Polycyclic TLR7 / 8 antagonists and their use in the treatment of immunodeficiency disorders

Abstract

To provide compounds of Formula (I) and pharmaceutically acceptable compositions thereof, useful as toll-like receptor 7 / 8 (TLR7 / 8) antagonists.SOLUTION: In the 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 on 17 December 2015, and U.S. Provisional Patent Application No. 62 / 353,603, filed on 23 June 2016. The contents of the aforementioned applications are incorporated herein by reference in their entirety.

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

[0003] Background of the Invention Toll-like receptors (TLRs) currently comprise a family of 10 receptor genes with distinct specificities, and are part of a cellular pathogen pattern recognition system involved in defense against various infectious diseases (bacteria, viruses, and fungi). Activation of TLRs leads to cytokine responses, such as interferon release and activation of specific immune cells. The functional expression of selected TLRs in tissues varies considerably. Some of these receptors are located on the cell surface; for example, TLR4 (stimulated by E. coli lipopolysaccharide LPS) is found on epithelial cells, while TLR3, 7, 8, and 9 are located on the endosomal membranes of specific immune cells. The latter are all activated by nucleic acids, but recognize various types of nucleic acids. For example, TLR9 is activated by single-stranded DNA containing CpG subsequences, TLR7 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 of TLR7 in the pathology of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223:271-283, 2008). In addition, TLR8 polymorphisms have been linked to rheumatoid arthritis (Enevold et al., J Rheumatol, 37:905-10, 2010). Although various TLR7, TLR8, and TLR9 inhibitors have been described, further TLR inhibitors are desired. In particular, polynucleotides containing one or more inhibitory motifs of TLR7, TLR8, and TLR9 are needed to precisely inhibit the immune response in target populations (e.g., patients with autoimmune diseases or inflammatory disorders).

[0005] For several years, significant global efforts have been made to leverage potent immune activation induced by TLR7, 8, or 9 agonists for cancer treatment. However, cancer immunotherapy has a long history of failures. In recent years, however, our knowledge of cancer immune surveillance mechanisms and the resulting function of subsets of immune cells has dramatically improved. TLR7 or TLR9 agonists are being clinically developed for monotherapy, combination therapy, or as vaccine adjuvants for cancer. The TLR agonist approach for cancer immunotherapy differs from earlier efforts using, for example, cytokines, interferons, or monovalent vaccines. Immune activation mediated by TLR agonists is multifaceted, mediated through specific immune cells (primarily dendritic cells and B cells, then other cells), resulting in innate and adaptive immune responses. Furthermore, rather than inducing only one type of interferon, many different isoforms are induced together, as well as not only type I (α, β) but also (indirectly) type II (γ, NK cells). [Overview of the Initiative]

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

[0007] In another embodiment, the present invention provides a compound of formula (I) that is a dual antagonist of TLR7 and TLR8. In another embodiment, the present invention provides a compound of formula (I) suitable for the treatment and / or prevention of disorders related to TLR7 / 8. In another embodiment, the present invention provides a compound that can alter, in particular inhibit, the activity or function of TLR7 / 8 in mammalian, and especially human, pathological conditions.

[0008] A method for treating and / or preventing autoimmune disorders is provided according to another aspect of the present invention.

[0009] In another embodiment, the present invention provides a compound of formula (I) that is selective for TLR7 or TLR8.

[0010] In another embodiment, the present invention provides a compound of formula (I) that is selective for TLR7 and TLR8. [Modes for carrying out the invention]

[0011] Detailed description of a specific embodiment 1. General description of the compounds of the present invention In certain embodiments, the present invention provides antagonists of TLR7 / 8. In some embodiments, such compounds include those of the formulas described herein or pharmaceutically acceptable salts thereof, where each variable is as defined or described herein.

[0012] 2. Compounds and Definitions The compounds of the present invention generally include those described above, which are further illustrated by the classes, subclasses, and types disclosed herein. Unless otherwise noted, the following definitions apply as used herein. For the purposes of the present invention, chemical elements are determined according to the periodic table, the CAS Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, all of which are incorporated herein by reference.

[0013] As used herein, the terms “aliphatic” or “aliphatic group” mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is not aromatic (also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”), having a single point bonded to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is not aromatic, is fully saturated, or contains one or more unsaturated units, and has a single bond site 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 hybrids thereof, e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0014] The term "lower alkyl" refers to C 1-4 This refers to linear or branched alkyl groups. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0015] The term "lower haloalkyl" refers to a C atom substituted with one or more halogen atoms. 1-4 This refers to linear or branched alkyl groups.

[0016] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, or phosphorus (this includes oxidized forms of nitrogen, sulfur, or phosphorus; quaternized forms of basic nitrogen, or; substituteable nitrogen in heterocycles, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR). + (Including those found in N-substituted pyrrolidinyls)

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

[0018] The term "divalent C" as used herein 1-8 (or C 1-6 "Saturated or unsaturated, straight or branched hydrocarbon chains" means straight or branched, divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0019] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n - where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Preferred 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 substituents. Preferred substituents include those described below for substituted aliphatic groups.

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

[0022] The term “aryl,” used alone or as part of a larger term such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, where 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 aromatic ring systems. Examples of aryl groups include phenyl, biphenyl, naphthyl, anthrasyl, and others, which optionally contain one or more substituents. As used herein, groups in which an aromatic ring is condensed with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridine, or tetrahydronaphthyl, are also included within the scope of the term “aryl.”

[0023] The terms "heteroaryl" and "hetero-", used alone or as part of a larger term such as "heteroaryl" or "heteroarylcoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 shared π 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 basic nitrogen. Heteroaryl groups include, non-limitingly, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “hetero-” also include groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclic rings, where the radical or bond site is on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups are optionally monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with "heteroaryl ring," "heteroaryl group," or "aromatic heteroform," all of which include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently and optionally substituted.

[0024] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocycle” are interchangeable and refer to stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moieties that are either saturated or partially unsaturated and, as defined above, have one or more, preferably 1 to 4, heteroatoms in addition to the carbon atom. When used in relation to the ring atoms of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It is an NR (like the N-substituted pyrrolidinyl).

[0025] The heterocyclic ring can be bonded to its pendant group with 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 the heterocyclyl ring is condensed to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl, where the radical or bond site is on the heterocyclyl ring. The heterocyclyl group is optionally monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl and heterocyclyl moiety are optionally substituted independently.

[0026] As used herein, the term “partially unsaturated” refers to a ring portion containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moieties, but not to include aryl or heteroaryl moieties as defined herein.

[0027] As described herein, certain compounds of the present invention include an "optionally substituted" moiety. Generally, the term "substituted" means that one or more hydrogens of a given moiety are replaced by a suitable substituent, whether preceded by the term "optionally". "Substituted" applies to one or more hydrogens that are either obvious or implicit from the structure (e.g., [ka] At least [ka] referring to; and, [ka] At least [ka] (This refers to [a specific group]). Unless otherwise specified, an "optionally substituted" group has suitable substituents at each of its substituted positions, and if any two or more positions of a given structure are substituted by two or more substituents selected from a specified group, these substituents may be the same or different at each position. The substituent combinations envisioned in the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, "stable" means a compound that remains substantially unchanged when produced, detected, and, in particular embodiments, subjected to conditions that enable their recovery, purification, and use for one or more purposes disclosed herein.

[0028] Suitable monovalent substituents on replaceable carbon atoms of the "optionally substituted" group are, independently, deuterium; halogen; -(CH2) 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°, -(CH2) 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 The linear or branched alkylene is C(O)ON(R°)2, where each R° is arbitrarily substituted as defined below, and independently of hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6-membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, the appearance of two independent R°s, together with their intervening atom(s), optionally substituted as defined below, to form a monocyclic or bicyclic 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable monovalent substituents on R° (or a ring formed by the appearance of two independent R° with intervening atoms) are, independently, deuterium, halogen, and -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2;-O(HaroR ● ), -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 alkylenes)C(O)OR ● , or -SSR ● And here each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 A 5-6 member saturated, partially unsaturated, or aryl ring, independently selected from Ph, or from nitrogen, oxygen, or sulfur, having 0-4 heteroatoms independently selected from the nitrogen, oxygen, or sulfur. Preferred divalent substituents on the saturated carbon atom of R° include =O and =S.

[0030] Preferred divalent substituents on the saturated carbon atom of the "arbitrarily 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- is included, and each R is independent here * The appearance of hydrogen is due to C being substituted as defined below. 1-6Selected from unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of a "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is hydrogen, C 1-6 aliphatic optionally substituted as defined below, or selected from unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur.

