 4.3, 1.6 Hz, 1H), 8.61 (dd, J = 8.6, 1.6 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.66 (dd, J = 8.6, 4.2 Hz, 1H);MS:m / z= 234 [M+H] + . Intermediate 9: 5-Bromo-8-trifluoromethyl-quinazoline [ka]

[0332] 5-Bromo-8-trifluoromethyl-quinazolineTo a solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (1.0 g; 3.69 mmol) and formamidine hydrochloride (594 mg; 7.38 mmol) in anhydrous acetonitrile (30 mL) was added potassium carbonate (1.8 g; 12.9 mmol) and 4Å molecular sieves (650 mg). The reaction mixture was heated at reflux overnight. The resulting suspension was cooled and filtered through Celite, the solid was washed with acetonitrile, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a PuriFlash column (40 g, 15 μm) eluting with hexane and ethyl acetate to give 5-bromo-8-trifluoromethyl-quinazoline (222 mg, 22%) as a light yellow solid. MS: m / z=277 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.81 (s, 1H), 9.56 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H). Intermediate 10: 5-Bromo-8-methyl-[1,7]naphthyridine [ka]

[0333] 5-Bromo-8-methyl-[1,7]naphthyridine To a mixture of 5-bromo-2-methyl-pyridin-3-ylamine (3.00 g; 16.0 mmol), glycerol (4.7 mL; 64.1 mmol), and iron(II) sulfate heptahydrate (892 mg; 3.2 mmol) was added sulfuric acid (5.6 mL; 96.2 mmol) dropwise. The resulting mixture was heated at 120° C. overnight. The reaction mixture was treated with ice, 2N sodium hydroxide solution, ethyl acetate, and dichloromethane. After filtration to remove the dark brown solid, the organic layer was separated, washed with brine, dried, and concentrated. The crude material was purified by chromatography on silica gel eluting with ethyl acetate and hexane to provide 5-bromo-8-methyl-[1,7]naphthyridine (470 mg, 13%). MS: m / z=224 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.14 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (s, 1H), 8.50 (dd, J = 8.6, 1.6 Hz, 1H), 7.96 (dd, J = 8.5, 4.1 Hz, 1H), 2.95 (s, 3H).

[0334] Example 1: Synthesis of Compound 1 (N-(2-(diethylamino)ethyl)-1-(1,8-naphthyridin-4-yl)piperidine-4-carboxamide) [ka]

[0335] Method H Ethyl 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate In a 25 mL reaction tube, ethyl piperidine-4-carboxylate (157 mg, 1.00 mmol) and DIEA (153 mg, 1.18 mmol) were added to a solution of 4-bromo-1,8-naphthyridine (190 mg, 0.91 mmol) in ethanol (10 mL) at room temperature. The tube was sealed, and the reaction mixture was heated to 100° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL), and the resulting mixture was extracted with DCM (50 mL×3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate as a yellow solid (211 mg, 81%).

[0336] (Note: In Method H, the solvent may be acetonitrile, dmso or NMP instead of EtOH, and the reaction temperature may range from 95° C. to 130° C.).

[0337] Method I 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylic acidTo a solution of ethyl 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate (210 mg, 0.74 mmol) in ethanol (9 mL) were added sodium hydroxide (147 mg, 3.67 mmol) and water (3 mL) at room temperature. The resulting mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The pH of the resulting mixture was adjusted to 5 with HCl solution (3 M). The mixture was extracted with DCM (50 mL×3), and the organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure to yield 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylic acid as a yellow solid (170 mg, 90%).

[0338] (Note: In Method I, sodium hydroxide can be replaced with lithium hydroxide, the solvent can be methanol or a mixture of methanol and THF instead of ethanol, and the reaction temperature can range from room temperature to 50°C.)

[0339] Method J N-(2-(diethylamino)ethyl)-1-(1,8-naphthyridin-4-yl)piperidine-4-carboxamideTo a solution of 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylic acid (114 mg, 0.44 mmol) in N,N-dimethylformamide (5 mL), (2-aminoethyl)diethylamine (103 mg, 0.89 mmol), DIEA (286 mg, 2.21 mmol), and HATU (177 mg, 0.46 mmol) were added at room temperature. The resulting solution was stirred at room temperature for 16 hours. Upon completion of the reaction, it was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (50 mL x 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: column, XBridge BEH130 Prep C18 OBD column, 19 × 150 mm, 5 μm, 13 nm; mobile phase, acetonitrile in water (containing 10 mmol / L NH4HCO3), 10% to 50% gradient over 10 min; detector, UV 254 nm. N-[2-(diethylamino)ethyl]-1-(1,8-naphthyridin-4-yl)piperidine-4-carboxamide was obtained as a yellow syrup (29 mg, 17%).

[0340] compound 1 :HPLC: Purity 94.5%, RT=0.80 min. MS:m / z=356.2 [M+H] + . 1 H NMR (300 MHz, CDCl3, ppm) δ 9.06 (dd, J = 4.2, 2.0 Hz, 1 H), 8.92 (d, J = 5.0 Hz, 1 H), 8.38 (dd, J = 8.4, 2.0 Hz, 1 H), 7.43 (dd, J = 8.4, 4.2 Hz, 1 H), 6.90 (d, J = 5.1 Hz, 1 H), 6.64 (s, 1 H), 3.72-3.60 (m, 2 H), 3.54-3.35 (m, 2 H), 3.01-2.86 (m, 2 H), 2.66 (d, J = 8.1 Hz, 6 H), 2.50-2.30 (m, 1H), 2.21-2.00 (m, 4H), 1.20-1.00 (m, 6H).

[0341] The following compounds were synthesized in a similar manner:

[0342] Compound 2 ((4-(diethylamino)piperidin-1-yl)(1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methanone) : From 8-chloropyrido[2,3-b]pyrazine, ethyl piperidine-4-carboxylate and N,N-diethylpiperidin-4-amine. HPLC: Purity 96.5%, RT = 1.18 min. MS: m / z = 397.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.97 (d, J = 1.7 Hz, 1 H), 8.81 (d, J = 1.7 Hz, 1 H), 8.69 (d, J = 5.4 Hz, 1 H), 7.04 (d, J = 5.5 Hz, 1 H), 4.42 (d, J = 12.3 Hz, 3 H), 4.05 (d, J = 13.6 Hz, 1H), 3.25-3.10 (m, 2 H), 3.06-2.93 (m, 2 H), 2.74-2.65 (m, 1 H), 2.55-2.45 (m, 5 H), 1.85-1.60 (m, 6H), 1.40-1.10 (m, 2H), 1.00-0.90 (m, 6H).

[0343] Compound 414 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid [2-(2,6-dimethyl-piperidin-1-yl)-ethyl]-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(3,5-dimethyl-piperidin-1-yl)-ethylamine. HPLC: Purity 95.7%, RT=2.60 min. MS: m / z=420 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 3.53 (dt, J = 12.9, 3.0 Hz, 2H), 3.39 (q, J = 5.6 Hz, 2H), 2.90 (td, J = 11.9, 2.8 Hz, 2H), 2.79 (d, J = 10.2 Hz, 2H), 2.48 (t, J = 6.0 Hz, 2H), 2.35 (tt, J = 11.1, 4.2 Hz, 1H), 2.13 (qd, J = 12.2, 11.2, 3.8 Hz, 2H), 2.04 (dd, J = 13.2, 3.7 Hz, 2H), 1.81-1.56 (m, 3H), 1.51 (t, J = 10.8 Hz, 2H), 0.87 (d, J = 6.5 Hz, 6H), 0.56 (q, J = 11.8 Hz, 1H).

[0344] Compound 415 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid (2-dimethylamino-ethyl)-amide) : From 5-bromoquinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and (2-aminoethyl)dimethylamine. HPLC: Purity 97.8%, RT = 1.84 min. MS: m / z = 352 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H), 3.53 (dt, J = 12.0, 2.8 Hz, 2H), 3.37 (q, J = 6.1, 4.9 Hz, 2H), 2.89 (td, J = 12.0, 2.7Hz, 2H), 2.49-2.40 (m, 2H), 2.36 (tt, J = 11.2, 4.1 Hz, 1H), 2.25 (s, 6H), 2.14 (qd, J = 12.3, 11.4, 3.8 Hz, 2H), 2.08-1.98 (m, 2H).

[0345] Compound 416 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid [2-(ethyl-methyl-amino)-ethyl]-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and (2-aminoethyl)(ethyl)methylamine. HPLC: Purity >99%, RT = 1.94 min. MS: m / z = 366 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 3.53 (dt, J = 12.0, 2.7 Hz, 2H), 3.37 (q, J = 5.3 Hz, 2H), 2.89 (td, J = 11.9, 2.7 Hz, 2H), 2.55-2.41 (m, 4H), 2.35 (tt, J = 11.2, 4.2 Hz, 1H), 2.23 (s, 3H), 2.13 (qd, J = 12.2, 11.3, 3.8 Hz, 2H), 2.08-1.99 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H).

[0346] Compound 419 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid (2-morpholin-4-yl-ethyl)-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 4-(2-aminoethyl)morpholine. HPLC: Purity >99%, RT = 1.92 min. MS: m / z = 394 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.6, 1.7 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.08 (s, 1H), 3.73 (t, J = 4.7 Hz, 4H), 3.54 (d, J = 12.2 Hz, 2H), 3.41 (q, J = 5.6 Hz, 2H), 2.91 (td, J = 11.9, 2.7 Hz, 2H), 2.53 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 4.7 Hz, 4H), 2.36 (tt, J = 11.2, 4.2 Hz, 1H), 2.14 (qd, J = 12.2, 11.4, 3.8 Hz, 2H), 2.08-1.98 (m, 2H).

[0347] Compound 420 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid (2-dimethylamino-1-methyl-ethyl)-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 1-dimethylamino-2-propylamine. HPLC: Purity >99%, RT = 2.06 min. MS: m / z = 366 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.46 (dd, J = 8.5, 1.7 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.5, 4.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 5.96 (s, 1H), 3.96 (dq, J = 9.5, 5.9 Hz, 1H), 3.54 (d, J = 12.2 Hz, 2H), 2.90 (td, J = 11.9, 2.8 Hz, 2H), 2.44-2.29 (m, 2H), 2.25 (s, 6H), 2.23-2.08 (m, 3H), 2.09-1.99 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H).

[0348] Compound 421 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(4-methyl-piperazin-1-yl)-ethylamine. HPLC: Purity 89.1%, RT=1.83 min. MS: m / z=407 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.6, 1.7 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.6, 4.2 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.16 (s, 1H), 3.54 (d, J = 12.3 Hz, 2H), 3.40 (q, J = 5.5 Hz, 2H), 2.91 (td, J = 11.9, 2.7 Hz, 2H), 2.54 (t, J = 6.0 Hz, 4H), 2.47 (s, 4H), 2.36 (ddd, J = 11.3, 7.0, 4.2 Hz, 1H), 2.31 (s, 3H), 2.13 (qd, J = 12.1, 11.3, 3.8 Hz, 2H), 2.07-2.01 (m, 2H).

[0349] Compound 422 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and n-(2-aminoethyl)pyrrolidine. HPLC: Purity >99%, RT = 2.05 min. MS: m / z = 378 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.5, 1.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.19 (s, 1H), 3.53 (dt, J = 12.1, 2.8 Hz, 2H), 3.40 (q, J = 5.4 Hz, 2H), 2.89 (td, J = 12.0, 2.6 Hz, 2H), 2.67-2.59 (m, 2H), 2.58-2.45 (m, 4H), 2.36 (tt, J = 11.3, 4.1 Hz, 1H), 2.14 (qd, J = 12.3, 11.5, 3.9 Hz, 2H), 2.03 (dd, J = 12.8, 3.1 Hz, 2H), 1.87-1.74 (m, 4H).

[0350] Compound 427 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-ethyl]-amide) : From 5-bromoquinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(4,4-difluoropiperidin-1-yl)ethylamine. HPLC: Purity >99%, RT = 2.23 min. MS: m / z = 428 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dd, J = 8.6, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.07-5.96 (m, 1H), 3.54 (ddt, J = 11.9, 4.1, 2.0 Hz, 2H), 3.41 (q, J = 5.6 Hz, 2H), 2.90 (td, J = 12.0, 2.6Hz, 2H), 2.67-2.48 (m, 6H), 2.35 (tt, J = 11.2, 4.1 Hz, 1H), 2.14 (qd, J = 12.3, 11.4, 3.8 Hz, 2H), 2.07-1.91 (m, 6H).

[0351] Compound 433 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid (1-methyl-pyrrolidin-2-ylmethyl)-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and (1-methylpyrrolidin-2-yl)methanamine. HPLC: Purity 98.9%, RT=2.01 min. MS: m / z=378 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.6, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 3.65 (ddd, J = 13.8, 7.8, 2.5 Hz, 1H), 3.59 - 3.48 (m, 2H), 3.13 (ddd, J = 13.7, 4.2, 2.3 Hz, 1H), 3.07 (t, J = 7.8 Hz, 1H), 2.90 (tt, J = 12.1, 3.6 Hz, 2H), 2.42 - 2.35 (m, 1H), 2.33 (s, 3H), 2.25 (q, J = 8.9 Hz, 1H), 2.21-2.08 (m, 2H), 2.04 (dd, J = 13.4, 3.8 Hz, 2H), 1.97-1.83 (m, 1H), 1.81-1.66 (m, 2H), 1.65-1.50 (m, 2H).

[0352] Compound 434 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid (1-cyclopropylmethyl-pyrrolidin-3-yl)-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 1-(cyclopropylmethyl)pyrrolidin-3-amine. HPLC: Purity 96.6%, RT=2.18 min. MS: m / z=404 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dd, J = 8.6, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.6, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.08 (s, 1H), 4.51 (tddd, J = 8.4, 6.3, 3.7, 2.3 Hz, 1H), 3.53 (dt, J = 11.9, 2.6 Hz, 2H), 3.05 (td, J = 8.8, 3.4 Hz, 1H), 2.88 (td, J = 11.9, 2.7 Hz, 2H), 2.80 (dd, J = 10.1, 2.6 Hz, 1H), 2.54 (dd, J = 10.1, 6.4 Hz, 1H), 2.43-2.20 (m, 5H), 2.12 (qd, J = 12.0, 11.5, 3.8 Hz, 2H), 2.06-1.97 (m, 2H), 1.65 (dtt, J = 11.5, 7.4, 3.2 Hz, 1H), 0.94-0.85 (m, 1H), 0.53 (ddd, J = 8.0, 5.5, 4.2 Hz, 2H), 0.19-0.07 (m, 2H).

[0353] Compound 435 ((S)-1-Ethyl-pyrrolidine-2-carboxylic acid [1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-amide) : From 5-bromoquinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 1-ethyl-l-proline. HPLC: Purity >99%, RT = 2.21 min. MS: m / z = 392 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.47 (dd, J = 8.6, 4.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.0 Hz, 2H), 3.38-3.23 (m, 2H), 3.19 (td, J = 6.9, 3.4 Hz, 1H), 3.08 (dd, J = 10.3, 4.4 Hz, 1H), 2.86 (tt, J = 11.9, 2.9 Hz, 2H), 2.68 (dq, J = 12.1, 7.3 Hz, 1H), 2.52 (dq, J = 12.1, 7.1 Hz, 1H), 2.34 (ddd, J = 10.5, 9.1, 6.2 Hz, 1H), 2.19 (dtd, J = 12.8, 10.2, 7.8 Hz, 1H), 1.98-1.67 (m, 6H), 1.62 (qd, J = 12.2, 4.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H).

[0354] Compound 439 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid (2-azetidin-1-yl-ethyl)-amide) : From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(azetidin-1-yl)ethan-1-amine. HPLC: Purity >99%, RT = 1.89 min. MS: m / z = 364 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.6, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 3.53 (dt, J = 12.3, 2.6 Hz, 2H), 3.31-3.15 (m, 6H), 2.88 (td, J = 11.9, 2.7 Hz, 2H), 2.55 (dd, J = 6.3, 5.3 Hz, 2H), 2.34 (tt, J = 11.2, 4.1 Hz, 1H), 2.22-1.98 (m, 6H).

[0355] Compound 440 (1-(8-cyano-quinoxalin-5-yl)-piperidine-4-carboxylic acid (2-piperidin-1-yl-ethyl)-amide) : From 8-bromo-quinoxaline-5-carbonitrile, ethyl piperidine-4-carboxylate and 1-(2-aminoethyl)piperidine. HPLC: Purity >99%, RT = 1.96 min. MS: m / z = 393 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.25 (s, 1H), 4.23 (dt, J = 12.4, 2.8 Hz, 1H), 3.35 (td, J = 6.0, 4.8 Hz, 2H), 3.12 (ddd, J = 12.4, 10.2, 3.9 Hz, 2H), 2.50-2.30 (m, 7H), 2.16-1.99 (m, 3H), 1.58 (p, J = 5.5 Hz, 4H), 1.46 (q, J = 6.1 Hz, 2H).

[0356] Compound 454 (4-[4-(8-cyano-quinoxalin-5-yl)-piperazin-1-yl]-N,N-dimethyl-4-oxo-butyramide): From 8-bromo-quinoxaline-5-carbonitrile, 1-boc-piperazine and N,N-dimethylsuccinamic acid. HPLC: Purity >99%, RT = 2.13 min. MS: m / z = 367 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.98 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 3.93 (t, J = 5.2 Hz, 2H), 3.87 (t, J = 5.1 Hz, 2H), 3.69 (t, J = 5.1 Hz, 2H), 3.58 (t, J = 5.2 Hz, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.83-2.66 (m, 4H).