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

[0032] Suitable substituents on substitutable nitrogen of a "optionally substituted" group are -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † , -C(S)NR †2, -C(NH)NR † 2, or -N(R † )S(O)2R † This includes; where each R † These are, independently, hydrogen, and C which is optionally substituted as defined below. 1-6 An aliphatic, unsubstituted -OPh, or unsubstituted 5-6 member 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 † The presence of these atoms, along with their intervening atoms, forms an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0- to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

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

[0034] In certain embodiments, the terms "optionally substituted," "optionally substituted alkyl," "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 refer to a group that is substituted or unsubstituted by independent substitution of one, two, three or more hydrogen atoms thereon by representative substituents, not limited to, the following: -F, -Cl, -Br, -I, deuterium, -OH, protected hydroxyl, alkoxy, oxo, thiooxo, -NO2, -CN, CF3, N3, -NH2, 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)-carbocyrill, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl -CONH2, -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyrill, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl -OCO2-alkyl, -OCO2-alkenyl, -OCO2-alkynyl, -OCO2-carbocykrill, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocyclyl, -OCONH2, -OCONH-alkyl, -OCONH-alkenyl, -OCONH-alkynyl, -OCONH-carbocykrill, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclyl, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyrill, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -NHCO2-alkyl, -NHCO2-alkenyl, -NHCO2-alkynyl, -NHCO2-carbocyrill, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocyclyl, -NHC(O)NH2, -NHC(O)NH-alkyl, -NHC(O)NH-alkenyl, -NHC(O)NH-alkenyl, -NHC(O)NH-carbocyrill, -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-carbocyrill, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclyl, -NHC(NH)NH2, -NHC(NH)NH-alkyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-carbocyrill, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)-carbocyrill, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocyclyl, -C(NH)NH-alkyl, -C(NH)NH-alkenyl, -C(NH)NH-alkynyl, -C(NH)NH-carbocyrill, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclyl -S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, -S(O)-carbocyrill, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclyl, -SO2NH2, -SO2NH-alkyl, -SO2NH-alkenyl, -SO2NH-alkynyl, -SO2NH-carbocyrill, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocyclyl, -NHSO2-alkyl, -NHSO2-alkenyl, -NHSO2-alkynyl, -NHSO2-carbocyrill, -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-carbocykrill, -S-aryl, -S-heteroaryl, -S-heterocyclyl, or methylthiomethyl.

[0035] As used herein, the term “medically acceptable salt” refers to a salt that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that has a reasonable benefit-risk ratio. Medicinally acceptable salts are well known in the art. For example, S.M. Berge et al., incorporated herein by reference, describe medically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Medicinally acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of medically acceptable, non-toxic acid addition salts are salts of amino groups formed by using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other salts that may be used as pharmaceuticals include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.

[0036] Suitable base-derived salts include alkali metals, alkaline earth metals, ammonium, and N+ (C 1-4 This includes alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, if preferred, include 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, the structures described herein also mean all isomers of that structure (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers); for example, including the R and S configurations of each chiral center, the Z and E double bond isomers, and the Z and E conformational isomer. Accordingly, the stereochemical isomers of the compound alone, as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers, are within the scope of the present invention. Unless otherwise specified, all tautomers of the compounds of the present invention are within the scope of the present invention.

[0038] In addition, unless otherwise specified, the structures described herein also mean that the compounds may differ only in the presence of one or more isotopically enriched atoms. For example, the substitution of hydrogen with deuterium or tritium, or carbon 13 C- or 14 Compounds having this structure, including substitution with 1C-enriched carbon, are within the scope of the present invention. In some embodiments, this group contains one or more deuterium atoms.

[0039] Furthermore, the compounds of formula I are intended to include their isotopic-labeled forms. The isotopic-labeled forms of the compounds of formula I are identical to the compounds, except that one or more atoms of the compound are replaced by one or more atoms having atomic masses or mass numbers different from those of atoms normally present in nature. Examples of isotopes that are readily available commercially and can be incorporated into the compounds of formula I by known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 It contains Cl. Any compound of formula I, its prodrug, or pharmaceutically acceptable salt containing one or more of the aforementioned isotopes and / or other isotopes of other atoms is intended to be part of the present invention. Isotope-labeled compounds of formula I can be used in a number of beneficial ways. For example, as an example 3 H or 14 Isotope-labeled compounds of formula I, which incorporate radioactive isotopes such as 13C, are suitable for tissue distribution assays of pharmaceuticals and / or substrates. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C) is particularly preferred due to its easy preparation and excellent detection ability. For example, deuterium ( 2The incorporation of relatively heavy isotopes such as H into compounds of formula I offers therapeutic advantages due to the higher metabolic stability of these isotope-labeled compounds. Higher metabolic stability directly translates to an increased in vivo half-life or a lower dose, which would represent a preferred embodiment of the present invention in most circumstances. Compounds of formula I that are isotope-labeled can typically be prepared by performing the procedures outlined in the synthesis scheme and related descriptions, the examples section and the preparation section of this text, by replacing the unlabeled reactants with readily available isotope-labeled reactants.

[0040] deuterium( 2 H) can also be incorporated into the compound of formula I for the purpose of manipulating the oxidative metabolism of the compound by first-order kinetic isotope effects. First-order kinetic isotope effects are changes in the rate of a chemical reaction resulting from the exchange of isotopic nuclei, which are then caused by a change in ground state energy necessary for covalent bond formation after this isotope exchange. The exchange of heavier isotopes usually results in lower ground state energy for chemical bonding, thus causing a decrease in the rate of rate-determining bond breakdown. If bond breakdown occurs within or near a saddle point region along the coordinates of a multicomponent reaction, the product distribution ratio is substantially altered. To explain: if deuterium is bonded to a carbon atom at an inexchangeable position, k M / k D A rate difference of 2 to 7 is common. When this rate difference is successfully applied to compounds of formula I that are easily oxidized, the in vivo profile of these compounds can be dramatically altered, resulting in improved pharmacokinetic properties.

[0041] During the discovery and development of therapeutic drugs, those skilled in the art can optimize pharmacokinetic parameters while maintaining desired 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 enables the theoretical design of deuterated compounds of formula I with improved stability through resistance to such oxidative metabolism. This results in a significant improvement in the pharmacokinetic profile of compounds of formula I, which includes improved in vivo half-life (t / 2) and maximum therapeutic concentration (C). max With respect to increases in F, area under the dose-response curve (AUC), and F; and with respect to decreases in clearance, dosage, and material costs: these can be expressed quantitatively.

[0042] To illustrate the above, the following is intended: A compound of formula I having multiple possible attack sites for oxidative metabolism, such as a benzyl hydrogen atom and a hydrogen atom bonded to a nitrogen atom, is prepared as a series of analogs in which various combinations of hydrogen atoms within it are replaced by deuterium atoms, resulting in some, almost all, or all of these hydrogen atoms being replaced by deuterium atoms. The determination of the half-life becomes preferable and more accurate to the extent that the improvement in resistance to oxidative metabolism is enhanced. In this scheme, 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 a favorable modification of the metabolite spectrum of the starting compound in order to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites are produced by oxidative carbon-hydrogen (CH) bond cleavage, it may be reasonable to assume that a deuterated analog would significantly reduce or eliminate the generation of undesirable metabolites, even if the specific oxidation is not the rate-limiting step. Further information regarding the technical aspects of 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] As used herein, the term "modulator" is defined as a compound that binds to and / or inhibits a target with measurable affinity. In certain embodiments, the modulator is IC 50 and / or having a binding constant of less than approximately 50 μM, less than approximately 1 μM, less than approximately 500 nM, less than approximately 100 nM, or less than approximately 10 nM.

[0045] As used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in TLR7 / 8 activity between a sample containing the compounds or compositions thereof of the present invention and TLR7 / 8, and an equivalent sample containing TLR7 / 8 in the absence of the compounds or compositions thereof.

[0046] The substituent and variable combinations envisioned in this invention are limited to those that result in the formation of stable compounds. As used herein, the term “stable” means a compound that is stable enough to enable production and maintains its 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] In this specification, the enumeration of chemical groups in the definition of a variable includes the definition of that variable as any single group or combination of the listed groups. In this specification, the enumeration of embodiments relating to a variable includes that embodiment as any single embodiment or any other embodiment or combination of some of them.

[0048] 3. Explanation of illustrative compounds In one embodiment, the present invention provides compounds of formula I or pharmaceutically acceptable salts thereof: [ka] (In the formula: Ring A is a heteroaryl having aryl, or 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; Ring B is a heteroaryl compound having aryl, or 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; R 1 It is either nonexistent, or -H, -CHF2, -CF3, -OMe, or -CN; Each R 2 These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R 3These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -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 These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R 5 These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R independently consists of hydrogen and C. 1-6 aliphatic, C 3-10 An aryl, a 3- to 8-membered saturated or partially unsaturated carbon ring, 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 they are bonded to, C 3-10 They form aryl, 3- to 8-membered saturated or partially unsaturated carbon rings, 3- to 7-membered heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; k is either 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 a particular embodiment, [ka] but, [ka] And if X is CH2; R 4 It is not H, methyl, or hydroxyl.

[0050] In a particular embodiment, [ka] but, [ka] And if X is O, then R 4 It is not -C(O)N(R)2.

[0051] In this particular embodiment, R 1 It does not exist.

[0052] In this particular embodiment, R 1 It is -H.

[0053] In this particular embodiment, R 1 It is -CHF2.

[0054] In this particular embodiment, R 1 It is -CF3.

[0055] In this particular embodiment, R 1 It is -OMe.

[0056] In this particular embodiment, R 1 It 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, pyridadinyl, or triazinyl; each of these is optionally substituted.

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

[0060] In a particular embodiment, ring A is as follows: [ka]

[0061] In a particular embodiment, ring A is as follows: [ka]

[0062] In certain embodiments, ring B is a C6 aryl, or a 5-6 member 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, pyridadinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of these is optionally substituted.

[0064] In a particular embodiment, ring B is as follows: [ka]

[0065] In a particular embodiment, ring B is as follows: [ka]

[0066] In this particular embodiment, each R 2 These are independently -H.

[0067] In this particular embodiment, each R 2 Independently, C 1-6 aliphatic, C 3-10 An aryl, a 3- to 8-membered saturated or partially unsaturated carbon ring, 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 this particular embodiment, each R 2 These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these is optionally substituted.

[0069] In this particular embodiment, each R 2These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, Chromanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydrofloflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indorenil, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinnyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridozazole, Pyridoimidazole, Pyridothiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidinil These are quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 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 these is optionally substituted.

[0070] In this particular embodiment, each R 2 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0071] In this particular embodiment, each R 3 It is independently -H.

[0072] In this particular embodiment, each R 3 Independently, C 1-6 aliphatic, C 3-10An aryl, a 3- to 8-membered saturated or partially unsaturated carbon ring, 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 this particular embodiment, each R 3 These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these is optionally substituted.

[0074] In this particular embodiment, each R 3 It is independently methyl.

[0075] In this particular embodiment, each R 3These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, Chromanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydrofloflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indorenil, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinnyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridozazole, Pyridoimidazole, Pyridothiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidinil These are quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 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 these is optionally substituted.

[0076] In this particular embodiment, each R 3 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0077] In a particular embodiment, X is C(R 4 ) is 2 or 0.

[0078] In a particular embodiment, X is C(R 4 )2. In a particular embodiment, X is CH2.

[0079] In a particular embodiment, X is O.

[0080] In this particular embodiment, each R 4 It is independently -H.

[0081] In this particular embodiment, each R 4 Independently, C 1-6 aliphatic, C 3-10 An aryl, a 3- to 8-membered saturated or partially unsaturated carbon ring, 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 this particular embodiment, each R 4 These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these is optionally substituted.

[0083] In this particular embodiment, each R 4These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, Chromanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydrofloflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indorenil, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinnyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridozazole, Pyridoimidazole, Pyridothiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidinil These are quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 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 these is optionally substituted.

[0084] In this particular embodiment, each R 4 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0085] In this particular embodiment, each R 4 These are independently -H, C 1-6 The compounds are aliphatic, -OR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; each of which is optionally substituted.

[0086] In this particular embodiment, each R 4These are independently -H, C 1-6 They are aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of which is optionally substituted.

[0087] In this particular embodiment, each R 4 These are, independently, the following: [ka] [ka] [ka] [ka]

[0088] In this particular embodiment, each R 4 These are, independently, the following: [ka]

[0089] In this particular embodiment, each R 5 These are independently -H.

[0090] In this particular embodiment, each R 5 Independently, C 1-6 aliphatic, C 3-10 An aryl, a 3- to 8-membered saturated or partially unsaturated carbon ring, 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 this particular embodiment, each R 5These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these is optionally substituted.

[0092] In this particular embodiment, each R 5These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, Chromanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydrofloflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indorenil, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinnyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridazinil, Pyridoxazole, Pyridoimidazole, Pyridothiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidyl Nyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 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 these is optionally substituted.

[0093] In this particular embodiment, each R 5 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0094] In this particular embodiment, each R 5 These are independently methyl, cyclopropyl, -F, or -CF3.

[0095] In this particular embodiment, each R 5 Independently: [ka] -F or -CF3.

[0096] In this particular embodiment, X, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 Each of k, m, n, p, r, and t is defined above and is described individually or in combination in the embodiments, classes, and subclasses described above and herein.

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

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

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

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

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

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

[0103] In certain embodiments, the present invention provides compounds of formula Ig, or pharmaceutically acceptable salts thereof: [ka] (In the formula, X, ring B, R 2 , R 3 , R 4 , R 5 Each of n, p, r, and t is defined above and is described individually or in combination in the embodiments, classes, and subclasses described above and herein.

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

[0105] In certain embodiments, the present invention provides compounds of formula Ij, or pharmaceutically acceptable salts thereof: [ka] (In the formula, X, R 2 , R 3 , R 4 , R 5Each of n, p, r, and t is defined above and is described individually or in combination in the embodiments, classes, and subclasses described above and herein.

[0106] In certain embodiments, the present invention provides compounds of formula Im, or pharmaceutically acceptable salts thereof: [ka] (In the formula, X, R 2 , R 3 , R 4 , R 5 Each of n, p, r, and t is defined above and is described individually or in combination in the embodiments, classes, and subclasses described above and herein.

[0107] In certain embodiments, the present invention provides compounds of formula In, or pharmaceutically acceptable salts thereof: [ka] (In the formula, X, R 1 , R 2 , R 3 , R 4 , R 5 (Each of k, n, p, r, and t is defined above and is described individually or in combination in the embodiments, classes, and subclasses described above and herein.)

[0108] In certain embodiments, the present invention provides compounds of formula Ip, or pharmaceutically acceptable salts thereof: [ka] (In the formula, X, R 2 , R 3 , R 4 , R 5 Each of n, p, r, and t is defined above and is described individually or in combination in the embodiments, classes, and subclasses described above and herein.

[0109] In a particular embodiment, the present invention provides compounds 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 compounds selected from those described above, or pharmaceutically acceptable salts thereof.

[0211] Various structural descriptions can show heteroatoms without bonded groups, radicals, charges, or counterions. Those skilled in the art will recognize that such descriptions show heteroatoms bonded to hydrogen (for example, [ka] teeth, [ka] I know that it means to indicate that it is understood to be so.

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

[0213] 4. Use, Formulation, and Administration Compositions that are acceptable as pharmaceuticals In another embodiment, the present invention provides compositions containing the compounds of the present invention or pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable carriers, adjuvants, or vehicles. The amount of the compounds in the compositions of the present invention is such that it is effective in measurably inhibiting TLR7 / 8 or their variants in a biological sample or in a patient. In a particular embodiment, the amount of the compounds in the compositions of the present invention is such that it is effective in measurably inhibiting TLR7 / 8 or their variants in a biological sample or in a patient. In a particular embodiment, the compositions of the present invention are formulated for administration to patients who require such compositions.

[0214] As used herein, the terms “patient” or “subject” mean 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 impair the pharmacological activity of the compound formulated with it. 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, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and lanolin.

[0216] "Pharmacovigilant derivatives" means any non-toxic salts, esters, ester salts, or other derivatives of the compounds of the present invention that can directly or indirectly provide the compounds of the present invention or their inhibitory metabolites or residues when administered to a recipient.

[0217] The compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir. As used herein, the term “parenteral” includes injection or infusion techniques into the subcutaneous, intravenous, intramuscular, intra-articular, intra-articular, intra-articular bursa, intrasternal, intramedullary, intrahepatic, intrafocal, and intracranial regions. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of the present invention comprise aqueous or oily suspensions. These suspensions are formulated using suitable dispersants or wetting agents and suspending agents in accordance with techniques known in the art. The sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol. Particularly acceptable vehicles and solvents used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are commonly used as solvents or suspension media.

[0218] For this purpose, any non-irritating, non-volatile oils used include synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in injectable preparations, particularly in their polyoxyethylated forms, as natural pharmaceutically acceptable oils such as olive oil or castor oil. These oily solutions or suspensions also include diluents or dispersants of long-chain alcohols, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of 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 solids, liquids, or other dosage forms, are also used for formulation purposes.

[0219] The pharmaceutically acceptable compositions of the present invention are administered orally in any orally acceptable dosage form. Examples of oral dosage forms include 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 an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorants are also optionally added, if desired.

[0220] Alternatively, the pharmaceutically acceptable compositions of the present invention may 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, and therefore melts in the rectum and releases the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0221] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the therapeutic target includes areas or organs that are easily accessible by topical application, such as diseases of the eyes, skin, or lower intestines. Suitable topical formulations can be readily prepared for each of these areas or organs.

[0222] Topical application for the lower intestinal tract may be effective with rectal suppositories (see above) or suitable enema formulations. Topically applied transdermal patches are also used.