[0357] Compound 456 (1-(8-Fluoro-pyrido[3,4-b]pyrazin-5-yl)-piperidine-4-carboxylic acid (2-diethylamino-ethyl)-amide) : From 5-chloro-8-fluoropyrido[3,4-b]pyrazine, ethyl piperidine-4-carboxylate and N,N-diethylethylenediamine. HPLC: Purity >99%, RT = 1.38 min. MS: m / z = 376 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.22 (d, J = 1.3 Hz, 1H), 6.23 (s, 1H), 4.83-4.72 (m, 2H), 3.36-3.26 (m, 2H), 3.20-3.07 (m, 2H), 2.59-2.48 (m, 6H), 2.48-2.37 (m, 1H), 2.04-1.89 (m, 4H), 1.02 (t, J = 7.1 Hz, 6H).

[0358] Example 2: Synthesis of Compound 3 (1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(2-(piperidin-1-yl)ethyl)piperidine-4-carboxamide) [ka]

[0359] Method K 1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(2-(piperidin-1-yl)ethyl)piperidine-4-carboxamide To a solution of N-[2-(piperidin-1-yl)ethyl]-1-[1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperidine-4-carboxamide (67 mg, 0.19 mmol) in acetone (5 mL) at 0 °C, MeI (53 mg, 0.37 mmol) and Cs2CO3 (100 mg, 0.31 mmol) were added. The resulting solution was stirred at 0 °C for 1.5 h. Upon completion of the reaction, it was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (30 mL × 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; Mobile phase: 10% to 23% gradient of acetonitrile in water (containing 10 mmol / L NH4HCO3) over 10 min; Detector: UV254. 1-[1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N-[2-(piperidin-1-yl)ethyl]piperidine-4-carboxamide, off-white solid (7 mg, 10%).

[0360] compound 3 :HPLC: Purity 99.1%, RT=0.81 min. MS:m / z=372.2 [M+H] + . 1 H NMR (300 MHz, CDCl3, ppm) δ 8.38 (s, 1 H), 7.95 (s, 1 H), 6.44 (s, 1 H), 4.76 (d, J = 13.2 Hz, 2 H), 4.04 (s, 3 H), 3.42-3.23 (m, 4 H), 2.60-2.30 (m, 7H), 2.10-1.40 (m, 10H). Example 3: Synthesis of Compound 4 (N,N-diethyl-1-((1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methyl)piperidin-4-amine) [ka]

[0361] (1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methanol: (1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methanol was prepared from 8-chloropyrido[2,3-b]pyrazine and piperidin-4-ylmethanol using Method H. (1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methanol was obtained as a yellow solid (275 mg, 89%).

[0362] Method L (1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methyl methanesulfonate To a solution of (1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methanol (250 mg, 1.02 mmol) and triethylamine (155 mg, 1.53 mmol) in dichloromethane (15 mL) was added methylsulfonyl chloride (152 mg, 1.33 mmol) in several batches at room temperature. The resulting solution was stirred at room temperature for 2 hours. Upon completion of the reaction, it was quenched by the addition of water (20 mL). The resulting mixture was extracted with dichloromethane (40 mL × 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give (1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methyl methanesulfonate as a brown solid (300 mg, 91%). MS: m / z=323.1 [M+H] + .

[0363] Method M N,N-Diethyl-1-((1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methyl)piperidin-4-amineTo a solution of (1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methyl methanesulfonate (170 mg, 0.53 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diethylpiperidin-4-amine (330 mg, 2.11 mmol) and DIEA (136 mg, 1.05 mmol, 2.00 equiv.) at room temperature. The resulting solution was stirred at 80° C. for 8 hours. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with DCM (50 mL×3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: column, XBridge BEH130 Prep C18 OBD column, 19 × 150 mm, 5 μm, 13 nm; mobile phase, acetonitrile in water (containing 10 mmol / L NH4HCO3), gradient from 10% to 23% over 18 min; detector, UV 254 nm. N,N-Diethyl-1-[(1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methyl]piperidin-4-amine was obtained as a brown solid (47 mg, 23%).

[0364] (Note: The reaction temperature for Method M can range from 80° C. to 130° C.).

[0365] compound 4 :HPLC: Purity 97.6%, RT=0.73 min. MS:m / z=383.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.96 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.4 Hz, 1H), 7.02 (d, J = 5.5 Hz, 1H), 4.39 (d, J = 12.5 Hz, 2H), 3.11-3.00 (m, 2H), 2.85 (d, J = 11.1 Hz, 2H), 2.49-2.31 (m, 5H), 2.13 (d, J = 6.7 Hz, 2H), 1.88-1.76 (m, 5H), 1.61 (d, J = 12.0 Hz, 2H), 1.45-1.21 (m, 4H), 0.95-0.85 (m, 6H). Example 4: Synthesis of Compound 5 (N,N-diethyl-1-((1-(quinolin-4-yl)piperidin-4-yl)methyl)piperidin-4-amine) [ka]

[0366] (1-(Quinolin-4-yl)piperidin-4-yl)methyl methanesulfonate : (1-(Quinolin-4-yl)piperidin-4-yl)methyl methanesulfonate was prepared from 4-chloroquinoline, piperidin-4-ylmethanol, and methanesulfonyl chloride using methods H and L. [1-(Quinolin-4-yl)piperidin-4-yl]methyl methanesulfonate was obtained as a yellow solid (550 mg, crude). MS: m / z=321.0 [M+H] + .

[0367] Method N N,N-Diethyl-1-((1-(quinolin-4-yl)piperidin-4-yl)methyl)piperidin-4-amineTo a solution of [1-(quinolin-4-yl)piperidin-4-yl]methyl methanesulfonate (450 mg, crude) in acetonitrile (8 mL) was added N,N-diethylpiperidin-4-amine (209 mg, 1.34 mmol) and CsCO (651 mg, 2.00 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with DCM (40 mL × 3). The organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: column, XBridge C18 OBD Prep column, 5 μm, 19 mm × 250 mm; mobile phase, 15% to 60% gradient of acetonitrile in water (containing 10 mmol / L NH4HCO3) over 8 min; detector, UV 254 nm. N,N-Diethyl-1-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]piperidin-4-amine was obtained as a light yellow solid (40 mg, 15% for 3 steps).

[0368] (Note: In Method N, the solvent may be DMF instead of acetonitrile, and the reaction temperature may range from 60° C. to 130° C.).

[0369] compound 5 :HPLC: Purity 99.7%, RT=0.53 min. MS:m / z=381.3 [M+H] + . 1 H NMR (300 MHz, CDCl3, ppm) δ 8.70 (d, J = 5.0 Hz, 1H), 8.08-7.94 (m, 2H), 7.70-7.55 (m, 1H), 7.50-7.40 (m, 1H), 6.82 (d, J = 5.0 Hz, 1H), 3.62 (d, J = 12.0 Hz, 2H), 2.97 (d, J = 11.5 Hz, 2H), 2.81 (dd, J = 12.8, 10.6 Hz, 2H), 2.78-2.48 (m, 5H), 2.27 (d, J = 7.0 Hz, 2H), 2.00-1.40 (m, 11H), 1.20-1.00 (m, 6H). Example 5: Synthesis of Compound 6 (4-(4-((2-(piperidin-1-yl)ethoxy)methyl)piperidin-1-yl)quinolone) [ka]

[0370] Method O 4-(4-((2-(piperidin-1-yl)ethoxy)methyl)piperidin-1-yl) To a solution of [1-(quinolin-4-yl)piperidin-4-yl]methanol (190 mg, 0.78 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (59 mg, 2.48 mmol) at room temperature. The resulting suspension was stirred at room temperature for 30 minutes, and then 1-(2-chloroethyl)piperidine hydrochloride (304 mg, 1.65 mmol) was added. The reaction mixture was stirred at room temperature for another 20 hours. Upon completion of the reaction, it was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (50 mL x 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; Mobile phase: 41% to 50% acetonitrile in water (containing 10 mmol / L NH4HCO3) gradient over 9 min; Detector: UV 254 nm. 4-(4-[[2-(piperidin-1-yl)ethoxy]methyl]piperidin-1-yl)quinoline, off-white solid (35 mg, 13%).

[0371] compound 6 :HPLC: Purity 98.9%, RT=1.17 min. MS:m / z=354.2 [M+H] + . 1H NMR (300 MHz, CDCl3, ppm) δ 8.70 (d, J = 5.0 Hz, 1 H), 8.06-7.96 (m, 2 H), 7.70-7.60 (m, 1 H), 7.50-7.40 (m, 1 H), 6.83 (d, J = 5.0 Hz, 1 H), 3.69-3.56 (m, 4 H), 3.41 (d, J = 6.0 Hz, 2 H), 2.90-2.75 (m, 2 H), 2.70-2.30 (m, 6 H), 2.00-1.35 (m, 11 H). Example 6: Synthesis of Compound 7 (2-morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)ethanamine) [ka]

[0372] N-(2-morpholinoethyl)-1-(quinolin-4-yl)piperidine-4-carboxamide N-(2-morpholinoethyl)-1-(quinolin-4-yl)piperidine-4-carboxamide was prepared from 4-chloroquinoline, ethyl piperidine-4-carboxylate, and 2-morpholinoethanamine using methods H, I, and J. N-[2-(morpholin-4-yl)ethyl]-1-(quinolin-4-yl)piperidine-4-carboxamide was obtained as a yellow oil (374 mg, crude). MS: m / z=369.1 [M+H] + .

[0373] Method P 2-Morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)ethanamineTo a solution of N-[2-(morpholin-4-yl)ethyl]-1-(quinolin-4-yl)piperidine-4-carboxamide (374 mg, crude) in tetrahydrofuran (5 mL) was added BH3-THF (10 mL, 1 M, 1.00 mmol) at room temperature. The resulting solution was then stirred at 65° C. for 6 hours. After cooling to room temperature, the reaction mixture was quenched with MeOH (2 mL) and extracted with DCM (50 mL×3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 25% gradient) to give 2-morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)ethanamine as a light yellow solid (50 mg, 10% for 4 steps).

[0374] compound 7 :HPLC: Purity 98.9%, RT=0.82 min. MS:m / z=355.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.58 (d, J = 5.2 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.91 (dd, J = 8.4, 1.3 Hz, 1H), 7.75-7.65 (m, 1H), 7.57-7.47 (m, 1H), 6.99 (d, J = 5.2 Hz, 1H), 3.80-3.60 (m, 6H), 3.21-2.80 (m, 6H), 2.70-2.40 (m, 2H), 2.06-1.91 (m, 3H), 1.77-1.50 (m, 2H), 1.34-1.19 (m, 2H). Example 7: Synthesis of Compound 8 (2-morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)ethanamine) [ka]

[0375] tert-Butyl (1-(quinolin-4-yl)piperidin-4-yl)methylcarbamatetert-Butyl (1-(quinolin-4-yl)piperidin-4-yl)methylcarbamate was prepared from 4-chloroquinoline and tert-butyl piperidin-4-ylmethylcarbamate using Method H. The crude product was purified by flash chromatography eluting with MeOH in DCM (0% to 15% gradient) to give tert-butyl N-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]carbamate as a light yellow solid (600 mg, 94%). MS: m / z=342.1 [M+H] + .

[0376] Method Q (1-(Quinolin-4-yl)piperidin-4-yl)methanamine To a solution of tert-butyl N-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]carbamate (557 mg, 1.63 mmol) in MeOH (10 mL) was added concentrated HCl solution (12 M, 1.5 mL) at room temperature. The resulting solution was stirred at room temperature for 24 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give [1-(quinolin-4-yl)piperidin-4-yl]methanamine dihydrochloride as a yellow solid (380 mg, 84%). MS: m / z=242.1 [M+H] + .

[0377] (Note: In Method Q, the solvent can be a 1:1 mixture of dioxane / MeOH or dioxane instead of MeOH).

[0378] 2-(piperidin-1-yl)-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)acetamide2-(Piperidin-1-yl)-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)acetamide was prepared from (1-(quinolin-4-yl)piperidin-4-yl)methanamine hydrochloride and 2-(piperidin-1-yl)acetic acid using Method J. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; Mobile phase: 40% to 55% gradient of acetonitrile in water (containing 10 mmol / L NH4HCO3) over 10 minutes; Detector: UV 254 nm. 2-(Piperidin-1-yl)-N-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]acetamide was obtained as a light yellow solid (152 mg, 72%).

[0379] compound 8 :HPLC: Purity 98.1%, RT=1.46 min. MS:m / z=367.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 8.66 (d, J = 4.9 Hz, 1 H), 8.01-7.90 (m, 2 H), 7.83-7.62 (m, 2 H), 7.58-7.48 (m, 1 H), 6.96 (d, J = 5.0 Hz, 1 H), 3.54 (d, J = 12.1 Hz, 2 H), 3.19-3.09 (m, 2 H), 2.91 (s, 2 H), 2.86-2.70 (m, 2 H), 2.50-2.30 (m, 4 H), 1.85-1.62 (m, 3 H), 1.62-1.31 (m, 8H).

[0380] The following compounds were synthesized in a similar manner:

[0381] Compound 388 (2-piperidin-1-yl-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide) : From 8-chloro-pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and piperidin-1-yl-acetic acid. HPLC: Purity 98.6%, RT=1.16 min. MS: m / z=369 [M+H] + . 1H NMR (400 MHz, クロロホルム-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.45 (s, 1H), 6.88 (d, J = 5.4 Hz, 1H), 4.45 (d, J = 12.7 Hz, 2H), 3.28 (t, J = 6.3 Hz, 2H), 3.08 (td, J = 12.4, 2.3 Hz, 2H), 2.97 (s, 2H), 2.46 (s, 4H), 1.98-1.79 (m, 3H), 1.64-1.52 (m, 6H), 1.46 (dd, J = 11.2, 5.5 Hz, 2H).

[0382] Compound 390 (2-Diethylamino-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-acetamide) :8-クロロ-ピリド[2,3-b]ピラジン、4-n-boc -アミノピペリジン and び2-(ジエチルアミノ) acid acid acid. HPLC: Purity>99%, RT=0.92 points. MS:m / z=343 [M+H] + . 1 H NMR (400 MHz, クロロホルム-d, ppm) δ 8.97 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 5.3 Hz, 1H), 8.74 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 5.4 Hz, 1H), 4.34 (dt, J = 13.0, 2.9 Hz, 2H), 4.13 (dddd, J = 15.0, 10.7, 8.6, 4.3 Hz, 1H), 3.26 (ddd, J = 12.9, 11.4, 2.6 Hz, 2H), 3.04 (s, 2H), 2.56 (q, J = 7.1 Hz, 4H), 2.13 (dd, J = 13.1, 3.8 Hz, 2H), 1.77 (qd, J = 11.5, 3.8 Hz, 2H), 1.03 (t, J = 7.1 Hz, 6H).

[0383] Compound 391 (3,4-Dimethoxy-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-benzamide): From 8-chloro-pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and 3,4-dimethoxybenzoic acid. HPLC: Purity >99%, RT = 1.90 min. MS: m / z = 408 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.27 (dd, J = 8.3, 2.1 Hz, 1H), 6.92-6.83 (m, 2H), 6.25 (t, J = 6.2 Hz, 1H), 4.45 (d, J = 12.4 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.45 (t, J = 6.3 Hz, 2H), 3.08 (td, J = 12.4, 2.4 Hz, 2H), 2.08-1.97 (m, 1H), 1.96 (d, J = 13.7 Hz, 2H), 1.65 (qd, J = 12.1, 3.9 Hz, 2H).

[0384] Compound 392 (Pyridine-2-carboxylic acid (1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-amide) : From 8-chloro-pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and 2-picolinic acid. HPLC: Purity 98.7%, RT = 1.19 min. MS: m / z = 349 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.99 (d, J = 1.8 Hz, 1H), 8.74 (d, J = 5.3 Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.59 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.80 (td, J = 7.7, 1.7 Hz, 1H), 7.62 (dt, J = 7.9, 1.1 Hz, 1H), 7.34 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 6.73 (t, J = 6.1 Hz, 1H), 6.58 (d, J = 5.4 Hz, 1H), 4.83 (d, J = 12.8 Hz, 1H), 4.04 (d, J = 13.5 Hz, 1H), 3.33 (td, J = 6.5, 2.6 Hz, 2H), 3.09 (td, J = 13.5, 2.7 Hz, 1H), 2.84 (td, J = 12.9, 2.9 Hz, 1H), 2.07 (ddt, J = 11.6, 8.3, 4.3 Hz, 1H), 2.00 (d, J = 15.3 Hz, 1H), 1.83 (d, J = 13.3 Hz, 1H), 1.47 (pd, J = 12.3, 4.2Hz, 2H).

[0385] Compound 394 (2-Dimethylamino-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide) : From 8-chloro-pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and N,N-dimethylglycine. HPLC: Purity >99%, RT = 0.89 min. MS: m / z = 329 [M+H] + . 1H NMR (400 MHz, クロロホルム-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.32 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.43 (dt, J = 12.8, 2.4 Hz, 2H), 3.28 (t, J = 6.3 Hz, 2H), 3.06 (td, J = 12.4, 2.4 Hz, 2H), 2.97 (s, 2H), 2.30 (s, 6H), 1.97-1.82 (m, 3H), 1.58 (dtd, J = 13.3, 11.7, 3.8 Hz, 2H).

[0386] Compound 396 (3-Diethylamino-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-propionamide) :8-クロロ-ピリド[2,3-b]ピラジン、4-(n-boc-アミノ)ピペリジン and び3-(ジエチルアミノ)プロパン acid acid acid から. HPLC: Purity 90.1%, RT=1.02 points. MS:m / z=357 [M+H] + . 1 H NMR (400 MHz, クロロホルム-d, ppm) δ 9.04 (s, 1H), 8.97 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 5.3 Hz, 1H), 8.75 (d, J = 1.7 Hz, 1H), 6.90 (d, J = 5.4 Hz, 1H), 4.27 (dt, J = 12.7, 3.1 Hz, 2H), 4.17-4.03 (m, 1H), 3.27 (ddd, J = 13.0, 11.1, 2.7 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 2.57 (q, J = 7.1 Hz, 4H), 2.38 (t, J = 5.8 Hz, 2H), 2.13 (dd, J = 12.8, 3.7 Hz, 2H), 1.73 (qd, J = 11.0, 3.8 Hz, 2H), 1.06 (t, J = 7.1 Hz, 6H).