[0223] For topical application, the pharmaceutically acceptable composition provided is formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Examples of carriers for topical administration of the compound are mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition provided may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers are, 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 aerosol or inhalation into the nose. Such compositions are prepared in accordance with well-known techniques in the field of pharmaceutical formulation and are prepared as solutions in saline solution using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

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

[0226] The amount of the compound of the present invention, which can be optionally combined with a carrier material to produce a composition in a single dosage form, will vary depending on the host being treated and the specific mode of administration. Preferably, the provided compositions should be formulated so that they can be administered to a patient receiving these compositions at doses of the compound from 0.01 to 100 mg / kg body weight / day.

[0227] It should 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, weight, overall health, sex, diet, administration time, excretion rate, concomitant medications, and the judgment of the attending physician, as well as the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will depend on the specific compound in the composition.

[0228] Use of compounds and pharmaceutically acceptable compositions The present invention further relates to a method for treating a subject suffering from TLR7 / 8-related disorder, comprising administering an effective amount of a compound of formula I and related formulas to the subject.

[0229] The compounds of the present invention are useful as anticancer 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 cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, cancers of the ovary, pancreas, prostate, rectum, renal cancer, small intestine, soft tissue, testicle, stomach, skin, ureter, vagina and vulva; hereditary cancers, retinoblastoma and Wilms' tumor; leukemia, lymphoma, non-Hodgkin lymphoma, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, multiple myeloma and T-cell lymphoma; myelodysplastic syndromes, plasma cell neoplasms, paraneoplastic syndromes, cancers 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 measuring a reduction in primary or metastatic tumor burden (minor, partial, or complete regression), changes in blood count, altered hormone or cytokine blood concentrations, inhibition of further increases in tumor burden, stabilization of the disease in the patient, evaluation of disease-related biomarkers or surrogate markers, extended overall survival in the patient, extended time to disease progression in the patient, extended progression-free survival in the patient, extended disease-free survival in the patient, improved quality of life in the patient, or changes in comorbidities (e.g., non-limitingly, pain, cachexia, mobilization, hospitalization, altered blood count, weight loss, wound healing, fever, etc.).

[0231] The compounds of the present invention are even more useful as immunoassay modifiers, modifying immune responses in numerous and diverse ways, and making them useful in the treatment of various disorders.

[0232] Methods for inhibiting an immune response in an individual are provided herein, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor (e.g., TLR inhibitor) to the individual using the compounds described herein. In some modifications, the TLR inhibitor inhibits a TLR7-dependent immune response. In some modifications, the TLR inhibitor inhibits a TLR8-dependent immune response. In some modifications, the TLR inhibitor inhibits both TLR7-dependent and TLR8-dependent immune responses. In some modifications, 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 revealed herein. In some preferred embodiments, the individual is a human patient.

[0233] The immunomodulatory methods provided herein include, but are not limited to, methods for suppressing and / or inhibiting immune responses, including immune responses. The disclosure also provides, but are not limited to, methods for improving symptoms associated with undesirable immune activation, including autoimmune symptoms. Immunosuppression and / or inhibition by the methods described herein may be practiced in individuals, including those suffering from disorders associated with undesirable activation of the immune response. The disclosure also provides methods for inhibiting TLR7 and / or TLR8-induced responses (e.g., in vitro or in vivo). In some modifications, cells are contacted with a TLR inhibitor in an amount effective in inhibiting the response from cells contributing to the immune response.

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

[0235] A method for inhibiting an immune response in an individual is provided herein, the method comprising administering to the individual an amount effective in inhibiting the immune response in the individual, at least one of the TLR inhibitors disclosed herein. In some modifications, the immune response is associated with an autoimmune disease. In a further embodiment, the inhibition of the immune response therein improves one or more symptoms of an autoimmune disease. In a further embodiment, the inhibition of the immune response therein treats an autoimmune disease. In yet another embodiment, the inhibition of the immune response therein prevents or delays the onset of an autoimmune disease. In some modifications, the TLR inhibitor inhibits a TLR7-dependent immune response. In some modifications, the TLR inhibitor inhibits a TLR8-dependent immune response. In some modifications, the TLR inhibitor inhibits both TLR7-dependent and TLR8-dependent immune responses. In some embodiments, at least one TLR inhibitor is administered in an amount effective in inhibiting the immune response in the individual.

[0236] Methods for treating or preventing autoimmune diseases in an individual, comprising administering an effective amount of TLR7 and / or TLR8 inhibitors to the individual, are also provided herein. In some embodiments, the autoimmune disease is characterized by arthralgia, positive antinuclear antibody test, cheek rash, or discoid rash. In some embodiments, the autoimmune disease is related to the skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is not manifested in the individual by symptoms of the 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 mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, irritable bowel disease (IBD), scleroderma, Sjögren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel diseases 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 duplication syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold sensitivity.

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

[0238] In another embodiment, 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, pyelonephritis, 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 pyelonephritis. 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 disease or disorder. In some embodiments, the autoimmune disease therein is associated with RNA-containing immune complexes. In some embodiments, the autoimmune disease is Sjögren's disease.

[0240] A method for inhibiting an immune response in an individual is provided herein, which comprises administering to the individual an amount effective in inhibiting the immune response in the individual of at least one TLR inhibitor disclosed herein. In some modifications, the immune response is related to an inflammatory disorder. As used herein, the term “inflammatory disorder” encompasses autoimmune diseases as well as inflammatory conditions without known autoimmune components (e.g., atherosclerosis, asthma, etc.). In a further embodiment, inhibition of the immune response improves one or more symptoms of an inflammatory disorder. In a further embodiment, inhibition of the immune response treats an inflammatory disorder. In yet another embodiment, inhibition of the immune response prevents or delays the onset of an 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 junctional dermatitis. In some further embodiments, junctional dermatitis is selected from the group consisting of lichen planus, lichenoid rash, lichenoid keratosis, linear lichen, chronic lichenoid keratosis, erythema multiforme, fixed drug eruption, pityriasis lichenoid, phototoxic dermatitis, radiation dermatitis, viral rash, dermatomyositis, secondary syphilis, sclerosing atrophic lichen, mycosis fungoides, bullous pemphigoid, lichen yellow, porokeratosis, chronic atrophic acrodermatitis, and degenerative 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 hepatic and / or pancreatic inflammation. In some further embodiments, the inflammatory disease is inflammatory hepatic disorder. In some other further embodiments, the inflammatory disease is inflammatory pancreatic disorder.

[0241] Methods for inhibiting an immune response in an individual are provided herein, which include administering to the individual an amount effective in inhibiting the immune response in the individual, at least one TLR inhibitor as disclosed herein. In some modifications, the immune response is related to chronic pathogen stimulation. In some modifications, the immune response is related to HIV infection. In a further embodiment, the inhibition of the immune response therein improves one or more symptoms of a viral disease or disorder resulting from HIV infection. In a further embodiment, the inhibition of the immune response therein treats a viral disease or disorder resulting from HIV infection. In yet another embodiment, the inhibition of the immune response therein prevents or delays the onset of a viral disease or disorder resulting from HIV infection. Other modifications provided herein relate to immunosuppressive therapy for individuals 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, at least one TLR inhibitor is administered in a dose effective in suppressing HIV-induced cytokine production in individuals exposed to or infected with HIV.

[0242] A method for inhibiting a TLR7 and / or TLR8-dependent immune response in an individual is provided herein, the method comprising administering to the individual an amount of a TLR inhibitor effective in inhibiting the immune response in the individual. In some modifications, 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 mellitus. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of diabetes. In some embodiments, this disease is Sjögren's disease. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of Sjögren's disease. In some modifications, the immune response is associated with inflammatory disorders. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of inflammatory disorders. In some modifications, the immune response is associated with chronic pathogen stimulation. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of chronic pathogen stimulation. In some modifications, the immune response is associated with viral diseases resulting from HIV infection. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of viral diseases resulting from HIV infection. In any modification, the TLR inhibitor is a polynucleotide containing one or more inhibitory motifs of TLR7, TLR8, and TLR9.

[0243] In some embodiments of any method of administering a TLR inhibitor to an individual (e.g., methods such as inhibiting an immune response, treating or preventing an autoimmune disease or inflammatory disorder), the TLR inhibitor has a therapeutically acceptable safety profile. The TLR inhibitor may have a therapeutically acceptable histological profile, including, if any, to the liver, kidneys, pancreas, or other organs, a toxicity that is, if any, is reasonably low. In some cases, polynucleotides are associated with toxicity to specific organs such as the liver, kidneys, and pancreas. In some embodiments, the TLR inhibitor has an unexpectedly advantageous safety profile. In some embodiments, the safety profile includes an assessment of toxicity, histological profile, and / or necrosis (e.g., liver, kidneys, 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 initial body weight of the individual being treated. In some embodiments, the TLR inhibitor induces a reduction 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., a lower severity score) compared to, for example, a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a better histological profile (e.g., a lower severity score) when, for example, evaluating the liver, kidneys, 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., a lower) necrosis score compared to, for example, 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 compared to, for example, a reference TLR inhibitor.