[0387] Compound 399 (3,3-dimethyl-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-butyramide): From 8-chloro-pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and 3,3-dimethylbutyric acid. HPLC: Purity 98.9%, RT = 2.00 min. MS: m / z = 342 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 5.51 (s, 1H), 4.43 (dt, J = 11.0, 3.3 Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 3.07 (td, J = 12.4, 2.3 Hz, 2H), 2.07 (s, 2H), 1.93-1.79 (m, 3H), 1.56 (qd, J = 13.5, 12.9, 3.7 Hz, 3H), 1.05 (s, 9H).

[0388] Compound 400 (4-piperidin-1-yl-1-(4-pyrido[2,3-b]pyrazin-8-yl-piperazin-1-yl)-butan-1-one) : From 8-chloro-pyrido[2,3-b]pyrazine, 1-boc-piperazine and 4-(piperidin-1-yl)butanoic acid hydrochloride. HPLC: Purity >99%, RT = 1.02 min. MS: m / z = 369 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 9.00 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 5.3 Hz, 1H), 8.76 (d, J = 1.7 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 3.96-3.79 (m, 5H), 3.83-3.66 (m, 4H), 2.51-2.27 (m, 8H), 1.87 (p, J = 7.3 Hz, 2H), 1.57 (p, J = 5.6 Hz, 4H), 1.50-1.37 (m, 2H).

[0389] Compound 402 (2-Azetidin-1-yl-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide): From 8-chloro-pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and 2-(azetidin-1-yl)acetic acid hydrochloride. HPLC: Purity >99%, RT = 0.94 min. MS: m / z = 341 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.3 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.19 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.43 (d, J = 12.5 Hz, 2H), 3.32 (t, J = 7.1 Hz, 4H), 3.26 (t, J = 6.3 Hz, 2H), 3.12 (s, 2H), 3.06 (td, J = 12.4, 2.3 Hz, 2H), 2.10 (p, J = 7.1 Hz, 2H), 1.96 - 1.78 (m, 3H), 1.58 (qd, J = 13.3, 3.7 Hz, 2H).

[0390] Compound 405 (2-Diethylamino-N-methyl-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide) : From 8-chloro-pyrido[2,3-b]pyrazine, tert-butyl methyl(piperidin-4-ylmethyl)carbamate and 2-(diethylamino)acetic acid hydrochloride. HPLC: Purity >99%, RT = 1.07 min. MS: m / z = 371 [M+H] + . 11H NMR (400 MHz, chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.41 (d, J = 12.7 Hz, 2H), 3.34 (d, J = 7.3 Hz, 2H), 3.28 (s, 2H), 3.16 (s, 3H), 3.08 (td, J = 12.3, 2.6 Hz, 2H), 2.61 (q, J = 7.4 Hz, 4H), 2.07 (ddtd, J = 14.7, 11.1, 7.6, 4.0 Hz, 1H), 1.84 - 1.77 (m, 2H), 1.59 (qd, J = 13.0, 12.5, 3.9 Hz, 2H), 1.05 (t, J = 6.9 Hz, 6H).

[0391] Compound 408 (2-(ethyl-methyl-amino)-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide) : From 8-chloro-pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and [ethyl(methyl)amino]acetic acid. HPLC: Purity 98.9%, RT = 1.35 min. MS: m / z = 343 [M+H] + . 1 1H NMR (400 MHz, chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5.3 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.43 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.44 (dt, J = 12.4, 2.4 Hz, 2H), 3.27 (t, J = 6.3 Hz, 2H), 3.07 (td, J = 12.5, 2.4 Hz, 2H), 3.01 (s, 2H), 2.49 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.96 - 1.81 (m, 3H), 1.58 (qd, J = 13.3, 3.7 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H).

[0392] Compound 409 (N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-2-piperidin-1-yl-acetamide) : From 5-bromo-quinoline-8-carbonitrile, 4-(boc-aminomethyl)piperidine and piperidin-1-yl-acetic acid. HPLC: Purity 99.0%, RT=2.25 min. MS: m / z=392 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.5 Hz, 2H), 3.33 (t, J = 6.5 Hz, 2H), 2.99 (s, 2H), 2.86 (td, J = 12.0, 2.3 Hz, 2H), 2.49 (s, 4H), 1.90 (d, J = 12.7 Hz, 2H), 1.79 (dtt, J = 14.0, 6.8, 3.9 Hz, 1H), 1.71 - 1.52 (m, 6H), 1.47 (s, 2H).

[0393] Compound 410 (N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-2-(ethyl-methyl-amino)-acetamide) : From 5-bromoquinoline-8-carbonitrile, 4-(boc-aminomethyl)piperidine and [ethyl(methyl)amino]acetic acid. HPLC: Purity 95.9%, RT = 2.09 min. MS: m / z = 366 [M+H] + . 1H NMR (400 MHz, クロロホルム-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.6, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.3 Hz, 2H), 3.33 (t, J = 6.5 Hz, 2H), 3.04 (s, 2H), 2.86 (td, J = 12.0, 2.3 Hz, 2H), 2.52 (q, J = 6.7 Hz, 2H), 2.32 (s, 3H), 1.91 (d, J = 12.8 Hz, 2H), 1.79 (ddt, J = 14.2, 6.9, 3.7 Hz, 1H), 1.62 (qd, J = 12.0, 3.8 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H).

[0394] Compound 411 (1-methyl-pyrrolidine-2-carboxylic acid (1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-amide) :8-クロロ-ピリド[2,3-b]ピラジン、4-(boc-アミノメチル)ピペリジン and び1-メチルピロリジン-2-カルボン acid から. HPLC: Purity 99.7%, RT=1.02 points. MS:m / z=355 [M+H] + . 1 H NMR (400 MHz, クロロホルム-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.44 (d, J = 12.6 Hz, 2H), 3.25 (td, J = 6.5, 2.3 Hz, 2H), 3.17-2.99 (m, 3H), 2.91 (dd, J = 10.1, 5.3 Hz, 1H), 2.42-2.31 (m, 4H), 2.31-2.17 (m, 1H), 1.99-1.65 (m, 6H), 1.65-1.48 (m, 2H).

[0395] Compound 412 (2-tert-butoxy-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide) : From 5-bromoquinoline-8-carbonitrile, 4-(boc-aminomethyl)piperidine and tert-butoxyacetic acid. HPLC: Purity >99%, RT = 3.73 min. MS: m / z = 381 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 3.92 (s, 2H), 3.50 (d, J = 11.9 Hz, 2H), 3.34 (t, J = 6.6 Hz, 2H), 2.85 (td, J = 12.0, 2.3 Hz, 2H), 1.92 (d, J = 13.4 Hz, 2H), 1.80 (dtt, J = 14.3, 6.9, 3.8 Hz, 1H), 1.62 (qd, J = 12.0, 3.8 Hz, 2H), 1.25 (s, 9H).

[0396] Compound 417 (2-Azetidin-1-yl-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide) : From 5-bromoquinoline-8-carbonitrile, 4-(boc-aminomethyl)piperidine and 2-(azetidin-1-yl)acetic acid hydrochloride. HPLC: Purity >99%, RT = 2.05 min. MS: m / z = 364 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 1H), 7.21 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.1 Hz, 2H), 3.43 - 3.20 (m, 6H), 3.14 (s, 2H), 2.85 (td, J = 12.1, 2.3 Hz, 2H), 2.11 (p, J = 7.0 Hz, 2H), 1.91 (d, J = 12.9 Hz, 2H), 1.78 (dtt, J = 14.3, 7.0, 3.8 Hz, 1H), 1.61 (qd, J = 12.0, 3.9 Hz, 2H).

[0397] Compound 418 (1-Methyl-pyrrolidine-2-carboxylic acid [1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-amide) : From 5-bromoquinoline-8-carbonitrile, 4-(boc-aminomethyl)piperidine and 1-methylpyrrolidine-2-carboxylic acid. HPLC: Purity >99%, RT = 2.11 min. MS: m / z = 378 [M+H] + . 11H NMR (400 MHz, chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.40 (dd, J = 8.5, 1.7 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (dt, J = 12.2, 3.2 Hz, 2H), 3.30 (td, J = 6.6, 2.0 Hz, 2H), 3.12 (ddd, J = 9.0, 6.6, 1.9 Hz, 1H), 2.93 (dd, J = 10.2, 5.3 Hz, 1H), 2.85 (tdd, J = 12.0, 4.0, 2.3 Hz, 2H), 2.45 - 2.33 (m, 4H), 2.26 (ddt, J = 12.7, 9.8, 8.5 Hz, 1H), 1.96 - 1.87 (m, 2H), 1.86 - 1.69 (m, 4H), 1.67 - 1.53 (m, 2H). Example 8: Synthesis of Compound 9 ((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine)

Chemical formula

[0398] Method R tert-Butyl (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-ylcarbamateTo a solution of 4-chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.11 mmol) in N,N-dimethylformamide (10 mL) was added tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (237 mg, 1.11 mmol), Pd(dba)·CHCl (115 mg, 0.11 mmol), DavePhos (87 mg, 0.22 mmol), and KPO (588 mg, 2.77 mmol) at room temperature. The resulting mixture was stirred at 130 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 2% gradient) to give tert-butyl N-[(3R,5S)-1-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl]carbamate as a yellow solid (150 mg, 38%). MS: m / z=359.1 [M+H] + .

[0399] (Note: the catalyst in Method R can be Pd2(dppf)Cl2·CHCl3 instead of Pd2(dba)3·CHCl3).

[0400] (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine(3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine was prepared from tert-butyl (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate using Method Q. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; Mobile phase: 3% to 65% methanol in water (containing 10 mmol / L NH4HCO3) gradient over 8 minutes; Detector: UV 254 nm. (3R,5S)-1-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-amine was obtained as an off-white solid (30 mg, 26%).

[0401] compound 9 :HPLC: Purity 97.8%, RT=0.91 min. MS:m / z=259.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 7.91 (d, J = 5.7 Hz, 1H), 6.49 (d, J = 5.7 Hz, 1H), 6.30 (d, J = 1.2 Hz, 1H), 4.22-4.12 (m, 1H), 4.00-3.91 (m, 1H), 3.71 (s, 3H), 3.11-3.00 (m, 1H), 2.63-2.41 (m, 5H), 2.17-2.07 (m, 1H), 2.00-1.80 (m, 1H), 1.10-0.96 (m, 4H). Example 9: Synthesis of Compound 10 ((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine) [ka]

[0402] (3R,5S)-5-Methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine(3R,5S)-5-Methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine was prepared from (3R,5S)-5-methylpiperidin-3-yl tert-butylcarbamate and 8-chloropyrido[2,3-b]pyrazine using methods H and Q. The crude product was purified by preparative HPLC using the following conditions: column, XBridge C18 OBD Prep column, 5 μm, 19 mm × 250 mm; mobile phase, acetonitrile in water (containing 10 mmol / L NH4HCO3), 3% to 22% gradient over 9 minutes; detector, UV 254 nm. (3R,5S)-5-Methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine was obtained as a yellow syrup (20 mg, 10% for two steps).

[0403] compound 10 :HPLC: Purity 94.1%, RT=1.10 min. MS:m / z=244.0 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.93 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 5.7 Hz, 1H), 4.78-4.68 (m, 1H), 4.56-4.46 (m, 1H), 3.12-2.98 (m, 1H), 2.80-2.60 (m, 2H), 2.19-2.08 (m, 1H), 2.08-1.88 (m, 1H), 1.18-0.89 (m, 4H).

[0404] The following compounds were synthesized in a similar manner:

[0405] Compound 11 ((3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-amine) : From tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate and 4-chloroquinoline. HPLC: Purity 99.9%, RT = 0.86 min. MS: m / z = 242.1 [M+H] + . 1H NMR (400 MHz, CD3OD, ppm) δ 8.64 (d, J = 5.2 Hz, 1H), 8.11-8.04 (m, 1H), 8.00-7.93 (m, 1H), 7.78-7.68 (m, 1H), 7.63-7.53 (m, 1H), 7.04 (d, J = 5.2 Hz, 1H), 3.83-3.74 (m, 1H), 3.64-3.55 (m, 1H), 3.35-3.20 (m, 1H), 2.60-2.40 (m, 2H), 2.24-2.07 (m, 2H), 1.13-0.99 (m, 4H).

[0406] Compound 12 (8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile) : From 8-chloroquinoxaline-5-carbonitrile and tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate. HPLC: Purity 98.3%, RT = 1.20 min. MS: m / z = 268.0 [M+H] + . 1 H NMR (300 MHz, CDCl3, ppm) δ 8.96 (s, 1H), 8.91 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 4.50-4.38 (m, 1H), 4.22-4.08 (m, 1H), 3.34-3.15 (m, 1H), 2.80-2.55 (m, 2H), 2.30-1.95 (m, 2H), 1.20-1.00 (m, 4H). Example 10: Synthesis of Compound 13 (N-((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl)-2-hydroxyacetamide) [ka]

[0407] N-((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl)-2-hydroxyacetamideN-((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl)-2-hydroxyacetamide was prepared from (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine and 2-hydroxyacetic acid using Method J. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (containing 10 mmol / L NH4HCO3), 3% to 75% gradient over 8 minutes; Detector: UV 254 nm. N-[(3R,5S)-1-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl]-2-hydroxyacetamide was obtained as a white solid (30 mg, 17%).

[0408] compound 13 :HPLC: Purity 96.9%, RT=0.67 min. MS:m / z=317.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 7.81 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.35 (d, J = 5.5 Hz, 1H), 6.20 (s, 1H), 5.42 (s, 1H), 4.00-3.91 (m, 1H), 3.88-3.74 (m, 4H), 3.57 (s, 3H), 2.51 (d, J = 11.5 Hz, 1H), 2.47-2.28 (m, 3H), 1.90-1.60 (m, 2H), 1.28-1.10 (m, 1H), 0.86 (d, J = 6.5 Hz, 3H).

[0409] The following compounds were synthesized in a similar manner:

[0410] Compound 14 (2-hydroxy-N-((3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-yl)acetamide): From (3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-amine and 2-hydroxyacetic acid. HPLC: Purity 98.3%, RT = 1.04 min. MS: m / z = 300.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.62 (d, J = 5.2 Hz, 1H), 8.15 (dd, J = 8.3, 1.4 Hz, 1H), 7.96 (dd, J = 8.4, 1.2 Hz, 1H), 7.78-7.68 (m, 1H), 7.64-7.54 (m, 1H), 7.05 (d, J = 5.3 Hz, 1H), 4.38-4.26 (m, 1H), 4.01 (s, 2H), 3.90-3.81 (m, 1H), 3.64 (d, J = 12.3 Hz, 1H), 2.70-2.50 (m, 2H), 2.19-2.10 (m, 2H), 1.37-1.25 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H).

[0411] Compound 15 (2-hydroxy-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)acetamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-hydroxyacetic acid. HPLC: Purity 95.3%, RT = 0.73 min. MS: m / z = 302.0 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.65 (d, J = 5.7 Hz, 1H), 7.13 (d, J = 5.6 Hz, 1H), 4.72-4.56 (m, 2H), 4.20-4.08 (m, 1H), 3.99 (s, 2H), 3.05-2.95 (m, 1H), 2.83-2.73 (m, 1H), 2.14-1.94 (m, 2H), 1.45-1.25 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H).

[0412] Compound 20 ((S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-hydroxy-3-methylbutanamide): From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-hydroxy-3-methylbutanoic acid. HPLC: Purity 98.4%, RT = 3.24 min. MS: m / z = 368.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.8 Hz, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 5.32 (d, J = 5.7 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H), 4.17 (d, J = 11.8 Hz, 1H), 4.05-3.85 (m, 1H), 3.66 (dd, J = 5.8, 4.0Hz, 1H), 2.94-2.84 (m, 1H), 2.73-2.63 (m, 1H), 2.03-1.86 (m, 3H), 1.40-1.20 (m, 1H), 0.95-0.85 (m, 6H), 0.78 (d, J = 6.8 Hz, 3H).

[0413] Compound 21 (((R)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-hydroxy-3-methylbutanamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-hydroxy-3-methylbutanoic acid. HPLC: Purity 97.6%, RT = 1.31 min. MS: m / z = 368.3 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.7 Hz, 1H), 8.94 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 5.34 (d, J = 5.6 Hz, 1H), 4.30-4.15 (m, 2H), 4.05-3.90 (m, 1H), 3.68 (dd, J = 5.6, 3.9 Hz, 1H), 2.98-2.88 (m, 1H), 2.75-2.60 (m, 1H), 2.02-1.85 (m, 3H), 1.40-1.20 (m, 1H), 0.96-0.85 (m, 6H), 0.78 (d, J = 6.8 Hz, 3H).

[0414] Compound 22 ((S)-2-hydroxy-3-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)butanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-hydroxy-3-methylbutanoic acid. HPLC: Purity 96.8%, RT = 1.05 min. MS: m / z = 344.0 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.17 (d, J = 5.7 Hz, 1H), 4.71-4.60 (m, 2H), 4.18-4.08 (m, 1H), 3.87 (s, 1H), 3.05-2.94 (m, 1H), 2.87-2.76 (m, 1H), 2.15-1.95 (m, 3H), 1.50-1.30 (m, 1H), 1.09-0.99 (m, 6H), 0.91 (d, J = 6.8 Hz, 3H).

[0415] Compound 23 ((R)-2-hydroxy-3-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)butanamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-hydroxy-3-methylbutanoic acid. HPLC: Purity 96.9%, RT = 1.02 min. MS: m / z = 344.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.7 Hz, 1H), 4.58-4.72 (m, 2H), 4.20-4.10 (m, 1H), 3.89 (m, 1H), 3.06-2.96 (m, 1H), 2.86-2.75 (m, 1H), 2.15-1.95 (m, 3H), 1.42-1.30 (m, 1H), 1.10-1.00 (m, 6H), 0.90 (d, J = 6.8 Hz, 3H).

[0416] Compound 32 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(dimethylamino)acetamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(dimethylamino)acetic acid. HPLC: Purity 96.9%, RT=1.25 min. MS: m / z=353.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.7 Hz, 1H), 8.94 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.33-4.13 (m, 2H), 4.05-3.88 (m, 1H), 2.97-2.79 (m, 3H), 2.72-2.60 (m, 1H), 2.21 (s, 6H), 1.98-1.82 (m, 2H), 1.34-1.20 (m, 1H), 0.92 (d, J = 6.2 Hz, 3H).

[0417] Compound 33 (2-(dimethylamino)-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)acetamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-(dimethylamino)acetic acid. HPLC: Purity 99.6%, RT = 1.31 min. MS: m / z = 329.0 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.74-4.59 (m, 3H), 4.20-4.04 (m, 1H), 3.10-2.89 (m, 3H), 2.83-2.73 (m, 1H), 2.34 (s, 6H), 2.16-1.93 (m, 2H), 1.40-1.28 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H).

[0418] Compound 36 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3-methyloxetane-3-carboxamide) : From 8-chloroquinoxaline-5-carbonitrile, (3R,5S)-tert-butyl 5-methylpiperidin-3-ylcarbamate and 3-methyloxetane-3-carboxylic acid. HPLC: Purity 99.2%, RT = 1.15 min. MS: m / z = 366.0 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.95-4.85 (m, 2H), 4.41-4.02 (m, 5H), 2.80-2.55 (m, 2H), 2.12-1.93 (m, 2H), 1.57 (s, 3H), 1.31-1.12 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H).

[0419] Compound 37 (3-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)oxetane-3-carboxamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-methyloxetane-3-carboxylic acid. HPLC: Purity 99.8%, RT = 0.88 min. MS: m / z = 342.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.90-4.80 (m, 2H), 4.73-4.61 (m, 2H), 4.39 (d, J = 6.1 Hz, 2H), 4.15-4.03 (m, 1H), 2.91-2.71 (m, 2H), 2.12-1.92 (m, 2H), 1.60 (s, 3H), 1.34-1.22 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H).

[0420] Compound 40 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3,3-dimethylbutanamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 3,3-dimethylbutanoic acid. HPLC: Purity 95.2%, RT = 3.11 min. MS: m / z = 366.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 1.7 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 4.38-4.19 (m, 2H), 3.99-3.84 (m, 1H), 2.79-2.63 (m, 2H), 2.00-1.80 (s, 4H), 1.24-1.10 (m, 1H), 1.02-0.87 (m, 12H).

[0421] Compound 41 (3,3-dimethyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)butanamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3,3-dimethylbutanoic acid. HPLC: Purity 94.8%, RT = 0.96 min. MS: m / z = 342.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.00 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 5.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.59 (d, J = 13.1 Hz, 1H), 4.46 (d, J = 12.6 Hz, 1H), 3.94-3.80 (m, 1H), 2.82-2.68 (m, 2H), 2.00-1.85 (m, 4H), 1.31-1.18 (m, 1H), 1.00-0.80 (m, 12H).

[0422] Compound 97 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-hydroxyacetamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-hydroxyacetic acid. HPLC: Purity 97.5%, RT=1.35 min. MS: m / z=326.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 9.05-8.83 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.34 (dd, J = 12.0, 4.3 Hz, 1H), 4.29-4.17 (m, 2H), 4.02 (s, 2H), 2.99-2.87 (m, 1H), 2.72 (t, J = 11.6 Hz, 1H), 2.16-2.00 (m, 2H), 1.42-1.30 (m, 1H), 1.04 (d, J = 6.4Hz, 3H).

[0423] Compound 108 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid. HPLC: Purity 98.7%, RT = 1.95 min. MS: m / z = 395.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.83 (m, 2H), 8.10 (d, J = 12.0 Hz, 1H), 7.28 (d, J = 12.0 Hz, 1H), 4.37-4.13 (m, 3H), 3.78-3.68 (m, 4H), 3.05 (s, 2H), 2.92-2.78 (m, 1H), 2.75-2.65 (m, 1H), 2.58-2.48 (m, 4H), 2.15-1.95 (m, 2H), 1.38-1.20 (m, 1H), 1.02 (d, J = 12.0Hz, 3H).

[0424] Compound 109 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(4-methylpiperazin-1-yl)acetic acid. HPLC: Purity 99.8%, RT=1.47 min. MS: m / z=408.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.41-4.12 (m, 3H), 3.14-3.01 (m, 2H), 2.86 (dd, J = 11.9, 10.6 Hz, 1H), 2.72 (dd, J = 12.6, 10.8 Hz, 1H), 2.60-2.40 (m, 7H), 2.32 (s, 3H), 2.09 (t, J = 14.0 Hz, 2H), 1.36-1.24 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H).

[0425] Compound 110 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-morpholinoacetic acid. HPLC: Purity 96.5%, RT = 1.31 min. MS: m / z = 371.3 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.11 (d, J = 5.7 Hz, 1H), 4.70-4.55 (m, 2H), 4.08 (t, J = 11.4 Hz, 1H), 3.74-3.65 (m, 4H), 3.11-2.84 (m, 3H), 2.75 (dd, J = 12.9, 11.1 Hz, 1H), 2.52-2.49 (m, 4H), 2.08-1.94 (m, 2H), 1.40-1.20 (m, 1H), 0.99 (d, J = 6.5 Hz, 3H).

[0426] Compound 111 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 3,3,3-trifluoropropanoic acid. HPLC: Purity 91.5%, RT=1.38 min. MS: m / z=378.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.93-8.80 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.44-4.30 (m, 1H), 4.29-4.03 (m, 2H), 3.14 (q, J = 10.7 Hz, 2H), 2.68 (dt, J = 23.6, 11.6 Hz, 2H), 2.14-1.93 (m, 2H), 1.21-1.16 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H).

[0427] Compound 120 (3,3,3-trifluoro-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]propanamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3,3,3-trifluoropropanoic acid. HPLC: Purity 95.3%, RT = 1.07 min. MS: m / z = 354.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.11 (d, J = 5.7 Hz, 1H), 4.75-4.56 (m, 2H), 4.15-3.98 (m, 1H), 3.15 (q, J = 10.7 Hz, 2H), 2.85-2.65 (m, 2H), 2.15-1.85 (m, 2H), 1.22 (td, J = 12.0, 12.0 Hz, 1H), 0.99 (d, J = 6.5 Hz, 3H).

[0428] Compound 130 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1H-imidazol-4-yl)acetamide hydrochloride) : From 2-(1H-imidazol-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.0%, RT=1.05 min. MS: m / z=367.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.98-8.85 (m, 3H), 8.11 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 12.7 Hz, 1H), 4.23-4.12 (m, 1H), 3.78 (br s, 2H), 2.85-2.65 (m, 2H), 2.20-1.95 (m, 2H), 1.27 (td, J = 11.9, 11.9 Hz, 1H), 1.15-0.95 (m, 3H).

[0429] Compound 131 (2-(1H-imidazol-4-yl)-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]acetamide): From 2-(1H-imidazol-4-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 99.2%, RT=0.79 min. MS: m / z=352.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 5.6 Hz, 1H), 6.96 (s, 1H), 4.72-4.63 (m, 2H), 4.12-4.00 (m, 1H), 3.52 (br s, 2H), 2.90-2.70 (m, 2H), 2.15-1.85 (m, 2H), 1.26 (td, J = 12.0, 12.0 Hz, 1H), 1.00 (d, J = 6.6 Hz, 3H).

[0430] Compound 132 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methyl-1H-imidazol-4-yl)acetamide) : From 2-(1-methyl-1H-imidazol-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 96.2%, RT=1.39 min. MS: m / z=390.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.82 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.3 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.01-6.95 (m, 1H), 4.44-4.28 (m, 2H), 4.20-4.08 (m, 1H), 3.71 (s, 3H), 3.48 (br s, 2H), 2.84-2.63 (m, 2H), 2.16-1.95 (m, 2H), 1.33-1.11 (m, 1H), 1.02 (d, J = 6.5 Hz, 3H).

[0431] Compound 133 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(1-methyl-1H-imidazol-4-yl)acetamide) : From 2-(1-methyl-1H-imidazol-4-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 95.9%, RT=0.84 min. MS: m / z=366.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.91 (s, 1H), 8.78 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.53 (s, 1H), 7.13 (d, J = 5.6 Hz, 1H), 6.96 (s, 1H), 4.77-4.57 (m, 2H), 4.13-3.99 (m, 1H), 3.69 (s, 3H), 3.47 (s, 2H), 2.90-2.70 (m, 2H), 2.15-1.85 (m, 1H), 1.26 (td, J = 12.0, 12.0 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H).

[0432] Compound 134 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methoxyacetamide) : From 2-methoxyacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 96.7%, RT=1.20 min. MS: m / z=340.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.82 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.35-4.15 (m, 3H), 3.88 (d, J = 0.6 Hz, 2H), 3.39 (s, 3H), 2.87 (dd, J = 11.8, 10.4 Hz, 1H), 2.67 (dd, J = 12.4, 10.6 Hz, 1H), 2.04 (d, J = 11.8 Hz, 2H), 1.30 (td, J = 12.5, 12.5 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H).

[0433] Compound 140 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methanesulfonamidoacetamide) : From 2-(methylsulfonamido)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 93.6%, RT=2.22 min. MS: m / z=403.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.81 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.38-4.05 (m, 3H), 3.74 (s, 2H), 2.97 (s, 3H), 2.87-2.68 (m, 2H), 2.16-2.00 (m, 2H), 1.26 (td, J = 11.8, 11.8 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H).

[0434] Compound 141 (2-methanesulfonamido-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]acetamide) : From 2-(methylsulfonamido)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 98.5%, RT=0.82 min. MS: m / z=379.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.11 (d, J = 5.7 Hz, 1H), 4.71-4.55 (m, 2H), 4.13-3.99 (m, 1H), 3.74 (s, 2H), 2.97 (s, 3H), 2.95-2.66 (m, 2H), 2.07 (d, J = 12.9 Hz, 1H), 2.00-1.90 (m, 1H), 1.27 (td, J = 12.0, 12.0 Hz, 1H), 0.99 (d, J = 6.5 Hz, 3H).

[0435] Compound 142 (2-(tert-butylamino)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide): From 2-(tert-butylamino)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.0%, RT=1.38 min. MS: m / z=381.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.80 (m, 2H), 8.12-8.03 (m, 1H), 7.25 (dd, J = 8.3, 6.2 Hz, 1H), 4.44-4.36 (m, 1H), 4.27 (d, J = 13.1 Hz, 1H), 4.18-4.14 (m, 1H), 3.25 (m, 2H), 2.80 (t, J = 11.3 Hz, 1H), 2.68 (t, J = 11.8 Hz, 1H), 2.16-2.02 (m, 2H), 1.32-1.21 (m, 1H), 1.13 (s, 9H), 1.03 (d, J = 6.4 Hz, 3H).

[0436] Compound 143 (2-(tert-butylamino)-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]acetamide) : From 2-(tert-butylamino)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 97.7%, RT=1.04 min. MS: m / z=357.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.74 (d, J = 1.7 Hz, 1H), 7.05 (d, J = 5.5 Hz, 1H), 4.65-4.45 (m, 2H), 4.25-4.11 (m, 1H), 3.25 (s, 2H), 2.86-2.70 (m, 2H), 2.19-2.09 (m, 1H), 2.07-1.93 (m, 1H), 1.25-1.05 (m, 10H), 0.99 (d, J = 6.6 Hz, 3H).

[0437] Compound 144 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-[(2-hydroxyethyl)(methyl)amino]acetamide): From 2-((2-hydroxyethyl)(methyl)amino)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 93.1%, RT=1.09 min. MS: m / z=383.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 8.97 (d, J = 1.8 Hz, 1H), 8.89 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 6.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 3.28 (d, J = 7.2 Hz, 2H), 3.92-4.02 (m, 1H),3.50-3.54 (m, 2H), 2.83-3.07 (m, 3H), 2.55-2.72 (m, 3H), 2.025(s, 3H), 1.89-1.98 (m, 3H), 1.88-2.01 (m, 1H), 1.19-1.31 (m, 2H), 0.93-1.01 (m, 3H).

[0438] Compound 145 (2-[(2-hydroxyethyl)(methyl)amino]-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]acetamide) : From 2-((2-hydroxyethyl)(methyl)amino)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 90.7%, RT=1.70 min. MS: m / z=359.2 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.94 (d, J = 1.5 Hz, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.69 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 4.43-4.56 (m, 2H), 4.28 (s, 1H), 3.91-3.96 (m, 1H), 3.48 (s, 2H), 2.97-3.03 (m, 1H), 2.83-2.91 (m, 1H), 2.61-2.72 (m, 2H), 2.49-2.52 (m, 2H), 2.24-2.28 (m, 3H), 1.76-2.01 (m, 2H), 1.21-1.33 (m,1H), 0.94 (d, J = 6.3 Hz, 3H).

[0439] Compound 163 (2-(tert-butoxy)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide) :2-tert-ブトキシ anhydride acid and び8-((3R,5S)-3-アミノ-5 -メチルピペリジン-1-イル)キノキサリン-5-カルボニトリルから. HPLC: Purity 99.3%, RT=1.54 points. MS:m / z=382.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 8.97-8.85 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.38-4.16 (m, 3H), 3.93 (s, 2H), 2.95 (dd, J = 11.9, 10.5 Hz, 1H), 2.73 (dd, J = 12.5, 10.6 Hz, 1H), 2.18-2.00 (m, 2H), 1.44-1.33 (m, 1H), 1.27 (s, 9H), 1.04 (d, J = 6.4 Hz, 3H).

[0440] Compound 164 (2-(tert-butoxy)-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]acetamide): From 2-tert-butoxyacetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 97.9%, RT=1.23 min. MS: m / z=358.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.73-4.58 (m, 2H), 4.17 (tt, J = 11.2, 4.2 Hz, 1H), 3.93 (s, 2H), 3.09-2.95 (m, 1H), 2.81 (dd, J = 12.8, 11.0 Hz, 1H), 2.15-1.95 (m, 2H), 1.43 (td, J = 11.8, 11.8 Hz, 1H), 1.28 (s, 9H), 1.05 (d, J = 6.5 Hz, 3H).

[0441] Compound 165 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2,2-difluorocyclopropane-1-carboxamide) : From 2,2-difluorocyclopropanecarboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.3%, RT=1.39 min. MS: m / z=372.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 8.4, 2.4 Hz, 1H), 4.47-4.27 (m, 2H), 4.25-4.09 (m, 1H), 2.84-2.64 (m, 2H), 2.59-2.45 (m, 1H), 2.20-1.95 (m, 3H), 1.81-1.73 (m, 1H), 1.25 (td, J = 12.0, 12.0 Hz, 1H), 1.03 (dd, J = 6.6, 2.4 Hz, 3H).

[0442] Compound 166 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(oxolan-2-ylmethoxy)acetamide) : 2-(oxolan-2-ylmethoxy)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.0%, RT=2.78 min. MS: m / z=410.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.40 (d, J = 11.9 Hz, 1H), 4.35-4.00 (m, 5H), 3.98-3.79 (m, 2H), 3.64 (dd, J = 10.5, 2.8 Hz, 1H), 3.53-3.43 (m, 1H), 2.87 (t, J = 11.3 Hz, 1H), 2.71 (t, J = 11.7 Hz, 1H), 2.18-1.89 (m, 5H), 1.72-1.56 (m, 1H), 1.32 (td, J = 11.9, 11.9 Hz, 1H), 1.05 (d, J = 6.5 Hz, 3H).

[0443] Compound 167 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2,3-dimethylbutanamide) : From 2,3-dimethylbutanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 98.7%, RT=1.52 min. MS: m / z=366.3 [M+H] + . 1H NMR (400 MHz, chloroform-d, ppm) δ 8.96 (d, J = 1.4 Hz, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.42-7.30 (m, 1H), 5.47 (d, J = 6.9 Hz, 1H), 4.39-4.19 (m, 3H), 2.94-2.79 (m, 2H), 2.18-1.79 (m, 4H), 1.30-1.16 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H), 1.01-0.89 (m, 9H).

[0444] Compound 168 (2,3-dimethyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]butanamide) : From 2,3-dimethylbutanoic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 98.7%, RT = 1.21 min. MS: m / z = 342.3 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.5 Hz, 1H), 8.80 (dd, J = 5.8, 1.8 Hz, 1H), 8.65 (dd, J = 5.6, 1.1 Hz, 1H), 7.16 (d, J = 5.7 Hz, 1H), 4.75-4.60 (m, 2H), 4.11-3.99 (m, 1H), 2.90-2.70 (m, 2H), 2.12-1.88 (m, 3H), 1.83-1.69 (m, 1H), 1.34-1.19 (m, 1H), 1.14-0.82 (m, 12H).

[0445] Compound 169 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1H-pyrazol-1-yl)acetamide) : From 2-(1H-pyrazol-1-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.4%, RT=1.18 min. MS: m / z=376.2 [M+H] + . 1H NMR (400 MHz, CD3OD, ppm) δ 8.93 (d, J = 1.7 Hz, 1H), 8.89 (d, J = 1.7 Hz, 1H), 8.19-8.06 (m, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.39-6.33 (m, 1H), 4.42 (d, J = 11.7 Hz, 1H), 4.34-4.26 (m, 1H), 4.22-4.11 (m, 1H), 3.37-3.27 (m, 1H), 3.15-2.95 (m, 1H), 2.85-2.65 (m, 2H), 2.22-1.98 (m, 2H), 1.26 (td, J = 12.0, 12.0 Hz, 1H), 1.03 (d, J = 6.4 Hz, 3H).