[0244] Accordingly, the present invention provides a method for activating TLR7 in animals, particularly mammals, preferably humans, comprising administering an effective amount of a compound of formula I to the animal. As with all compositions for inhibiting immune responses, the effective amount and method of administration of a particular TLR inhibitor formulation may vary based on the individual, the condition being treated, and other factors apparent to those skilled in the art. The effective amount of the compound will vary according to factors known in the art, but the dose is expected to 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 viral infections in animals, comprising administering an effective amount of the compound of formula I to the animals. An effective amount for treating or inhibiting a viral infection is an amount that causes a reduction in one or more signs of viral infection, such as viral foci, viral load, viral production rate, and mortality, compared to untreated control animals. The exact amount will vary depending on known factors, but is expected to be a dose as previously shown for TLR7 activation, or a dose of about 100 ng / kg to about 50 mg / kg, preferably about 10 μg / kg to about 5 mg / kg.

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

[0247] The method of the present invention can be performed either in vitro or in vivo. The sensitivity of specific cells to treatment with the compounds of the present invention can be determined, in particular, by in vitro testing, whether in research or clinical application. Typically, cells are cultured with the compounds of the present invention at various concentrations for a period usually ranging from about one hour to one week, for a duration sufficient for the active substance to inhibit TLR7 / 8 activity. In vitro treatment can be performed using biopsy samples or cultured cells derived from cell lines.

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

[0249] To identify signaling pathways and detect interactions between various signaling pathways, scientists have developed suitable models or model systems, such as cell culture models and transgenic animal models. Interacting compounds can be utilized to modify signals in relation to determining specific stages of a signaling cascade. The compounds of the present invention can also be used as reagents to test TLR7 / 8-dependent signaling pathways in animal and / or cell culture models or in the clinical diseases mentioned in this application.

[0250] Furthermore, subsequent provisions of this Specified Use of Compounds of Formula (I) and their derivatives in the manufacture of medicinal products for prophylactic or therapeutic treatment and / or monitoring are considered demonstrable and applicable, even if only for convenience, and not limited to the use of the compounds for 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 prophylactic or therapeutic treatment and / or monitoring of diseases induced, mediated and / or transmitted 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 pharmaceuticals for prophylactic or therapeutic treatment and / or monitoring of diseases induced, mediated and / or transmitted by TLR7 / 8 activity. In certain embodiments, the present invention provides the use of compounds of formula I or physiologically acceptable salts thereof for the manufacture of pharmaceuticals for prophylactic or therapeutic treatment of TLR7 / 8-mediated disorders.

[0252] Compounds of formula (I) and / or physiologically acceptable salts thereof can further be used as intermediates for the preparation of further pharmaceutically active ingredients. Preferably, these pharmaceuticals are prepared by non-chemical methods, for example, by combination of the active ingredient with at least one solid, liquid, and / or semi-liquid carrier or excipient, and by combination with, or more than, 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 and act as a treatment. The aforementioned compounds and medical products in the inventive use are used particularly in therapeutic treatments. The therapeutically relevant effects are 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 the disease or pathological condition to normal, either partially or completely. Monitoring is considered a type of treatment when these compounds are administered at intervals, for example, to enhance the response and to completely eradicate the pathogen and / or symptoms of the disease. 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 to preemptively prevent the onset of a disorder related to TLR7 / 8 activity, or to treat symptoms that have occurred and symptoms that persist.

[0254] In the sense of the present invention, preventive measures are effective when the subject has any of the aforementioned physiological or pathological prerequisites, such as a familial predisposition, a gene deficiency, or a disease previously suffered from.

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

[0256] In the sense of the present invention, “pharmaceutical” means any substance in the field of pharmaceuticals, comprising one or more compounds of formula (I) or preparations thereof (e.g., pharmaceutical compositions or pharmaceutical formulations), which can be used for the prevention, treatment, monitoring or recovery health management of patients suffering from diseases related to TLR7 / 8 activity, such that a change in the pathogenicity of the patient’s overall condition or the condition of a particular 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 using two or more compounds in the pharmaceutical composition, i.e., a compound of formula (I) is combined with at least one other substance as an active ingredient, which is either another compound of formula (I) or a compound with a different structural skeleton. These active ingredients may be used simultaneously or sequentially.

[0258] The TLR inhibitors disclosed herein can be administered in combination with one or more additional therapeutic agents. As described herein, TLR inhibitors can be combined with physiologically acceptable carriers. The methods described herein may be practiced in combination with other therapies that constitute the 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 corticosteroids. 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., Corton), aldosterone and its derivatives, prodrugs, isomers and analogs, dexamethasone and its derivatives, prodrugs, isomers and analogs (i.e., Decadron), prednisone and its derivatives, prodrugs, isomers and analogs (i.e., Prelon), fludrocortisone and its derivatives, prodrugs, isomers and analogs, hydrocortisone and its derivatives, prodrugs, isomers and analogs (i.e., cortisol or Cortef), hydroxycortisone, and This includes, but is not limited to, its derivatives, prodrugs, isomers and analogs, betamethasone and its derivatives, prodrugs, isomers and analogs (i.e., Celeston), budesonide and its derivatives, prodrugs, isomers and analogs (i.e., Entcort EC), methylprednisolone and its derivatives, prodrugs, isomers and analogs (i.e., Mellodol), prednisolone and its derivatives, prodrugs, isomers and analogs (i.e., Deltazone, Curtan, Methycorten, Olason, or Stellapred), triamcinolone and its derivatives, prodrugs, isomers and analogs (i.e., Kenacort or Kenalog), and similar products. In some embodiments, the corticosteroid is fludrocortisone or its derivatives, prodrugs, isomers or analogs. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone or its derivatives, prodrugs, isomers, or analogs. In some embodiments, the corticosteroid is hydroxycortisone.

[0260] In some embodiments, corticosteroids are administered at a dose of approximately 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 to 80 mg, 80 to 120 mg, 120 mg to 200 mg, 200 mg to 500 mg, or 500 mg to 1000 mg per day. In some embodiments, corticosteroids are administered at a dose of approximately 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 combination therapy may be delivered in amounts of, 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 concurrently with one or more additional therapeutic agents, non-limited to corticosteroids (concurrent administration). In some embodiments, the TLR inhibitor is administered sequentially with additional therapeutic agents, non-limited to corticosteroids (sequential administration). In some embodiments, sequential administration includes administering the TLR inhibitor or subsequently the additional therapeutic agent within one minute, 5 minutes, 30 minutes, 1 hour, 5 hours, 24 hours, 48 ​​hours, or within one week. In some embodiments, the TLR inhibitor is administered via the same route of administration as the additional therapeutic agent. In some embodiments, the TLR inhibitor is administered via a different route of administration than the additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered parenterally (e.g., by central venous line, intra-arterial, intra-venous, intramuscular, intraperitoneal, intradermal, or subcutaneous injection), orally, intra-gastrointestinal, topically, nasopharyngeal, and intrapulmonary (e.g., by inhalation or intranasal). In some embodiments, the additional therapeutic agent is a corticosteroid.

[0263] The disclosed compound of formula I can be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term “anticancer agent” refers to any substance administered to a cancer patient for the purpose of treating cancer.

[0264] The anticancer treatments previously defined may be applied as monotherapy or may be used in conjunction with conventional surgery, radiotherapy, or drug therapy in addition to the compounds of Formula I disclosed herein. Such drug therapies, such as chemotherapy or targeted therapy, may include one or more, but preferably one, of the following antitumor agents: Alkylating agentAltrethamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Chlormetine, Cyclophosphamide, Dacarbazine, Ifosfamide, Improsulfan, Tosylate, Lomustine, Melphalan, Mitobronitol, Mitractol, Nimustine, Ranimustine, Temozolomide, Thiotepa, Treosulfan, Mechloretamine, Carbocon; Apadiquon, Fotemustine, Gluphosphamide, Palifosfamide, Pipobroman, Trophosphamide, Uramustine, TH-302 4 VAL-083 4 etc; platinum compound : Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lovaplatin, nedaplatin, picoplatin, satraplatin; lovaplatin, nedaplatin, picoplatin, satraplatin, etc.; DNA modifiers : Amrubicin, Bisanthren, Decitabine, Mitoxantrone, Procarbazine, Trabectedin, Clofarabine; Amsacrin, Brostaricin, Pixantrone, Laromustine 1,3 etc; Topoisomerase inhibitors : Etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, berotecan, eriptinium acetate, boreroxine, etc. Microtubule-acting drugs : Cabazitaxel, docetaxel, eribulin, ixabepirone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunin; phosbulatabrin, tesetaxel, etc. antimetabolites :Asparaginase 3 Azacitidine, calcium levofolate, capecitabine, cladribine, cytarabine, enocitabine, phloxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nerarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxyfluridine, ellacitarabine, larcitrexed, sapacitabine, tegaflu 2,3, trimethrexate, etc. anticancer antibiotics : Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, rebamisol, miltefosine, mitomycin C, romidepsin, streptozocin, barurubicin, dinostatin, zorubicin, daunorubicin, plicamycin; acralubicin, peplomycin, pirarubicin, etc. Hormones / Antagonists Abarelix, abiraterone, bicalutamide, buserelin, carsterone, chlorotrianicene, degarelix, dexamethasone, estradiol, fluocortone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, alpha-thyroid hormone, toremifene, trilostane, triptorelin, diethylstilbestrol; acorbifen, danazol, deslorerin, epithiostanol, orteronel, enzalutamide 1,3 etc; Aromatase inhibitors : Aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestan, etc. Small molecule kinase inhibitorsCrizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, ariseltib, dabrafenib, dacomitinib, dinacicrib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, lincitinib, ma Citinib, Midostaurine, Motesanib, Neratinib, Orantinib, Perifosine, Ponatinib, Radotinib, Rigosertib, Tipifalnib, 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 , Ideralicib 1,3 , Fedratinib 1 XL-647 4 etc; Photosensitizer : Methoxsalen 3 ;Sodium porfimers, talaporfin, temoporfin, etc.; antibody Alemtuzumab, becilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3 Katsumakisomab, elotuzumab, epratuzumab, falletuzumab, mogamulizumab, necitumubab, nimotuzumab, obinutuzumab, okalatuzumab, olegobomab, ramucirumab, rilotumumab, siltuximab, tosirituzumab, zaltumubab, zanolimumab, matsuzumab, dalotuzumab 1,2,3 Onartuzumab 1,3 , Lakotsu Mobabu1 Tabalmab 1,3 EMD-525797 4 nivolumab 1,3 etc; Cytokine Aldesleukin, Interferon α 2 Interferon α2a 3 Interferon α2b 2,3 ; Selmoleukin, Tasonelmin, Teseloukin, Oprelbekin 1,3 Recombinant interferon β-1a 4 etc; Drug complex Denileukin diffittox, Ibritumomab tiuxetan, Iobenguan I123, Prednimustine, Trastuzumab emtansine, Estramustine, Gemtuzumab, Ozogamicin, Aflibercept; Syntredekin vesudotox, Edtreotide, Inotuzumab ozogamicin, Naptumobab estafenatox, Oportuzumab monatox, Technetium (99mTc) alsitumomab 1,3 , Bintaferid 1,3 etc; vaccine :Cyproisel 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, Ibandronate, Imiquimod, Lenalidomide, Lentinan, Methylosine, Mifamlutide, Pamidronic Acid, Pegaspargase, Pentostatin, Ciproisel 3Schizophyllan, Tamibarotene, Temsirolimus, Thalidomide, Tretinoin, Bismodesib, Zoledronic acid, Vorinostat; Celecoxib, Silengitide, Entinostat, Etanidazole, Ganetespib, Idronoxyl, Iniparib, Ixazomib, Ronidamine, Nimorazole, Panobinostat, Pelletinoin, Pritidepsin, Pomalidomide, Procodazole, Ridaforolimus, Tascinimod, Terotristat, Thimalfacin, Tirapazamin, Tosedostat, Travedersen, Ubenimex, Valspodar, Genjicin 4 Picibanil 4 Leorisin 4 Retaspimycin hydrochloride 1,3 Trevananib 2,3 , bililysine 4 carfilzomib 1,3 Endostatin 4 , Imcotel 4 , belinostat 3 MGN-1703 4 . ( 1 Prop. INN (Proposed International Common Name); 2 Rec. INN (Recommended International Common Name); 3 USAN (United States Common Name); 4 (Not INN).

[0265] In some embodiments, the combination of a TLR inhibitor with one or more additional therapeutic agents reduces the effective dose of the TLR inhibitor and / or one or more additional therapeutic agents (including, but not limited to, dose volume, dose concentration, and / or total drug dose administered) to achieve the same results compared to the effective dose administered when the TLR inhibitor or the additional therapeutic agent is administered alone. In some embodiments, the combination of a TLR inhibitor with a corticosteroid reduces the effective dose 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 drug administration compared to the 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 the administration of the additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the side effects associated with the 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 its derivatives, prodrugs, isomers, or analogs. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, an effective dose combination of a TLR inhibitor and an additional therapeutic agent is more potent than an effective dose of the TLR inhibitor or the additional therapeutic agent alone.

[0266] TLR inhibitors are also useful as vaccine adjuvants for use with any substance that modifies either the humoral and / or cellular immune response, such as, for example, viable viruses, bacteria, or parasitic immunogens; inactivated viruses, tumor-derived, protozoa, 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, a combination of 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, a combination of TLR inhibitors and vaccines are used in the treatment of infections.

[0267] In some embodiments, combination therapies including, but not limited to, a combination of a TLR inhibitor and a corticosteroid are used in the treatment of autoimmune diseases or inflammatory disorders. In some embodiments, the autoimmune disease is selected from, but is not limited to, rheumatoid arthritis, systemic lupus erythematosus, autoimmune skin diseases, multiple sclerosis, pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type 1 diabetes. In some embodiments, the autoimmune disease is Sjögren's disease.

[0268] Kits containing TLR inhibitors and accompanying documentation relating to their use in methods for inhibiting TLR7- and / or TLR8-dependent immune responses are also provided herein.

[0269] The kit may include one or more containers containing the TLR inhibitor (or formulation containing the TLR inhibitor) described herein, and a set of package inserts, generally in writing, but also acceptable, may include an electronic storage medium (e.g., magnetic disk or optical disk) containing the package inserts, relating to the use and dosage of the TLR inhibitor or formulation for the intended treatment (e.g., suppression of response to TLR7 and / or TLR8 agonists, suppression of TLR7 and / or TLR8-dependent immune responses, improvement of one or more symptoms of an autoimmune disease, improvement of symptoms of a chronic inflammatory disease, reduction of virus-responsive cytokine production, and / or treatment and / or prevention of one or more symptoms of a disease or disorder mediated by TLR7 and / or TLR8). The package inserts included in the kit generally include information regarding dosage, administration schedule, and route of administration for the intended treatment. The containers for the TLR inhibitor (or formulation containing the TLR inhibitor) may be in the form of unit doses, bulk packaging (e.g., repeated-dose packaging), or divided unit doses. The kit also includes a container for the adjuvant.

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

[0271] As used herein, the terms “treatment,” “to treat,” and “being treated” refer to the regression, reduction, delay of onset, or inhibition of progression of a disease or disorder, or one or more of its symptoms, as described herein. In some embodiments, treatment is administered after the onset of one or more symptoms. In other embodiments, treatment is administered asymptomatically. For example, treatment is administered to susceptible individuals before the onset of symptoms (e.g., considering medical history and / or genetic or other susceptibility factors). Treatment may also be continued after remission of symptoms, for example, to prevent or delay their relapse.

[0272] The compounds and compositions of the methods of the present invention are administered in any amount and via any route of administration that is effective in treating or alleviating the severity of previously provided disorders. 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, and the mode of administration. The compounds of the present invention are preferably formulated into unit dosage forms in uniform doses that are easy to administer. As used herein, the term “unit dosage form” refers to a physically distinct unit of substance suitable for the patient being treated. However, it will be understood that the total daily dose of the compounds or compositions of the present invention will be determined by the attending physician within reasonable medical judgment. The specific effective dose level for any particular patient or organism will vary depending on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient’s age, weight, general condition, sex, and diet; the timing of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with 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 may be administered to humans and other animals orally, rectally, parenterally, intrasacral, vaginally, intraperitoneally, topically (as powders, ointments, or droplets), orally, or via oral or intranasal spray, 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 dose level of about 0.01 mg to about 100 mg, preferably about 1 mg to about 50 mg, per kg of body weight per day, once or more, to obtain the desired therapeutic effect.

[0274] In certain embodiments, the therapeutically effective dose of compounds of formula (I) and related formulas, as well as other active ingredients, depends on numerous factors, including, for example, the age and weight of the animal, the exact state and severity of the disease requiring treatment, the nature of the formulation and method of administration, and is ultimately determined by the attending physician or experienced physician. However, the effective dose of a compound is generally in the range of 0.1 to 100 mg per kg of recipient (mammal) body weight per day, and particularly typically in the range of 1 to 10 mg per kg of body weight per day. Thus, the practical dose per day for an adult mammal weighing 70 kg is usually 70 to 700 mg, where this amount is administered as a single daily dose or usually as a series of partial doses per day (e.g., 2, 3, 4, 5, or 6 times), resulting in the same total daily dose. The effective dose of a salt or solvate or its physiologically functional derivative can be determined as an effective dose fraction of the compound itself.