[0446] Compound 170 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(1H-pyrazol-1-yl)acetamide) : From 2-(1H-pyrazol-1-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 98.9%, RT=1.73 min. MS: m / z=352.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.56-7.51 (m, 1H), 7.13 (d, J = 5.6 Hz, 1H), 6.34 (t, J = 2.2 Hz, 1H), 4.95-4.80 (m, 2H), 4.75-4.61 (m, 2H), 4.15-3.99 (m, 1H), 2.94-2.82 (m, 1H), 2.81-2.70 (m, 1H), 2.17-2.06 (m, 1H), 2.05-1.95 (m, 1H), 1.28 (td, J = 12.0, 12.0 Hz, 1H), 1.01 (d, J = 6.6 Hz, 3H).

[0447] Compound 171 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-methylpyrrolidine-2-carboxamide) : From 1-methylpyrrolidine-2-carboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 98.5%, RT=1.85 min. MS: m / z=379.1 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.38-4.05 (m, 3H), 3.16-3.03 (m, 1H), 2.91-2.75 (m, 2H), 2.73-2.59 (m, 1H), 2.40-2.26 (m, 4H), 2.21-1.97 (m, 3H), 1.85-1.71 (m, 3H), 1.33-1.19 (m, 1H), 0.99 (d, J = 6.3 Hz, 3H).

[0448] Compound 172 (Methyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]pyrrolidine-2-carboxamide) : From 1-methylpyrrolidine-2-carboxylic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: Purity 97.5%, RT=2.22 min. MS: m / z=355.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.88 (d, J = 1.8 Hz, 1H), 8.76 (t, J = 1.4 Hz, 1H), 8.61 (d, J = 5.6 Hz, 1H), 7.08 (dd, J = 5.7, 1.3 Hz, 1H), 4.66-4.50 (m, 2H), 4.11-3.97 (m, 1H), 3.16-3.00 (m, 1H), 3.01-2.64 (m, 3H), 2.40-1.66 (m, 10H), 1.29 (td, J = 11.8, 11.8 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H).

[0449] Compound 175 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]-3,3-dimethylbutanamide) : From 3,3-dimethylbutanoic acid and cis-8-(3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 95.1%, RT = 2.95 min. MS: m / z = 392.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.46-4.26 (m, 2H), 4.11-4.00 (m, 1H), 2.91-2.69 (m, 2H), 2.21-2.09 (m, 1H), 2.06 (s, 2H), 1.40-1.02 (m, 2H), 1.01 (s, 9H), 0.63-0.38 (m, 3H), 0.18 (d, J = 3.5 Hz, 2H).

[0450] Compound 179 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]-2-(dimethylamino)acetamide) : From 2-(dimethylamino)acetic acid hydrochloride and cis-8-(3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 97.2%, RT = 2.42 min. MS: m / z = 379.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.38-4.20 (m, 2H), 4.16-3.99 (m, 1H), 3.01-2.80 (m, 4H), 2.29 (s, 6H), 2.23-2.06 (m, 1H), 1.44 (q, J = 11.8 Hz, 1H), 1.21-1.07 (m, 1H), 0.69-0.38 (m, 3H), 0.27-0.11 (m, 2H).

[0451] Compound 230 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-hydroxycyclopropane-1-carboxamide) : From 1-hydroxycyclopropane-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: Purity 98.8%, RT = 3.40 min. MS: m / z = 352.1 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.94-8.80 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.35-4.09 (m, 3H), 2.98-2.86 (m, 1H), 2.78-2.62 (m, 1H), 2.15-1.95 (m, 2H), 1.40-1.15 (m, 3H), 1.00-0.89 (m, 5H).

[0452] Compound 232 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-4-yl)acetamide) : From 2-(1-methylpiperidin-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: Purity 95.5%, RT = 2.03 min. MS: m / z = 407.3 [M+H] + . 1 H NMR (300 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.57 (d, J = 7.3 Hz, 1H), 4.38-4.14 (m, 3H), 2.95-2.69 (m, 4H), 2.30 (s, 3H), 2.19-1.93 (m, 6H), 1.89-1.68 (m, 3H), 1.47-1.09 (m, 3H), 0.98 (d, J = 6.6 Hz, 3H).

[0453] Compound 233 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1,4-dimethylpiperidin-4-yl)acetamide): From 2-(1,4-dimethylpiperidin-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 95.7%, RT=2.95 min. MS: m / z=421.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.38-4.30 (m, 2H), 4.15 (t, J = 11.9 Hz, 1H), 2.83-2.55 (m, 4H), 2.46 (s, 2H), 2.33 (s, 3H), 2.22-1.95 (m, 4H), 1.72-1.67 (m, 2H), 1.56-1.48 (m, 2H), 1.21 (td, J = 12.1, 12.1 Hz, 1H), 1.08 (s, 3H), 1.01 (d, J = 6.3 Hz, 3H).

[0454] Compound 234 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-[1-(2,2-difluoroethyl)piperidin-4-yl]acetamide) : From 2-(1-methylpiperidin-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: Purity 93.9%, RT = 2.45 min. MS: m / z = 457.3 [M+H] + . 1 H NMR (300 MHz, Chloroform-d, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.10-5.70 (m, 1H), 5.51 (d, J = 7.2 Hz, 1H), 4.35-4.10 (m, 3H), 2.98-2.85 (m, 2H), 2.85-2.62 (m, 4H), 2.28-1.63 (m, 8H), 1.42-1.06 (m, 4H), 0.95 (d, J = 6.6 Hz, 3H).

[0455] Compound 235 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-difluorocyclobutane-1-carboxamide) : From 3,3-difluorocyclobutane-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: Purity 93.9%, RT = 4.03 min. MS: m / z = 386.0 [M+H] + . 1 H NMR (300 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.63 (d, J = 6.9 Hz, 1H), 4.30-4.22 (m, 3H), 2.96-2.63 (m, 7H), 2.17-1.99 (m, 2H), 1.21 (td, J = 11.3, 11.3 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H).

[0456] Compound 236 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-methylpyrrolidine-3-carboxamide) : From 3,3-difluorocyclobutane-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: Purity 97.5%, RT = 2.06 min. MS: m / z = 379.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 4.33 (dd, J = 12.5, 4.6 Hz, 2H), 4.23-4.08 (m, 1H), 2.93-2.86 (m, 3H), 2.83-2.69 (m, 2H), 2.65-2.52 (m, 1H), 2.46-2.40 (m, 4H), 2.28-2.19 (m, 1H), 2.12 (apparent d, J = 12.3 Hz, 1H), 2.08-1.93 (m, 2H), 1.35-1.10 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H).

[0457] Compound 265 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-hydroxypropanamide) : From 2-hydroxypropanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.3%, RT=1.16 min. MS: m / z=340.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.81 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.27-4.22 (m, 2H), 4.12-4.07 (m, 2H), 2.86 (dd, J = 12.0, 10.4 Hz, 1H), 2.74-2.60 (m, 1H), 2.07-2.03 (m, 2H), 1.36-1.30 (m, 4H), 0.99 (d, J = 6.4 Hz, 3H).

[0458] Compound 266 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-3-yl)acetamide hydrochloride): From 2-(1-methylpiperidin-3-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 96.3%, RT=1.19 min. MS: m / z=407.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 9.01-8.89 (m, 2H), 8.15 (d, J = 8.2 Hz, 1H), 7.57 (dd, J = 7.8, 2.9 Hz, 1H), 4.29-4.08 (m, 3H), 3.45 (d, J = 12.2 Hz, 2H), 3.07-2.79 (m, 6H), 2.72 (t, J = 11.3 Hz, 1H), 2.31-2.03 (m, 5H), 2.04-1.65 (m, 3H), 1.37-1.14 (m, 2H), 1.00 (d, J = 6.4Hz, 3H).

[0459] Compound 269 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpyrrolidin-3-yl)acetamide) : From 2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 95.1%, RT=2.41 min. MS: m / z=393.2 [M+H] + . 1 H NMR (300 MHz, Chloroform-d, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.79 (t, J = 1.5 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 7.1 Hz, 1H), 4.36-4.08 (m, 3H), 2.84-2.64 (m, 3H), 2.64-2.24 (m, 9H), 2.19-1.88 (m, 3H), 1.58-1.52 (m, 1H), 1.25-0.90 (m, 4H). Example 11: Synthesis of Compound 16 (8-((3S,5R)-3-methyl-5-(methylamino)piperidin-1-yl)quinoxaline-5-carbonitrile hydrochloride) [ka]

[0460] Method S tert-Butyl (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl(methyl)carbamate To a solution of tert-butyl N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate (152 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (18 mg, 0.74 mmol, 1.78 equiv.) at room temperature. The mixture was stirred at room temperature for 10 minutes, and then iodomethane (70 mg, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, it was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give tert-butyl N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-N-methylcarbamate as a yellow solid (180 mg, crude).

[0461] 8-((3S,5R)-3-Methyl-5-(methylamino)piperidin-1-yl)quinoxaline-5-carbonitrile hydrochloride 8-((3S,5R)-3-Methyl-5-(methylamino)piperidin-1-yl)quinoxaline-5-carbonitrile hydrochloride was prepared from tert-butyl (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl(methyl)carbamate and iodomethane using Method Q. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (containing 0.02% v / v HCl), 30% to 40% gradient over 10 minutes; Detector: UV 254 nm. 8-[(3S,5R)-3-methyl-5-(methylamino)piperidin-1-yl]quinoxaline-5-carbonitrile hydrochloride was obtained as a yellow solid (36 mg, 26% for two steps).

[0462] compound 16:HPLC: Purity 90.3%, RT=1.97 min. MS:m / z=282.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 2.0 Hz, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.63-4.53 (m, 1H), 4.14-4.04 (m, 1H), 3.02-2.90 (m, 1H), 2.70-2.55 (m, 2H), 2.50 (s, 3H), 2.26-2.14 (m, 1H), 2.10-1.90 (m, 1H), 1.10-0.96 (m, 4H).

[0463] The following compounds were synthesized in a similar manner:

[0464] Compound 17 ((3R,5S)-N,5-dimethyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine) : From tert-butyl (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-ylcarbamate and iodomethane. HPLC: Purity 92.8%, RT = 0.71 min. MS: m / z = 258.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 5.05-4.95 (m, 1H), 4.54-4.35 (m, 1H), 2.99-2.63 (m, 3H), 2.52 (s, 3H), 2.27-2.14 (m, 1H), 2.06-1.88 (m, 1H), 1.14-1.00 (m, 4H). Example 12: Synthesis of Compound 18 ((3R,5S)—N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine) [ka]

[0465] (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine (3R,5S)-N-(2-Methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine was prepared from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 1-bromo-2-methoxyethane using Method N. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: MeOH in water (containing 10 mmol / L NH4HCO3), 3% to 80% gradient over 8 minutes; Detector: UV 254 nm. (3R,5S)—N-(2-Methoxyethyl)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine, yellow oil (60 mg, 31%).

[0466] compound 18 :HPLC: Purity 96.8%, RT=1.88 min. MS:m / z=302.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 4.61 (br s, 2H), 4.46 (d, J = 12.6 Hz, 1H), 3.60-3.52 (m, 2H), 3.39 (s, 3H), 3.02-2.90 (m, 3H), 2.80-2.68 (m, 2H), 2.25-2.15 (m, 1H), 2.05-1.95 (s, 1H), 1.18-1.02 (m, 3H).

[0467] The following compounds were synthesized in a similar manner:

[0468] Compound 19 (8-((3R,5S)-3-(2-methoxyethylamino)-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile): From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 1-bromo-2-methoxyethane. HPLC: Purity 97.8%, RT=1.22 min. MS: m / z=326.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.89 (s, 1H), 8.85 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 4.59-4.47 (m, 1H), 4.14-4.03 (m, 1H), 3.55-3.45 (m, 2H), 3.34 (s, 3H), 3.06-2.78 (m, 3H), 2.66-2.51 (m, 2H), 2.20-1.85 (m, 2H), 1.10-0.91 (m, 4H).

[0469] Compound 38 (8-((3R,5S)-3-(cyanomethylamino)-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-chloroacetonitrile. HPLC: Purity 90.7%, RT=1.24 min. MS: m / z=307.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.93-8.86 (m, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.65-4.52 (m, 1H), 4.05 (dd, J = 13.3, 3.4 Hz, 1H), 3.72 (s, 2H), 3.25-3.10 (m, 1H), 2.66-2.50 (m, 2H), 2.20-1.90 (m, 2H), 1.11-0.93 (m, 4H).

[0470] Compound 39 (2-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-ylamino)acetonitrile hydrochloride) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-chloroacetonitrile. HPLC: Purity 87.2%, RT = 0.97 min. MS: m / z = 283.0 [M+H] + .1 H NMR (400 MHz, CD3OD, ppm) δ 9.12-9.02 (m, 2H), 8.55 (d, J = 6.6 Hz, 1H), 7.40 (d, J = 6.9 Hz, 1H), 5.92-5.72 (m, 1H), 4.60-4.30 (m, 2H), 3.95-3.60 (m, 2H), 3.20-3.10 (m, 1H), 2.48-2.38 (m, 1H), 2.16-2.06 (m, 1H), 1.65-1.52 (m, 1H), 1.16-0.96 (m, 4H).

[0471] Compound 121 (2-[[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]amino]acetamide) : (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-chloroacetamide. HPLC: Purity 99.1%, RT = 0.75 min. MS: m / z = 301.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.93 (d, J = 1.8 Hz, 1H), 8.83 (t, J = 1.7 Hz, 1H), 8.64 (dd, J = 5.8, 1.5 Hz, 1H), 7.09-7.02 (m, 1H), 5.03-4.90 (m, 1H), 4.41 (dd, J = 12.8, 4.2 Hz, 1H), 3.49-3.34 (m, 2H), 3.00-2.86 (m, 1H), 2.80-2.64 (m, 2H), 2.26-2.13 (m, 1H), 2.03-1.90 (m, 1H), 1.19-1.01 (m, 4H).

[0472] Compound 122 (2-[[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]amino]acetamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-chloroacetamide. HPLC: Purity 99.5%, RT=1.03 min. MS: m / z=325.2 [M+H] + . 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.29-7.15 (m, 1H), 4.62-4.48 (m, 1H), 4.12-4.02 (m, 1H), 3.46-3.31 (m, 2H), 2.99 (tt, J = 11.0, 4.0 Hz, 1H), 2.72-2.56 (m, 2H), 2.22-1.88 (m, 2H), 0.96 (m, 4H).

[0473] Compound 126 (1-methyl-3-[[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]amino]pyrrolidin-2-one) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-bromo-1-methylpyrrolidin-2-one. HPLC: Purity 99.0%, RT = 1.13 min. MS: m / z = 341.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.07 (t, J = 5.4 Hz, 1H), 5.08-4.88 (m, 1H), 4.48-4.38 (m, 1H), 3.76-3.62 (m, 1H), 3.48-3.35 (m, 2H), 3.21-3.04 (m, 1H), 2.87 (s, 3H), 2.80-2.65 (m, 2H), 2.56-2.39 (m, 1H), 2.28-2.12 (m, 1H), 2.02-1.76 (m, 2H), 1.18-0.99 (m, 4H).

[0474] Compound 176 (cis-8-[3-cyclopropyl-5-[(2-methoxyethyl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile) : From 3,3-dimethylbutanoic acid and cis-8-(3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.0%, RT = 1.42 min. MS: m / z = 352.2 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.61-4.45 (m, 1H), 4.30-4.24 (m, 1H), 3.61-3.45 (m, 2H), 3.37 (s, 3H), 3.05-2.75 (m, 4H), 2.74-2.68 (m, 1H), 2.37-2.25 (m, 1H), 1.31-1.03 (m, 2H), 0.71-0.41 (m, 3H), 0.30-0.12 (m, 2H). Example 13: Synthesis of Compound 24 ((R)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide) [ka]

[0475] (R)-2-Amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide (R)-2-Amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide was prepared from 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)propanoic acid using Methods J and Q. The crude product was purified by preparative HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; 10 min gradient of 30% to 80% MeOH in water (containing 10 mmol / L NH4HCO3); Detector, UV 254 nm. (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide was obtained as a yellow solid (25 mg, 26% for two steps).

[0476] compound 24 :HPLC: Purity 94.4%, RT=1.39 min. MS:m / z=339.1 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.44-4.26 (m, 2H), 4.20-4.03 (m, 1H), 3.50-3.38 (m, 1H), 2.87-2.62 (m, 2H), 2.20-1.99 (m, 2H), 1.35-1.17 (m, 4H), 1.04 (d, J = 6.4 Hz, 3H).

[0477] The following compounds were synthesized in a similar manner:

[0478] Compound 25 ((S)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: Purity 91.3%, RT=1.40 min. MS: m / z=339.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.97 (d, J = 1.8 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.44-4.26 (m, 2H), 4.20-4.02 (m, 1H), 3.52-3.38 (m, 1H), 2.89-2.64 (m, 2H), 2.20-2.01 (m, 3H), 1.37-1.22 (m, 4H), 1.05 (d, J = 6.4 Hz, 3H).

[0479] Compound 26 ((R)-2-amino-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)propanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: Purity 94.9%, RT = 0.55 min. MS: m / z = 315.1 [M+H] + .1 H NMR (300 MHz, DMSO-d6, ppm) δ 8.99 (s, 1H), 8.83 (s, 1H), 8.71 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 5.5 Hz, 1H), 4.55 (d, J = 13.4 Hz, 1H), 4.39 (m, J = 13.4 Hz, 1H), 3.92-3.76 (m, 1H), 3.45-3.35 (m, 1H), 2.90-2.60 (m, 2H), 2.03-1.75 (m, 4H), 1.33-1.08 (m, 4H), 0.92 (d, J = 6.5 Hz, 3H).

[0480] Compound 27 ((S)-2-amino-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)propanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: Purity 94.0%, RT = 0.93 min. MS: m / z = 315.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.7 Hz, 1H), 7.12 (d, J = 5.6 Hz, 1H), 4.72-4.58 (m, 2H), 4.07-3.93 m, 1H), 3.46-3.34 (m, 1H), 2.90-2.65 (m, 2H), 2.15-1.92 (m, 2H), 1.36-1.15 (m, 4H), 0.99 (d, J = 6.5 Hz, 3H).

[0481] Compound 28 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(methylamino)acetamide hydrochloride) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(tert-butoxycarbonyl(methyl)amino)acetic acid. HPLC: Purity 98.3%, RT=1.21 min. MS: m / z=339.1 [M+H] + .1 H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 4.28-4.06 (m, 2H), 3.75 (s, 2H), 2.82-2.57 (m, 5H), 2.16-1.97 (m, 2H), 1.25-1.13 (m, 1H), 0.99 (d, J = 6.5 Hz, 3H).

[0482] Compound 29 (N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)-2-(methylamino)acetamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-(tert-butoxycarbonyl(methyl)amino)acetic acid. HPLC: Purity 99.6%, RT = 0.83 min. MS: m / z = 315.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.00 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.72 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 5.5 Hz, 1H), 4.58-4.38 (m, 2H), 4.00-3.85 (m, 1H), 3.40-3.30 (m, 2H), 2.88-2.68 (m, 2H), 2.38 (s, 3H), 2.01-1.79 (m, 2H), 1.30-1.16 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H). Compound 30 (1-amino-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)cyclopropanecarboxamide hydrochloride) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid. HPLC: Purity 99.8%, RT = 0.84 min. MS: m / z = 327.1 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 8.99 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 4.15-4.00 (m, 1H), 3.36-3.13 (m, 2H), 3.13-2.99 (m, 1H), 2.13 - 1.86 (m, 2H), 1.67-1.27 (m, 6H), 1.06 (d, J = 6.4 Hz, 3H).

[0483] Compound 31 (1-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)cyclopropanecarboxamide hydrochloride) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid. HPLC: Purity 97.5%, RT=1.22 min. MS: m / z=351.1 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.35-4.08 (m, 3H), 2.85-2.60 (m, 2H), 2.08-1.93 (m, 2H), 1.59-1.15 (m, 5H), 0.98 (d, J = 6.3 Hz, 3H).

[0484] Compound 34 (2-amino-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)acetamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-(tert-butoxycarbonylamino)acetic acid. HPLC: Purity 99.6%, RT = 0.83 min. MS: m / z = 300.9 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.98 (s, 1H), 8.81 (s, 1H), 8.69 (d, J = 5.3 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 5.4 Hz, 1H), 4.55-4.46 (m, 1H), 4.46-4.37 (m, 1H), 3.94-3.82 (m, 1H), 3.07 (s, 2H), 2.86-2.76 (m, 1H), 2.74-2.64 (m, 1H), 2.30-2.78 (m, 4H), 1.29-1.15 (m, 1H), 0.91 (d, J = 6.4 Hz, 3H).

[0485] Compound 35 (2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)acetamide hydrochloride) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(tert-butoxycarbonylamino)acetic acid. HPLC: Purity 96.6%, RT=1.19 min. MS: m / z=325.1 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.45-4.33 (m, 1H), 4.27-4.07 (m, 2H), 3.66 (s, 2H), 2.85-2.60 (m, 2H), 2.18-1.95 (m, 2H), 1.27-1.13 (m, 1H), 0.99 (d, J = 6.4 Hz, 3H).

[0486] Compound 102 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(ethyl(methyl)amino)propanoic acid. HPLC: Purity 99.7%, RT = 1.54 min. MS: m / z = 367.2 [M+H] + . 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 4.46-4.37 (m, 1H), 4.35-4.26 (m, 1H), 4.24-4.12 (m, 1H), 3.08 (d, J = 5.9 Hz, 1H), 2.81 (t, J = 11.3 Hz, 1H), 2.70 (t, J = 11.3 Hz, 1H), 2.17-1.85 (m, 3H), 1.33-1.21 (m, 1H), 1.06-0.93 (m, 9H).

[0487] Compound 103 ((2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-(ethyl(methyl)amino)propanoic acid. HPLC: Purity 97.8%, RT = 2.07 min. MS: m / z = 367.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.94-8.90 (m, 2H), 8.11 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.46-4.37 (m, 1H), 4.36-4.27 (m, 1H), 4.17 (dd, J = 11.2, 7.1 Hz, 1H), 3.07 (d, J = 6.0 Hz, 1H), 2.81 (t, J = 11.4 Hz, 1H), 2.69 (t, J = 11.8 Hz, 1H), 2.17-2.00 (m, 2H), 1.99-1.89 (m, 1H), 1.32-1.18 (m, 1H), 1.07-0.95 (m, 9H).

[0488] Compound 104 ((2R)-2-amino-3-methyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]butanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid. HPLC: Purity 94.0%, RT = 0.90 min. MS: m / z = 343.1 [M+H]+ . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.89 (s, 1H), 8.75 (s, 1H), 8.62 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 4.99-4.59 (m, 2H), 4.26-3.92 (m, 1H), 3.07-2.95 (d, J = 11.5 Hz, 1H), 2.85-2.62 (m, 2H), 2.12-1.82 (m, 3H), 1.45-1.20 (m, 1H), 1.13-0.85 (m, 9H).

[0489] Compound 105 ((2S)-2-amino-3-methyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]butanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid. HPLC: Purity 97.6%, RT = 1.65 min. MS: m / z = 343.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.95 (s, 1H), 8.82 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.17 (d, J = 5.7Hz, 1H), 4.87 (s, 2H), 4.18-4.02 (m, 1H), 3.08 (d, J = 6.0 Hz, 1H), 2.95-2.84 (m, 1H), 2.79 (t, J = 12.1 Hz, 1H), 2.17-1.85 (m, 3H), 1.30 (d, J = 12.0 Hz, 1H), 1.07-0.9 (m, 9H).

[0490] Compound 106 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-hydroxypropanamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid. HPLC: Purity 92.4%, RT=0.93 min. MS: m / z=355.2 [M+H] + . 1H NMR (400 MHz, CD3OD, ppm) δ 8.89-9.11 (m, 2H), 8.10 (d, J = 12 Hz, 1H), 7.29 (d, J = 12 Hz, 1H), 4.39-4.01 (m, 3H), 3.63-3.73 (m, 2H), 3.41-3.2 (m, 1H), 2.84-2.55 (m, 2H), 2.18-1.95 (m, 2H), 1.35-1.20 (m, 1H), 1.02 (d, J = 8 Hz, 3H).

[0491] Compound 107 ((2R)-2-amino-3-hydroxy-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]propanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid. HPLC: Purity 95.0%, RT = 0.96 min. MS: m / z = 331.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.92 (s, 1H), 8.80 (s, 1H), 8.65 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.75-4.59 (m, 2H), 4.15-4.01 (m, 1H), 3.72-3.62 (m, 2H), 3.40-3.32 (m, 1H), 2.91-2.80 (m, 1H), 2.79-2.69 (m, 1H), 2.11 (d, J = 16.0 Hz, 1H), 2.05-1.85 (m, 1H), 1.35-1.23 (m, 1H), 1.01 (d, J = 8.0 Hz, 3H).

[0492] Compound 116 ((2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-(pyridin-3-yl)propanamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)-3-(pyridin-3-yl)propanoic acid. HPLC: Purity 98.2%, RT=6.08 min. MS: m / z=416.2 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.82 (m, 2H), 8.38 (dt, J = 3.0, 1.5 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 7.8, 1.9 Hz, 1H), 7.35 (dd, J = 7.8, 4.9 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.33-4.15 (m, 2H), 4.07-3.92 (m, 1H), 3.51 (t, J = 6.9 Hz, 1H), 2.93 (d, J = 6.9 Hz, 2H), 2.70-2.49 (m, 2H), 1.97 (br s, 1H), 1.82-1.77 (m, 1H), 1.06-0.87 (m, 4H).

[0493] Compound 117 ((2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-phenylacetamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid. HPLC: Purity 99.9%, RT=1.66 min. MS: m / z=401.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 1.7 Hz, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.25-8.09 (m, 2H), 7.45-7.17 (m, 6H), 4.40-4.20 (m, 3H), 3.91-3.80 (m, 1H), 2.88-2.56 (m, 2H), 1.96-1.82 (m, 2H), 1.28-1.04 (m, 1H), 0.90 (d, J = 6.3 Hz, 3H).

[0494] Compound 118 ((2S)-2-amino-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-3-(pyridin-3-yl)propanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-(tert-butoxycarbonylamino)-3-(pyridin-3-yl)propanoic acid. HPLC: Purity 98.4%, RT = 1.79 min. MS: m / z = 392.2 [M+H]+ . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.7 Hz, 1H), 8.40-8.38 (m, 2H), 7.72-7.68 (m, 1H), 7.36 (dd, J = 7.9, 4.9 Hz, 1H), 7.09 (d, J = 5.7 Hz, 1H), 4.63-4.54 (m, 2H), 3.99-3.89 (m, 1H), 3.54-3.49 (m, 1H), 2.93 (d, J = 6.9Hz, 2H), 2.80-2.58 (m, 2H), 2.00-1.74 (m, 2H), 1.12-0.85 (m, 4H).

[0495] Compound 119 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-phenylacetamide) : From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid. HPLC: Purity 97.3%, RT=1.87 min. MS: m / z=401.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 9.02 (d, J = 1.8 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.25-8.12 (dd, J = 24.8, 8.0 Hz, 2H), 7.43-7.19 (m, 6H), 4.38-4.15 (m, 3H), 3.96-3.84 (m, 1H), 2.82-2.68 (m, 2H), 1.99-1.80 (m, 2H), 1.27-1.23 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H).

[0496] Compound 128 (3-amino-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]oxetane-3-carboxamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-((tert-butoxycarbonyl)amino)oxetane-3-carboxylic acid. HPLC: Purity 97.4%, RT=0.79 min. MS: m / z=343.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.9 Hz, 1H), 8.63 (d, J = 5.7 Hz, 1H), 7.13 (d, J = 5.7 Hz, 1H), 4.73-4.55 (m, 2H), 4.20-3.50 (m, 3H), 3.00-2.68 (m, 2H), 2.20-1.85 (m, 3H), 1.70-1.58 (m, 1H), 1.40-1.10 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H).

[0497] Compound 129 (3-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]oxetane-3-carboxamide) : From 3-(tert-butoxycarbonylamino)oxetane-3-carboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 99.0%, RT=1.05 min. MS: m / z=367.2 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.97-8.86 (m, 2H), 8.10 (dt, J = 8.6, 2.3 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.39-4.09 (m, 4H), 3.99-3.74 (m, 2H), 2.96-2.80 (m, 1H), 2.79-2.63 (m, 1H), 2.18-1.85 (m, 3H), 1.38-1.23 (m, 1H), 1.04 (dd, J = 6.6, 2.0 Hz, 3H).

[0498] Compound 268 (2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-cyclopropylacetamide): From 2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 47.7+47.3%, RT=2.04+2.17 min. MS: m / z=365.2 [M+H] + . 1 H NMR (300 MHz, Chloroform-d, ppm) δ 8.93 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 7.99 (dd, J = 8.4, 2.8 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.39-4.11 (m, 3H), 3.07-2.65 (m, 3H), 2.20-1.90 (m, 4H), 1.23 (d, J = 14.2 Hz, 2H), 1.15-1.01 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H), 0.72-0.50 (m, 3H), 0.37 (s, 1H).

[0499] Compound 277 (4-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide) : From 4-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: Purity 93.8%, RT=2.08 min. MS: m / z=381.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.94-8.83 (m, 2H), 8.07 (dd, J = 8.3, 1.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.42-4.24 (m, 2H), 4.13 (tt, J = 10.2, 4.2 Hz, 1H), 2.80-2.60 (m, 4H), 2.23 (s, 2H), 2.13-1.97 (m, 2H), 1.27 - 1.12 (m, 1H), 1.10-0.92 (m, 10H). Example 14: Synthesis of Compound 42 ((R)-3-amino-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)pyrrolidin-2-one) [ka]

[0500] (R)-2-(benzyloxycarbonylamino)-4-(methylthio)butanoic acid At room temperature, (2R)-2-amino-4-(methylsulfanyl)butanoic acid (4.90 g, 32.84 mmol) and sodium carbonate (16.91 g, 159.54 mmol) were dissolved in water (100 mL), and a solution of benzyl chloroformate (5.59 g, 32.74 mmol) in dioxane (50 mL) was added dropwise over 10 minutes. The resulting solution was then stirred at room temperature for 5 hours. Upon completion of the reaction, it was quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (300 mL x 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified on a C18 reverse-phase column eluting with acetonitrile in water (gradient of 0% to 50% in 30 min) to give (2R)-2-[[(benzyloxy)carbonyl]amino]-4-(methylsulfanyl)butanoic acid as a yellow oil (3.48 g, 36%).

[0501] (3-(benzyloxycarbonylamino)-3-carboxypropyl)dimethylsulfonium At room temperature, (2R)-2-[[(benzyloxy)carbonyl]amino]-4-(methylsulfanyl)butanoic acid (3.31 g, 11.67 mmol) was slowly added to CHCl (15 mL, 0.48 mol). The resulting solution was stirred at room temperature for 15 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give [(3R)-3-[[(benzyloxy)carbonyl]amino]-3-carboxypropyl]dimethylsulfanium as a brown oil (3.50 g, crude). This crude material was used directly in the next step without further purification.

[0502] ((R)-3-(benzyloxycarbonylamino)-4-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-ylamino)-4-oxobutyl)dimethylsulfonium: ((R)-3-(benzyloxycarbonylamino)-4-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-ylamino)-4-oxobutyl)dimethylsulfonium was prepared from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (3-(benzyloxycarbonylamino)-3-carboxypropyl)dimethylsulfonium using Method J to give N-[(1R)-3-(dimethylsulfaniumyl)-1-[[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]carbamoyl]propyl]carbamate as a brown solid (3.10 g, crude). This crude material was used directly in the next step without further purification.

[0503] Benzyl (R)-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)-2-oxopyrrolidin-3-ylcarbamate Benzyl (R)-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)-2-oxopyrrolidin-3-ylcarbamate was prepared from ((R)-3-(benzyloxycarbonylamino)-4-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-ylamino)-4-oxobutyl)dimethylsulfonium using Method N. The crude product was purified on a C18 reverse-phase column eluting with acetonitrile in water (gradient of 0% to 80% in 45 min) to give benzyl N-[(3R)-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-oxopyrrolidin-3-yl]carbamate as a yellow solid (270 mg, 5% for 3 steps).

[0504] (R)-3-amino-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)pyrrolidin-2-oneTo a solution of benzyl N-[(3R)-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-oxopyrrolidin-3-yl]carbamate (125 mg, 0.27 mmol) in acetic acid (2 mL) was added dropwise a solution of HBr in AcOH (40%, 7 mol / L, 3 mL, 21 mmol) at room temperature. The resulting solution was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: MeOH in water (10 mmol / L NH4HCO3) with a 10-minute gradient from 30% to 80%; Detector: UV 254 nm. (3R)-3-amino-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]pyrrolidin-2-one was obtained as a brown solid (30 mg, 32%).

[0505] compound 42 :HPLC: Purity 96.0%, RT=1.84 min. MS:m / z=327.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.98 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.70 (d, J = 5.3 Hz, 1H), 7.11 (d, J = 5.4 Hz, 1H), 4.44 (dd, J = 12.8, 3.9 Hz, 1H), 4.28-4.17 (m, 1H), 4.05-3.95 (m, 1H), 3.39-3.10 (m, 4H), 2.75-2.63 (m, 1H), 2.28-1.70 (m, 5H), 1.63-1.38 (m, 2H), 0.92 (d, J = 6.5 Hz, 3H). Example 15: Synthesis of Compound 43 ((2S,6R)-2,6-dimethyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) [ka]

[0506] (2S,6R)-2,6-dimethyl-4-(pyrido[2,3-b]pyrazin-8-yl) (2S,6R)-2,6-Dimethyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine was prepared from 8-chloropyrido[2,3-b]pyrazine and (2R,6S)-2,6-dimethylmorpholine using Method H. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: MeOH in water (10 mmol / L NH4HCO3), 25% to 75% gradient over 10 min; Detector: UV 254 nm. (2R,6S)-2,6-Dimethyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as a yellow solid (30 mg, 21%).

[0507] compound 43 :HPLC: Purity 99.0%, RT=0.93 min. MS:m / z=245.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.02 (d, J = 5.6 Hz, 1H), 4.52-4.41 (m, 2H), 3.97-3.83 (m, 2H), 2.84-2.68 (m, 2H), 1.22 (d, J = 6.3 Hz, 6H). Example 16: Synthesis of Compound 44 (8-((2R,6S)-2,6-dimethylmorpholino)quinoxaline-5-carbonitrile) [ka]

[0508] 8-((2R,6S)-2,6-dimethylmorpholino)quinoxaline-5-carbonitrile8-((2R,6S)-2,6-Dimethylmorpholino)quinoxaline-5-carbonitrile was prepared from 8-bromoquinoxaline-5-carbonitrile and (2R,6S)-2,6-dimethylmorpholine using Method M. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; Mobile phase: MeOH in water (10 mmol / L NH4HCO3), 30% to 80% gradient over 10 min; Detector: UV 254 nm. 8-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]quinoxaline-5-carbonitrile was obtained as a yellow solid (30 mg, 39%).

[0509] compound 44 :HPLC: Purity 98.0%, RT=1.30 min. MS:m / z=269.2 [M+H] + . 1 H NMR (400 MHz, DMSO, ppm) δ 9.04 (d, J = 1.8 Hz, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.19-4.10 (m, 2H), 3.91-3.79 (m, 2H), 2.75-2.61 (m, 2H), 1.14 (d, J = 6.2 Hz, 6H).