[0275] In certain embodiments, the pharmaceutical formulation may be administered in unit dosage forms containing a predetermined amount of the active ingredient per unit dose. Such units may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 100 mg of the compound of the present invention, depending on the disease condition being treated, the method of administration, and the patient's age, weight, and condition. Alternatively, the pharmaceutical formulation may be administered in unit dosage forms containing a predetermined amount of the active ingredient per unit dose. Preferred unit dose formulations include those containing a daily dose, a partial dose, or corresponding fractions of the active ingredient, as previously described. Furthermore, this type of pharmaceutical formulation may be prepared using processes generally known in the pharmaceutical art.

[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, the liquid dosage form may optionally include 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, as well as mixtures thereof. In addition to inert diluents, oral compositions may also include auxiliary agents such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavorings, and fragrances.

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

[0278] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0279] To extend the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This is achieved by using liquid suspensions of crystalline or amorphous substances that are not very soluble in water. Thus, the absorption rate of the compound depends on its dissolution rate, which can then depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound types is achieved by dissolving or suspending the compound in an oily vehicle. Depot formulations for injection are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydride). Depot formulations for injection are also prepared by capturing the compound in liposomes or microemulsions that are compatible with biological tissues.

[0280] A preferred composition for rectal or vaginal administration is a suppository that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity, releasing 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 an inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or calcium hydrogen phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia gum; c) humectants such as glycerol; d) agar-agar, calcium carbonate, potato Alternatively, it may be mixed with disintegrants such as tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers 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, and sodium lauryl sulfate, as well as mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may optionally include buffers.

[0282] Similar solid compositions are also used as fillers in soft and hard gelatin-filled capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, draggies, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical technology. These may optionally contain opacifying agents and may optionally be compositions that release the active ingredient(s) only in or preferentially there to a specific portion of the intestinal tract in a delayed manner. Examples of embeddable compositions include polymers and waxes. Similar solid compositions are also used as fillers in soft and hard gelatin-filled capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0283] The active compound may also be in a microencapsulated form with one or more excipients, as noted above. Solid dosage forms of tablets, draggies, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical technology. 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 may also include additional substances other than inert diluents, as is common practice, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, these dosage forms may also optionally contain buffers. These may optionally contain opacifiers and may be compositions that release the active ingredient(s) only in or preferentially in specific parts of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

[0284] Dosage forms for topical or transdermal administration of the compounds 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, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of the present invention. In addition, the present invention intends to be used in transdermal patches, which have the added advantage of providing controlled delivery of the compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the inflow of the compounds beyond the skin. This rate can be controlled by providing a rate-controlling membrane or by dispersing the compounds in a polymer matrix or gel.

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

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

[0287] The compounds of the present invention are useful in vitro as unique tools for understanding the biological role of TLR7 / 8, including evaluating the many factors that influence and are influenced by TLR7 / 8 generation and TLR7 / 8 interactions. Since these compounds provide important structure-activity relationship (SAR) information that facilitates development, they are also useful in the development of other compounds that interact with TLR7 / 8. The compounds of the present invention that bind to TLR7 / 8 can be used as reagents for detecting TLR7 / 8 in living cells, fixed cells, biological fluids, tissue homogenates, purified natural biological materials, etc., for example, by labeling such compounds, cells expressing TLR7 / 8 can be identified. In addition, based on their ability to bind to TLR7 / 8, the compounds of the present invention can be used in the purification of TLR7 / 8-expressing cells inside enzyme-purified or permeabilized cells, such as in situ staining, FACS (fluorescence-activated cell sorting), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and ELISA (enzyme-linked immunosorbent assay). The compounds of the present invention can also be used as commercially available research reagents for various medical research and diagnostic applications.Such uses may include, but are not limited to, the following: use as a calibration standard for quantifying the activity of candidate TLR7 / 8 inhibitors in various functional assays; use as a blocking reagent in random compound screening, i.e., in the search for a novel family of TLR7 / 8 ligands, these compounds can be used to block the recovery of the TLR7 / 8 compounds claimed herein; use in co-crystallization with TLR7 / 8, i.e., the compounds of the present invention can form crystals of compounds bound to TLR7 / 8, allowing for 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 a known amount such as a TLR7 / 8 inhibitor; use in assays as a probe for determining the expression of TLR7 / 8 in cells; and use in the development of assays for detecting compounds that bind to the same site as TLR7 / 8-binding ligands.

[0288] The compounds of the present invention can be applied either on their own or / or in combination with physical measurements relating to the diagnosis of therapeutic effects. Pharmaceutical compositions containing these compounds and the use of these compounds for treating TLR7 / 8-mediated conditions represent a promising novel approach to broad-spectrum therapies that produce direct and immediate improvement of health conditions in either humans or animals. The novel orally bioavailable and active chemical entities of the present invention improve patient convenience and physician compliance.

[0289] Compounds of formula (I), their salts, isomers, tautomers, enantiomers, diastereomers, racemates, derivatives, prodrugs, and / or metabolites are characterized by high specificity and stability, low manufacturing costs, and convenient handling. These characteristics form the basis for reproducible action, including the lack of cross-activity with respect to reliable and safe interactions with target structures.

[0290] As used herein, “biological sample” includes, but is not limited to, cell cultures or extracts thereof; biopsy materials obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0291] Modifying the activity of TLR7 / 8 variants in biological samples is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, preservation of biological specimens, and biological assays. [Examples]

[0292] As shown in the following examples and specific illustrative embodiments, the compounds are prepared according to the following general procedure. While the general method illustrates the synthesis of specific compounds of the present invention, it will be understood that the following general method, and other methods known to those skilled in the art, can be applied to all compounds and their subclasses and types as described herein.

[0293] The symbols and conventions used in the following descriptions of processes, schemes, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0294] Unless otherwise specified, all temperatures are expressed in degrees Celsius (°C).

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

[0296] All NMR experiments were recorded 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 contain 0.03%–0.05% v / v tetramethylsilane, which is the reference signal ( 1 H and 13 For both C, d was set to 0.00. If the deuterated solvent did not contain tetramethylsilane, the peak of the remaining undeuterated solvent was used as a reference signal, in accordance with the published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997).

[0297] LC-MS analysis was performed using one of the following two instruments:

[0298] - A SHIMADZU LC-MS instrument consisting of a UFLC 20-AD system and an LCMS 2020 MS detector. The column used was Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. A linear gradient was applied over 2.2 minutes, starting with 95% A (A: 0.05% TFA in water) and ending with 100% B (B: 0.05% TFA in acetonitrile), with a total trial time of 3.6 minutes. 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. This mass spectrometer was equipped with an electrospray ionizer (ES) that operates in positive or negative mode. This mass spectrometer scanned from m / z 90 to 900 with a scan time of 0.6 seconds.

[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. This 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 × 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 / MSWaters ZMD (ESI).

[0300] HPLC data were obtained using 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. Unless otherwise specified, the gradient method was 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, and 10 min: 5% B.

[0301] In general, the compounds of formula (I) and related formulas 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. In general, the synthetic route for any individual compound of formula (I) and related formulas depends on the specific substituents of each molecule, such as factors understood by those skilled in the art. The general methods and procedures described below in the examples can be used to prepare the compounds of formula (I) and related formulas. The reaction conditions shown in the following scheme, such as temperature, solvent, or co-reagents, are shown as examples only and are not limiting. It will be understood that, given typical or preferred experimental conditions (i.e., reaction temperature, time, number of moles of reagent, solvent, etc.), other experimental conditions may also be used unless otherwise specified. Optimal reaction conditions vary depending on the specific reactants or solvents used, and such conditions can be determined by those skilled in the art using conventional optimization procedures. For all methods of protection and deprotection, see Philip J. Kocienski, "Protecting Groups," Georg Thieme Verlag Stuttgart, New York, 1994, and Theodora W. Greene and Peter GM 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), oxyaldehyde (1.00 g, 17.20 mmol) was added 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 using ethyl acetate 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), benzenesulfonyl chloride (4.95 g, 28.02 mmol), 4-dimethylaminopyridine (228 mg, 1.87 mmol), and triethylamine (5.67 g, 56.04 mmol) were added at room temperature. The resulting solution was then stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography using ethyl acetate in petroleum ether (0% to 50% gradient) to obtain 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]At -78°C, a solution of 1-(benzenesulfonyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (1.86 g, 6.40 mmol) in THF (35 mL) was dropwise added to n-BuLi solution (2.5 M in THF, 5 mL, 12.80 mmol) 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. Next, the reaction mixture was slowly warmed from -78°C to 0°C over 3 hours with stirring. When the reaction was complete, it was quenched by adding saturated NH4Cl solution (20 mL), and the resulting mixture was extracted with ethyl acetate (60 mL x 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 using ethyl ethyl acetate in petroleum ether (0% to 5% gradient) to obtain 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 Potassium carbonate (592 mg, 4.30 mmol) was added at room temperature 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). 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). Insoluble solids in this mixture were filtered, and the filtrate was concentrated under reduced pressure to yield 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), Cs2CO3 (1.40 g, 4.30 mmol) and iodoethane (676 mg, 4.30 mmol) were added at room temperature. The resulting mixture was then stirred at 40°C for 3.5 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (30 mL). Insoluble solids in this mixture were filtered, and the filtrate was concentrated under reduced pressure to yield a yellow oily substance (333 mg, 89% for both steps) containing 4-chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridine. 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] At -78°C, 3.4 mL of LDA solution (2M in THF, 6.85 mmol) was added dropwise to a solution of 1-(benzenesulfonyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.85 mmol) in 30 mL of tetrahydrofuran. The resulting solution was stirred at -78°C for 1 hour, after which 0.97 g of iodomethane (6.85 mmol) was slowly added. The resulting mixture was then stirred at -78°C for 5 hours. When the reaction was complete, it was quenched with H₂O (30 mL), and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, and dried over Na₂SO₄. The solvent was removed under reduced pressure, yielding 1-(benzenesulfonyl)-4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine as a brown oily substance (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 using MeOH in DCM (0%~10% gradient), yielding 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (900 mg, 79% for both steps). MS: m / z = 166.9 [M+H] + .