[0510] The following compounds were synthesized in a similar manner:

[0511] compound 45 ((2S,6R)-2,6-Dimethyl-4-(quinolin-4-yl)morpholine): from 4-chloroquinoline and (2R,6S)-2,6-dimethylmorpholine. HPLC: Purity 99.9%, RT=1.33 min. MS: m / z=243.2 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 8.60 (d, J = 5.2 Hz, 1H), 8.06 (dd, J = 8.6, 1.5 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.73-7.63 (m, 1H), 7.57-7.47 (m, 1H), 6.97 (dd, J = 5.3, 1.8 Hz, 1H), 4.06-3.94 (m, 2H), 3.47 (d, J = 11.7 Hz, 2H), 2.64-2.50 (m, 2H), 1.21 (dd, J = 6.3, 1.1 Hz, 6H). Example 17: Synthesis of Compound 46 ((2S,6R)-4-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylmorpholine) [ka]

[0512] (2S,6R)-4-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylmorpholine (2S,6R)-4-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylmorpholine was prepared from 4-chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine and (2R,6S)-2,6-dimethylmorpholine using Method R. Column: 5 μm, 19 mm x 250 mm; Mobile phase: 25% to 70% MeOH in water (10 mmol / L NH4HCO3) gradient over 10 min; Detector: UV 254 nm. (2R,6S)-4-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-2,6-dimethylmorpholine was obtained as a white solid (32 mg, 12%).

[0513] compound 46 :HPLC: Purity 95.0%, RT=1.88 min. MS:m / z=260.1 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 7.88 (d, J = 5.7 Hz, 1H), 6.44 (d, J = 5.7 Hz, 1H), 6.22 (s, 1H), 3.92-3.74 (m, 4H), 3.67 (s, 3H), 2.63-2.48 (m, 2H), 2.40 (s, 3H), 1.21 (d, J = 6.2 Hz, 6H). Example 18: Synthesis of Compound 47 ((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) [ka]

[0514] (R)-1-Amino-3-(benzyloxy)propan-2-ol To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (5.22 g, 31.82 mmol) in ethanol (25 mL) at room temperature, a solution of NH in MeOH (25 mL, 7 M, 175 mmol) and NH.HO (28%, 14.8 mol / L, 53 mL, 0.78 mol) were added sequentially. The resulting solution was stirred at room temperature for 16 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give (2R)-1-amino-3-(benzyloxy)propan-2-ol as a colorless oil (6.2 g, crude).

[0515] (R)-1-Amino-3-(benzyloxy)propan-2-ol To a solution of (2R)-1-amino-3-(benzyloxy)propan-2-ol (6.20 g, crude) in ethanol (50 mL) was added (2S)-methyl 2-chloropropanoate (3.33 g, 54.42 mmol) at room temperature. The resulting solution was stirred at 70° C. for 20 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to give (2S)-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide as a light yellow oil (5.65 g, 65% for two steps).

[0516] (2R,6R)-6-(benzyloxymethyl)-2-methylmorpholin-3-oneTo a solution of (2S)-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide (4.12 g, 15.18 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (1.02 g, 42.50 mmol) in small portions at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, it was quenched by the slow addition of water (30 mL). The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 100% gradient) to yield (2R,6R)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one as a light yellow oil (2.68 g, 75%).

[0517] (2R,6R)-2-(benzyloxymethyl)-6-methylmorpholine To a solution of (2R,6R)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one (5.40 g, 22.93 mmol) in tetrahydrofuran (50 mL), LiAlH (2.00 g, 52.56 mmol) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, it was quenched by the addition of water (40 mL). The resulting mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with brine, and dried over Na SO . The solvent was removed under reduced pressure to give (2R,6R)-2-[(benzyloxy)methyl]-6-methylmorpholin-3-one as a light yellow oil (5.40 g, crude).

[0518] ((2R,6R)-6-methylmorpholin-2-yl)methanolTo a solution of (2R,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine (1.00 g, crude) in dichloromethane (20 mL) at −78° C., a solution of BBr3 (5 mL, 3 M, 15.00 mmol) in dichloromethane was added dropwise over 10 minutes. The resulting solution was then stirred at −78° C. for 3 hours. Upon completion of the reaction, it was quenched by the slow addition of NaOH solution (1 M, 15 mL). The resulting mixture was extracted with dichloromethane (60 mL×3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give [(2R,6R)-6-methylmorpholin-2-yl]methanol as a white solid (500 mg, crude).

[0519] ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanol : ((2R,6R)-6-Methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanol was prepared from ((2R,6R)-6-methylmorpholin-2-yl)methanol and 8-chloropyrido[2,3-b]pyrazine using Method M. The crude product was purified by flash chromatography, eluting with EtOAc in petroleum ether (0% to 50% gradient) to give [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methanol as a yellow oil (2.00 g, 28% for 3 steps).

[0520] Method T

[0521] ((2R,6R)-6-Methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonateTo a solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methanol (638 mg, 2.45 mmol) in N,N-dimethylformamide (30 mL) at 5°C, sodium hydride (203 mg, 8.45 mmol) was added in small portions. The resulting mixture was stirred at 5°C for 10 minutes, and then a solution of 4-methylbenzene-1-sulfonyl chloride (926 mg, 4.86 mmol) in dichloromethane (3 mL) was added dropwise over 5 minutes. The reaction mixture was then stirred at room temperature for 8 hours. Upon completion of the reaction, it was quenched by the addition of water (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methyl 4-methylbenzene-1-sulfonate as a yellow solid (600 mg, crude).

[0522] Method U

[0523] (2R,6S)-2-Methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholineTo a solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methyl 4-methylbenzene-1-sulfonate (60 mg, crude) in N,N-dimethylformamide (5 mL) was added 1-methylpiperazine (21 mg, 0.21 mmol) and TEA (42 mg, 0.41 mmol) at room temperature. The resulting solution was stirred at 130 °C for 10 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with DCM (30 mL × 3). The organic phases were combined, washed with brine, and dried over Na SO . The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm, 10 nm; mobile phase, 25% to 75% MeOH in water (containing 10 mmol / L NH4HCO3) gradient over 10 min; detector, UV 254 nm. (2R,6S)-2-Methyl-6-[(4-methylpiperazin-1-yl)methyl]-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as a yellow solid (30 mg, 36% for two steps).

[0524] compound 47 :HPLC: Purity 94.7%, RT=1.41 min. MS:m / z=343.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.65-4.53 (m, 1H), 4.47-4.37 (m, 1H), 4.10-3.85 (m, 2H), 2.85-2.39 (m, 11H), 2.35-2.25 (m, 4H), 1.23 (d, J = 6.2 Hz, 3H). Example 19: Synthesis of Compound 48 ((2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) [ka]

[0525] (2R,6S)-2-Methyl-6-(piperazin-1-ylmethyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine (2R,6S)-2-Methyl-6-(piperazin-1-ylmethyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine was prepared from ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and tert-butyl piperazine-1-carboxylate using Methods U and Q. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: MeOH in water (containing 0.02% v / v HCl), 3% to 8% gradient over 10 min; Detector: UV 254 nm. (2R,6S)-2-Methyl-6-(piperazin-1-ylmethyl)-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as a light brown solid (15 mg, 22% for two steps).

[0526] compound 48 :HPLC: Purity 99.5%, RT=0.92 min. MS:m / z=329.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.64-4.52 (m, 1H), 4.47-4.37 (m, 1H), 4.12-3.83 (m, 2H), 2.95-2.40 (m, 12H), 1.23 (d, J = 6.2 Hz, 3H). Example 20: Synthesis of Compound 49 ((2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(quinolin-5-yl)morpholine) [ka]

[0527] (2R,6S)-2-Methyl-6-(piperazin-1-ylmethyl)-4-(quinolin-5-yl)morpholine(2R,6S)-2-Methyl-6-(piperazin-1-ylmethyl)-4-(quinolin-5-yl)morpholine was prepared from ((2R,6R)-6-methylmorpholin-2-yl)methanol, 5-chloroquinoline, 4-methylbenzene-1-sulfonyl chloride, and tert-butyl piperazine-1-carboxylate using methods M, T, U, and Q. The crude product was purified by preparative HPLC using the following conditions: column, XBridge C18 OBD Prep column, 5 μm, 19 mm × 150 mm; mobile phase, 30% to 80% MeOH in water (containing 10 mmol / L NH4HCO3) gradient over 10 min; detector, UV 254 nm. 4-[(2R,6S)-2-Methyl-6-(piperazin-1-ylmethyl)morpholin-4-yl]quinoline was obtained as an off-white solid (35 mg, 15% for 4 steps).

[0528] compound 49 :HPLC: Purity 95.1%, RT=0.53 min. MS:m / z=327.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.61 (d, J = 5.1 Hz, 1H), 8.13-8.03 (m, 1H), 7.98-7.88 (m, 1H), 7.74-7.64 (m, 1H), 7.58-7.48 (m, 1H), 6.99 (d, J = 5.2 Hz, 1H), 4.20-3.94 (m, 2H), 3.72-3.32 (m, 2H), 2.92-2.82 (m, 4H), 2.75-2.38 (m, 8H), 1.22 (d, J = 6.2 Hz, 3H). Example 21: Synthesis of Compound 50 (8-((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile) [ka]

[0529] 8-((2R,6S)-2-Methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile hydrochloride8-((2R,6S)-2-Methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile hydrochloride was prepared from ((2R,6R)-6-methylmorpholin-2-yl)methanol, 8-bromoquinoxaline-5-carbonitrile, 4-methylbenzene-1-sulfonyl chloride, and 1-methylpiperazine using methods M, T, and U. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: 15% to 40% MeOH in water (containing 0.02% v / v HCl) gradient over 10 minutes; Detector: UV 254 nm. 8-((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile hydrochloride was obtained as a black solid (50 mg, 20% for 3 steps).

[0530] compound 50 :HPLC: Purity 98.5%, RT=1.48 min. MS:m / z=367.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.57-4.39 (m, 1H), 4.30-4.20 (m, 1H), 4.18-3.40 (m, 12H), 3.02 (s, 3H), 2.90-2.74 (m, 2H), 1.30 (d, J = 6.1 Hz, 3H). Example 22: Synthesis of Compound 51 ((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(quinolin-5-yl)morpholine) [ka]

[0531] (2R,6S)-2-Methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(quinolin-5-yl)morpholine(2R,6S)-2-Methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(quinolin-5-yl)morpholine was prepared from ((2R,6R)-6-methyl-4-(quinolin-5-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 1-methylpiperazine using Method U. The crude product was purified by preparative HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase, 20% to 40% MeOH in water (containing 10 mmol / L NH4HCO3) gradient over 8 minutes; Detector, UV 254 nm. 4-[(2R,6S)-2-methyl-6-[(4-methylpiperazin-1-yl)methyl]morpholin-4-yl]quinoline was obtained as a light brown solid (45 mg, 55%).

[0532] compound 51 :HPLC: Purity 99.9%, RT=1.10 min. MS:m / z=341.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.61 (d, J = 5.1 Hz, 1H), 8.13-8.03 (m, 1H), 8.01-7.88 (m, 1H), 7.77-7.61 (m, 1H), 7.59-7.47 (m, 1H), 6.99 (d, J = 5.1 Hz, 1H), 4.19-3.94 (m, 2H), 3.62-3.42 (m, 2H), 2.84 (s, 2H), 2.70-2.36 (m, 10H), 2.26 (s, 3H), 1.22 (d, J = 6.2 Hz, 3H).

[0533] The following compounds were synthesized in a similar manner:

[0534] Compound 52 ((2R,6S)-2-methyl-6-((4-propylpiperazin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) : From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 1-propylpiperazine. HPLC: Purity 96.3%, RT=0.99 min. MS: m / z=371.30 [M+H] + .1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.64-4.52 (m, 1H), 4.47-4.35 (m, 1H), 4.11-3.83 (m, 2H), 2.88-2.25 (m, 14H), 1.62-1.43 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H).

[0535] Compound 53 ((2S,6R)-2-(((S)-3,4-dimethylpiperazin-1-yl)methyl)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) : From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and (S)-1,2-dimethylpiperazine hydrochloride. HPLC: Purity 97.8%, RT = 0.86 min. MS: m / z = 357.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.68-4.52 (m, 1H), 4.49-4.37 (m, 1H), 4.11-3.85 (m, 2H), 2.98 (d, J = 15.9 Hz, 1H), 2.89-2.70 (m, 4H), 2.59 - 2.20 (m, 8H), 2.06-1.92 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H).

[0536] Compound 54 ((2R,6S)-2-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)-6-((3,3,4-trimethylpiperazin-1-yl)methyl)morpholine): From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 1,2,2-trimethylpiperazine. HPLC: Purity 98.2%, RT = 1.63 min. MS: m / z = 371.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.02 (d, J = 5.6 Hz, 1H), 4.81-4.67 (m, 1H), 4.41-4.29 (m, 1H), 4.05-3.82 (m, 2H), 2.89-2.15(m, 13H), 1.22 (d, J = 6.3 Hz, 3H), 1.08 (s, 6H).

[0537] Compound 55 (N,N-dimethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidin-4-amine) : From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and N,N-dimethylpiperidin-4-amine. HPLC: Purity 93.3%, RT=0.83 min. MS: m / z=371.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.64-4.52 (m, 1H), 4.48-4.36 (m, 1H), 4.09-3.83 (m, 2H), 3.24-3.08 (m, 1H), 3.02 (d, J = 11.2 Hz, 1H), 2.85-2.73 (m, 2H), 2.60-2.39 (m, 2H), 2.35-1.99 (m, 9H), 1.92-1.78 (m, 2H), 1.63-1.49 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H).

[0538] Compound 56 ((2R,6S)-2-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)-6-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)morpholine) : From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 4-(pyrrolidin-1-yl)piperidine. HPLC: Purity 98.8%, RT=0.90 min. MS: m / z=397.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.47-4.35 (m, 1H), 4.09-3.83 (m, 2H), 3.19-3.06 (m, 1H), 3.04-2.91 (m, 1H), 2.87-2.71 (m, 2H), 2.70-2.39 (m, 6H), 2.22-1.86 (m, 5H), 1.88-1.72 (m, 4H), 1.68-1.47 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H).

[0539] Compound 57 (8-((2R,6S)-2-methyl-6-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile) : From ((2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate and 4-(pyrrolidin-1-yl)piperidine. HPLC: Purity 97.4%, RT=2.24 min. MS: m / z=421.2 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 8.98 (d, J = 1.8 Hz, 1H), 8.84 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 4.24 (d, J = 12.2 Hz, 1H), 4.13-3.97 (m, 3H), 3.08 (s, 1H), 2.91 (s, 1H), 2.80-2.40 (m, 6H), 2.20-1.40 (m, 13H), 1.27 (d, J = 6.2 Hz, 3H).

[0540] Compound 58 ((2S,6R)-2-(1,4'-bipiperidin-1'-ylmethyl)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) : From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 1,4'-bipiperidine. HPLC: Purity 94.8%, RT = 1.11 min. MS: m / z = 411.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.64-4.50 (m, 1H), 4.49-4.35 (m, 1H), 4.09-3.85 (m, 2H), 3.25-2.97 (m, 2H), 2.86-2.72 (m, 2H), 2.65-2.29 (m, 6H), 2.15-1.80 (m, 4H), 1.69-1.41 (m, 9H), 1.23 (d, J = 6.2 Hz, 3H).

[0541] Compound 59 (8-((2S,6R)-2-(1,4'-bipiperidin-1'-ylmethyl)-6-methylmorpholino)quinoxaline-5-carbonitrile) : From ((2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate and 1,4'-bipiperidine. HPLC: Purity 98.8%, RT = 0.72 min. MS: m / z = 435.2 [M+H] + . 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.28-3.90 (m, 4H), 3.25-3.15 (m, 1H), 3.10-3.00 (m, 1H), 2.80-2.35 (m, 9H), 2.20-1.80 (m, 4H), 1.70-1.40 (m, 8H), 1.22 (d, J = 6.2 Hz, 3H).

[0542] Compound 60 ((2R,6S)-2-methyl-6-((4-morpholinopiperidin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) : From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 4-(piperidin-4-yl)morpholine. HPLC: Purity 96.3%, RT=1.85 min. MS: m / z=413.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.65-4.43 (m, 1H), 4.47-4.35 (m, 1H), 4.10-3.83 (m, 2H), 3.72-3.63 (m, 4H), 3.24-3.10 (m, 1H), 3.09-2.98 (m, 1H), 2.88-2.70 (m, 2H), 2.61-2.41 (m, 6H), 2.27-2.01 (m, 3H), 1.96-1.82 (m, 2H), 1.62-1.44 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H).

[0543] Compound 467 (8-[(2R,6S)-2-methyl-6-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}morpholin-4-yl]quinoxaline-5-carbonitrile: From [(2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl]methyl 4-methylbenzene-1-sulfonate and 4-(piperidin-4-yl)morpholine. HPLC: Purity 99.8%, RT = 1.46 min. MS: m / z = 437.3 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.97 (d, J = 1.8 Hz, 1H), 8.90 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.28 (dt, J = 12.2, 2.3 Hz, 1H), 4.19-4.08 (m, 2H), 4.01 (ddd, J = 10.3, 6.4, 2.5 Hz, 1H), 3.76-3.69 (m, 4H), 3.22 (d, J = 12.0 Hz, 1H), 3.07 (d, J = 11.6 Hz, 1H), 2.75 (ddd, J = 12.5, 10.3, 2.7 Hz, 2H), 2.64-2.45 (m, 6H), 2.28-2.07 (m, 3H), 1.93 (d, J = 9.9 Hz, 2H), 1.66-1.54 (m, 2H), 1.27 (d, J = 6.2Hz, 3H). Example 23: Synthesis of Compound 61 (N-(1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidin-4-yl)isobutyramide) [ka]

[0544] N-(1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidin-4-yl)isobutyramideN-(1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidin-4-yl)isobutyramide was prepared from tert-butyl 4-aminopiperidine-1-carboxylate, isobutyric acid, and ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl trifluoromethanesulfonate using Methods J, Q, and U. The crude product was purified by prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase, 30% to 80% MeOH gradient in water (containing 10 mmol / L NH4HCO3) over 8 minutes; Detector, UV 254 nm. (2R,6S)-2-Methyl-6-[[4-(morpholin-4-yl)piperidin-1-yl]methyl]-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as a yellow solid (15 mg, 1.4%).

[0545] compound 61 :HPLC: Purity 96.6%, RT=1.21 min. MS:m / z=413.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.47-4.35 (m, 1H), 4.10-3.85 (m, 2H), 3.71-3.54 (m, 1H), 3.08 (d, J = 12.0 Hz, 1H), 2.96 (d, J = 11.9 Hz, 1H), 2.87-2.61 (m, 2H), 2.64-2.12 (m, 5H), 1.83 (d, J = 12.4 Hz, 2H), 1.65-1.45 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.9 Hz, 6H). Example 24: Synthesis of Compound 62 (N-ethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidine-4-carboxamide) [ka]

[0546] 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid To a solution of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (1.19 g, 4.87 mmol) in methanol (24 mL) and tetrahydrofuran (24 mL) was added a solution of LiOH (599 mg, 24.99 mmol) in water (8 mL) at room temperature. The resulting mixture was stirred at room temperature for 15 hours. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 2 with hydrogen chloride solution (1 M). The resulting mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid as a white solid (1.10 g, 84%). MS: m / z = 128.0 [MH] + .

[0547] N-Ethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidine-4-carboxamide N-Ethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidine-4-carboxamide was prepared from 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, ethanamine, and ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl trifluoromethanesulfonate using Methods J, Q, and U. The crude product was purified by prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase, 30% to 80% MeOH in water (containing 10 mmol / L NH4HCO3) gradient over 10 min; Detector, UV 254 nm. N-Ethyl-1-[[(2S,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methyl]piperidine-4-carboxamide was obtained as a yellow solid (20 mg, 10%).

[0548] compound 62 HPLC: Purity 90.4%, RT = 1.11 min. MS: m / z = 399.3 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.47-4.35 (m, 1H), 4.08-3.83 (m, 2H), 3.23-3.09 (m, 3H), 3.05-2.93 (m, 1H), 2.86-2.72 (m, 2H), 2.60-2.40 (m, 2H), 2.23-2.01 (m, 3H), 1.87-1.68 (m, 4H), 1.23 (d, J = 6.2 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H). Example 25: Synthesis of Compound 63 ((3-aminoazetidin-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanone)

change

[0549] (2R,6R)-6-Methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxylic acidTo a solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methanol (90 mg, 0.35 mmol) in dichloromethane (15 mL) at 10 °C, (acetyloxy)(phenyl)-lambda 3-iodanyl acetate (234 mg, 0.73 mmol) and TEMPO (11 mg, 0.07 mmol) were added. The resulting solution was stirred at 10 °C for 30 minutes, then warmed to room temperature and stirred for an additional 17 hours at room temperature. Upon completion of the reaction, it was quenched with saturated NaSO solution (2.5 mL). The pH of the mixture was adjusted to 9 with sodium hydroxide solution (1 M). The resulting mixture was washed with water (5 mL × 3), and the combined aqueous phases were diluted with BuOH (10 mL). The pH of this aqueous solution was adjusted to 5 with HSO (5 M), and the resulting solution was extracted with BuOH (10 mL × 3). The organic phases were combined and concentrated under reduced pressure to give (2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine-2-carboxylic acid as a yellow solid (76 mg, crude). MS: m / z = 275.0 [M−H] + This crude product was used in the next step without further purification.

[0550] (3-aminoazetidin-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanone (3-Aminoazetidin-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanone was prepared from (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-carboxylic acid and tert-butyl azetidin-3-ylcarbamate hydrochloride using Methods J and Q. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: MeOH in water (10 mmol / L NH4HCO3), 30% to 70% gradient over 10 min; Detector: UV 254 nm. 1-[[(2R,6R)-6-Methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]carbonyl]azetidin-3-amine was obtained as a light yellow solid (15 mg, 6%).

[0551] compound 63 :HPLC: Purity 98.5%, RT=0.86 min. MS:m / z=329.1 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.98 (d, J = 1.7 Hz, 1H), 8.86 (dd, J = 3.3, 1.8 Hz, 1H), 8.74 (d, J = 5.5 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 4.88-4.78 (m, 1H), 4.76-4.64 (m, 1H), 4.59-4.07 (m, 4H), 4.06-3.62 (m, 3H), 3.17-3.05 (m, 1H), 2.97-2.81 (m, 1H), 1.32 (d, J = 6.0Hz, 3H).

[0552] The following compounds were synthesized in a similar manner:

[0553] Compound 64 ((2R,6R)-6-methyl-N-((R)-piperidin-3-yl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxamide) : From (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxylic acid and (R)-3-aminopiperidine-1-carboxylate tert-butyl ester. HPLC: Purity 93.0%, RT = 0.96 min. MS: m / z = 357.2 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.5 Hz, 1H), 4.91-4.83 (m, 1H), 4.49-4.29 (m, 2H), 4.07-3.95 (m, 2H), 3.11 (d, J = 11.5 Hz, 1H), 3.06-2.79 (m, 3H), 2.70-2.52 (m, 2H), 1.9-1.72 (m, 2H), 1.65-1.53 ​​(m, 2H), 1.33 (d, J = 6.2 Hz, 3H).

[0554] Compound 65 ((2R,6R)-6-methyl-N-(1-methylpiperidin-4-yl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxamide) : From (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxylic acid and 1-methylpiperidin-4-amine. HPLC: Purity 95.8%, RT = 1.00 min. MS: m / z = 371.1 [M+H] + . 1 H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 4.49-4.27 (m, 2H), 4.06-3.94 (m, 1H), 3.87-3.68 (m, 2H), 3.05-2.83 (m, 4H), 2.32-2.10 (m, 5H), 1.91-1.77 (m, 2H), 1.72-1.56 (s, 2H), 1.33 (d, J = 6.2 Hz, 3H).

[0555] Compound 468 ((2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methyl-N-(1-methylpiperidin-4-yl)morpholine-2-carboxamide) : From (2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholine-2-carboxylic acid and 1-methylpiperidin-4-amine. HPLC: Purity 98.0%, RT = 1.19 min. MS: m / z = 395.2 [M+H] + . 11H NMR (400 MHz, CD3OD, ppm) δ 8.96 (dd, J = 17.8, 1.7 Hz, 2H), 8.16 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.54 (dt, J = 12.4, 2.4 Hz, 1H), 4.42 (dd, J = 10.7, 2.8 Hz, 1H), 4.21 - 4.04 (m, 2H), 3.79 (td, J = 11.0, 5.6 Hz, 1H), 2.98 - 2.78 (m, 4H), 2.32 (s, 3H), 2.19 (t, J = 12.0 Hz, 2H), 1.95 - 1.83 (m, 2H), 1.74 - 1.58 (m, 2H), 1.40 - 1.25 (m, 3H). Example 26: Synthesis of Compound 66 ((3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine)

Chem.

[0556] [[ID=ll]] tert-Butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamateTo a solution of 5-bromo-8-(trifluoromethyl)quinoline (950 mg, 3.44 mmol) in DMF (10 mL) at room temperature, tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (718 mg, 3.35 mol), KPO (2.19 g, 10.29 mmol), Pd(dba)CHCl (356 mg, 0.34 mmol), and DavePhos (270 mg, 0.69 mmol) were added. The resulting mixture was heated to 130 °C and stirred for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexanes (0% to 14% gradient) to give tert-butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate as a yellow solid (1.10 g, 77%). MS: m / z=410.2 [M+H] + .

[0557] (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine To a solution of tert-butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate (787 mg, 1.92 mmol) in methanol (10 mL) at room temperature was added a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 M). The resulting solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: XBridge BEH130 Prep C18 OBD column, 150 mm, 5 μm, 13 nm; Mobile phase: acetonitrile in water (containing 0.05% NH4OH), 30% to 60% gradient over 10 minutes; Detector: UV 254 nm. (3R,5S)-5-Methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine was obtained as a light yellow solid (500 mg, 83%).

[0558] compound 66 :HPLC: Purity 99.7%, RT=3.18 min. MS:m / z=310.0 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.94 (dd, J = 4.4, 1.6 Hz, 1H), 8.67-8.57 (m, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.6, 4.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 3.59-3.50 (m, 1H), 3.42-3.33 (m, 1H), 3.27-3.17 (m, 1H), 2.52-2.36 (m, 2H), 2.21-2.07 (m, 2H), 1.08-0.93 (m, 4H). Example 27: Synthesis of Compound 67 ((3R,5S)—N-(2-methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine) [ka]

[0559] 3-Methoxybenzene-1,2-diamine To a solution of 2-methoxy-6-nitroaniline (4.75 g, 28.25 mmol) in methanol (150 mL) at room temperature, Pd / C (10%, 500 mg) was added under a nitrogen atmosphere. The reaction flask was evacuated and flushed with hydrogen. The reaction mixture was hydrogenated using a hydrogen balloon under a H atmosphere at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give 3-methoxybenzene-1,2-diamine as a dark red oil (3.66 g, 94%). MS: m / z=139.1 [M+H] + .

[0560] 5-MethoxyquinoxalineAt room temperature, a solution of oxyaldehyde in HO (40%, 4 mL) was added to a solution of 3-methoxybenzene-1,2-diamine (3.66 g, 26.53 mmol) in water (100.00 mL). NaHSO (7.59 g, 72.94 mmol) was then slowly added. The resulting solution was stirred at room temperature for 15 minutes. Upon completion of the reaction, the insoluble solid in the reaction mixture was filtered. The filtrate was extracted with DCM (300 mL × 3), and the organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 100% gradient) to give 5-methoxyquinoxaline as a dark red oil (3.02 g, 71%). MS: m / z = 161.0 [M+H] + .

[0561] 5-Bromo-8-methoxyquinoxaline To a solution of 5-methoxyquinoxaline (3.02 g, 18.86 mmol) in toluene (100 mL) and acetonitrile (100 mL) was added NBS (5.04 g, 28.29 mmol) at room temperature. The resulting solution was then stirred at 50 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 100% gradient) to give 5-bromo-8-methoxyquinoxaline as a yellow solid (4.23 g, 94%). MS: m / z = 238.8 [M+H] + .

[0562] tert-Butyl N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamateTo a solution of 5-bromo-8-methoxyquinoxaline (1.92 g, 8.04 mmol) in DMF (30 mL), tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (1.52 g, 7.09 mmol), KPO (5.13 g, 24.17 mmol), Pd(dba)CHCl (760 mg, 0.73 mmol), and Davephos (570 mg, 1.45 mmol) were added at room temperature. The resulting mixture was then stirred at 130 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL). The resulting mixture was extracted with DCM (100 mL × 3). The organic phases were combined, washed with brine, and dried over NaSO. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexanes (0% to 100% gradient) to give tert-butyl N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate as a dark red oil (1.11 g, 37%). MS: m / z=373.1 [M+H] + .

[0563] (3R,5S)-1-(8-Methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine To a solution of tert-butyl N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate (429 mg, 1.15 mmol) in dioxane (10 mL) was added a hydrogen chloride solution in dioxane (4 M, 30 mL) at room temperature. The resulting solution was then stirred at room temperature for 1 hour. Upon completion of the reaction, it was quenched by the addition of H2O (50 mL). The pH value of the resulting mixture was then adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with DCM (100 mL x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine as a dark red oil (180 mg, 57%). MS: m / z=273.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.92 (s, 1H), 8.86 (s, 1H), 7.20-7.13 (m, 2H), 3.94 (s, 3H), 3.67 (d, J = 10.0 Hz, 1H), 3.59 (dd, J = 11.4, 3.1 Hz, 1H), 2.96 (td, J = 10.1, 9.0, 5.2 Hz, 1H), 2.20 (dt, J = 15.5, 10.8 Hz, 2H), 1.95 (d, J = 12.2 Hz, 2H), 0.91 (d, J = 6.3 Hz, 3H), 0.79 (q, J = 12.0 Hz, 1H).

[0564] (3R,5S)-N-(2-Methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine To a solution of (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine (90 mg, 0.33 mmol) in acetonitrile (5 mL), 1-bromo-2-methoxyethane (45 mg, 0.34 mmol) and potassium carbonate (238 mg, 1.72 mmol) were added at room temperature. The resulting solution was heated to 100° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was quenched by the addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC using the following conditions: column, XBridge BEH130 Prep C18 OBD column, 150 mm, 5 μm, 13 nm; mobile phase, acetonitrile in water (containing 0.05% NH4OH), 35% to 65% gradient over 10 min; detector, UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine was obtained as a yellow syrup (38 mg, 32%).

[0565] compound 67 :HPLC: Purity 92.7%, RT=0.99 min. MS:m / z=331.3 [M+H] + . 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.81 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 4.04 (s, 3H), 3.92-3.84 (m, 1H), 3.60-3.48 (m, 3H), 3.36 (s, 3H), 3.11 (dd, J = 13.9, 8.0 Hz, 1H), 2.97-2.81 (m, 2H), 2.41-2.29 (m, 2H), 2.20-2.04 (m, 2H), 1.04-0.87 (m, 4H).

[0566] The following compounds were synthesized in a similar manner:

[0567] Compound 201 ((2R)-2-hydroxy-N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide) : From (S)-2-hydroxy-3-methylbutanoic acid and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: Purity 97.9%, RT = 1.12 min. MS: m / z = 373.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.99-8.85 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.22-7.12 (m, 2H), 5.29 (d, J = 5.8 Hz, 1H), 4.04 (s, 1H), 3.93 (s, 3H), 3.69-3.55 (m, 3H), 2.62-2.50 (m, 1H), 2.27 (t, J = 11.0 Hz, 1H), 2.03-1.85 (m, 3H), 1.23-1.12 (m, 1H), 0.91 and 0.89 (d, J = 8.2 Hz, 6H), 0.76 (d, J = 6.7 Hz, 3H).

[0568] Compound 202 (N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): From 3,3-dimethylbutanoic acid and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: Purity 98.8%, RT = 1.33 min. MS: m / z = 371.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d, ppm) δ 8.98-8.82 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.22-7.12 (m, 2H), 4.08-3.90 (m, 4H), 3.70-3.61 (m, 2H), 2.48-2.32 (m, 1H), 2.30-2.28 (m, 1H), 2.02-1.86 (m, 4H), 1.05-0.85 (m, 13H).

[0569] Compound 203 (2-(dimethylamino)-N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide) : From 2-(dimethylamino)acetic acid and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: Purity 98.3%, RT=1.92 min. MS: m / z=371.3 [M+H] + . 1 H NMR (400 MHz, CD3OD, ppm) δ 8.84 (d, J = 1.8 Hz, 1H)...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula: Ring A is aryl or heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; Ring B is aryl or heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; R 1 does not exist or is -H, -CHF 2 , -CF 3 , -OMe, or -CN; Each R 2 are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 , -SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 , -NRSO 2 R or -N(R) 2 and Each R 3 are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 , -SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 , -NRSO 2 R or -N(R) 2 and X is C(R 4 ) 2 , O, N.R. 4 , S, S(R 4 ), or S(R 4 ) 2 and Each R 4 are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 , -SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 , -NRSO 2 R or -N(R) 2 and Each R 5 are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO 2 , -SO 2 R, -SOR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 , -NRSO 2 R or -N(R) 2 and Each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or Two R groups on the same atom, together with the atom to which they are attached, form a C 3-10 forming an aryl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; k is 0 or 1; n is 0, 1, or 2; p is 0, 1, or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

2. 2. The compound of claim 1, wherein Ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; each of which is optionally substituted.

3. 3. The compound of claim 1, wherein ring A is: 【Chemistry 2】

4. The compound of any one of claims 1 to 3, wherein ring A is: 【Transformation 3】

5. 5. The compound of any of claims 1 to 4, wherein Ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of which is optionally substituted.

6. The compound of any one of claims 1 to 5, wherein Ring B is: 【Chemistry 4】

7. The compound of any one of claims 1 to 6, wherein Ring B is: 【Transformation 5】

8. The X is CH 2 The compound according to any one of claims 1 to 7, wherein

9. 9. The compound of claim 1, wherein X is O.

10. R 4 each independently represents -H, C 1-6 Aliphatic, -OR, -C(O)R, -CO 2 R, -C(O)N(R) 2 , -NRC(O)R, -NRC(O)N(R) 2 , -NRSO 2 R or -N(R) 2 10. The compound of any of claims 1-9, wherein:

11. R 4 each independently represents -H, C 1-6 Aliphatic, -C(O)N(R) 2 , -NRC(O)R, or -N(R) 2 11. The compound of any of claims 1-10, wherein:

12. 10. The compound of claim 1, which is a compound of formula Ih, or a pharmaceutically acceptable salt thereof: 【Transformation 6】

13. 10. The compound of claim 1, which is a compound of formula IJ, or a pharmaceutically acceptable salt thereof: 【Transformation 7】

14. 10. The compound of claim 1, which is a compound of formula Im, or a pharmaceutically acceptable salt thereof: 【Transformation 8】

15. A compound according to any one of claims 1 to 14 selected from Table 1.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

17. A method for inhibiting the activity of TLR7 / 8, or a mutant thereof, in a patient or biological sample, the method comprising the step of administering to the patient or contacting with the biological sample a compound according to any one of claims 1 to 15 or a physiologically acceptable salt thereof.

18. 16. A method of treating a TLR7 / 8-mediated disorder in a patient in need thereof, comprising administering to said patient a compound according to any one of claims 1 to 15 or a physiologically acceptable salt thereof.

19. 19. The method of claim 18, wherein the disorder is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyper-IgDemia and periodic fever syndrome, cryopin periodic fever syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer.

20. 10. A method of treating cancer in a subject, comprising administering to the subject a compound of claim 1 or a physiologically acceptable salt thereof.

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