[0309] Method G 4-Chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine At -10°C, sodium hydroxide (240 mg, 6.00 mmol) was added 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). Next, iodomethane (284 mg, 2.00 mmol) was added, and the resulting mixture was stirred at -10°C for 4 hours. When the reaction was complete, the reaction mixture was diluted with DCM (100 mL), and the resulting mixture was washed with water (30 mL x 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 by elution with siRNA in petroleum ether (0%~10% gradient), yielding 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-methylpiperidine-3-ylcarbamate [ka]

[0310] tert-butyl 5-methylpyridine-3-ylcarbamateAt room temperature, a solution of 5-methylpyridine-3-amine (9.50 g, 88.0 mmol) in tetrahydrofuran (150 mL) was dropwise added to a solution of NaHMDS (2 M in THF, 110 mL, 220.0 mmol) over 10 minutes. The resulting solution was stirred at room temperature for 1 hour. Then, Boc2O (21.14 g, 92.4 mmol) was added. This reaction mixture was stirred at room temperature for a further 2 hours. When the reaction was complete, it was quenched by adding saturated NH4Cl solution (100 mL). The resulting mixture was extracted with ethyl acetate (150 mL x 3), the organic phase was combined, washed with brine, and dried over Na2SO4. This solvent was removed under reduced pressure, and the residue was purified by flash chromatography using butyl in petroleum ether (0% to 35% gradient) to obtain tert-butyl N-(5-methylpyridine-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-methylpiperidine-3-ylcarbamateIn a 500 mL pressurized tank reactor, tert-butyl N-(5-methylpyridine-3-yl)carbamate (14.22 g, 68.43 mmol), PtO2 (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. This mixture was hydrogenated at 70 °C for 24 hours under a hydrogen pressure of 15 atm. After the reaction was complete, the reaction mixture was cooled to room temperature. 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 x 3), the organic phase was combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, yielding tert-butyl N-(5-methylpiperidine-3-yl)carbamate as a light brown solid (14.19, 97%). MS: m / z = 215.2 [M + H] + .

[0312] tert-butyl (3R,5S)-5-methylpiperidine-3-ylcarbamate A solution of (2R,3R)-2,3-bis[(4-methoxyphenyl)carbonyloxy]butanediol (28.95 g, 69.19 mmol) in isopropanol (13 mL) was added to a solution of tert-butyl N-(5-methylpiperidine-3-yl)carbamate (11.70 g, 54.60 mmol) in acetone (200 mL) at room temperature. The resulting mixture was stirred at room temperature for 24 hours, and precipitation occurred. When the reaction was complete, the precipitate was collected by filtration, yielding a white solid, which was added in small amounts at 0°C to a solution of potassium carbonate (29.06 g, 210.27 mmol) in water (15 mL). 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, yielding tert-butyl N-[(3R,5S)-5-methylpiperidine-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 of the resulting mixture was adjusted to 7 with sodium hydroxide solution (6 M). The mixture was then concentrated under reduced pressure, and insoluble solids were filtered from the remaining mixture. The pH of the filtrate was then adjusted to 3 with hydrochloric acid solution (6 M), and precipitation occurred. The precipitate was collected by filtration and dried in a vacuum oven, yielding 4-chloro-2,3-dinitrobenzoic acid as a bright 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), iron powder (1000 mg, 3.58 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Insoluble solids in the reaction mixture were filtered, and the filtrate was concentrated under reduced pressure to yield 2,3-diamino-4-chlorobenzoic acid as a black oily substance (3.12 g, crude). MS: m / z = 186.9 [M + H] + .

[0315] 8-Chloroquinoxaline-5-carboxylic acidA solution of 2,3-diamino-4-chlorobenzoic acid (3.12 g, crude) in ethanol (40 mL) was mixed with a solution of oxyaldehyde (40%, 14.4 mol / L, 20 mL, 0.29 mol) in H2O at room temperature. The resulting solution was stirred at 75°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL), and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, yielding 8-chloroquinoxaline-5-carboxylic acid as a yellow oily substance (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 complete, 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 NH4OH 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. When the reaction was complete, the reaction mixture was diluted with 20 mL of H2O and extracted with ethyl acetate (50 mL x 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 using ethyl sorbate in petroleum ether (0% to 50% gradient) to obtain 8-chloroquinoxaline-5-carboxamide as a yellow oily substance (1.20 g, 6% over 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), POCl3 (4.00 g, 22.88 mmol) was added 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 x 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 using ethyl acetate in petroleum ether (0%~2% gradient) to obtain 8-chloroquinoxaline-5-carbonitrile as a yellowish-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 CH3CN (80 mL), 1-bromopyrrolidine-2,5-dione (27.00 g, 151.74 mmol) was added 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 solids in this mixture were filtered, the filtrate was washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, yielding 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), NBS (19.23 g, 108.08 mmol) and AIBN (0.71 g, 4.32 mmol) were added at room temperature. The resulting solution was then stirred at 80 °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). Insoluble solids in this mixture were filtered, and the filtrate was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using ethyl acetate in petroleum ether (0%~5% gradient) to obtain 5-bromo-8-(dibromomethyl)quinoxaline as a bright yellow solid (7.15 g, 70%). MS: m / z = 378.7 [M+H] + .

[0320] 8-Bromoquinoxaline-5-Carboaldehyde A solution of 5-bromo-8-(dibromomethyl)quinoxaline (13.50 g, 35.71 mmol) in ethanol (290 mL) was added dropwise to 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. When the reaction was complete, the reaction mixture was diluted with CH3CN (300 mL), and a precipitate was formed. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to yield 8-bromoquinoxaline-5-carboaldehyde 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-carboaldehyde (10 g, crude) in ethanol (100 mL), NaOAc (6.34 g, 73.42 mmol) and NH2OH HCl (3.12 g, 42.65 mmol) were added at room temperature. The resulting mixture was stirred at 70°C for 3 hours. When the reaction was complete, the insoluble solids in the reaction mixture were filtered at 70°C, and the filtrate was cooled to 0°C to form a precipitate. The precipitate was collected by filtration and dried in an oven to yield (E)-N-[(8-bromoquinoxaline-5-yl)methylidene]hydroxylamine as a yellow solid (2.96 g, 33% for both steps). MS: m / z = 253.9 [M + H] + .

[0322] 8-Bromoquinoxaline-5-Carbonitrile To a solution of (E)-N-[(8-bromoquinoxaline-5-yl)methylidene]hydroxylamine (3.47 g, 13.82 mmol) in acetonitrile (20 mL), Cu(OAc)2 (577 mg, 3.18 mmol) and acetic acid (1.24 g, 20.73 mmol) were added 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). Insoluble solids in the mixture were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using ethyl sorbate in petroleum ether (0%~15% gradient), yielding 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 hours. The completion of the reaction was monitored by LC-MS. After 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 minutes, the reaction mixture was neutralized with 1.5 N HCl solution. The precipitated solid was filtered, washed with ice-cooled water, and dried under vacuum to yield 8-methyl-3H-quinazolin-4-one (125 g, 94%) as a yellowish-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. 8-methylquinazoline-4(3H)-one (125 g) was added in small increments. The reaction mixture was refluxed at 120 °C for 12 hours. The completion of the reaction was monitored by TLC and LC-MS. After 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 in an ice-cooled solution of saturated K2CO3 with constant stirring. The organic layer was then separated, washed with brine, dried on sodium sulfate, and concentrated under vacuum to obtain 4-chloro-8-methylquinazoline (120 g, 86%) as a yellow solid. This 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 in small increments. The reaction mixture was heated at 45°C for 12 hours. The completion of the reaction was monitored by LC-MS and TLC. After completion, the reaction mixture was cooled to RT, the solvent was evaporated to dryness, the resulting residue was dissolved in EtOH (500 mL), 5N NaOH solution (500 mL) was added, and the mixture was refluxed for 6 hours. The completion of the reaction was monitored by LC-MS. After completion, the reaction mixture was cooled to RT and extracted with MTBE (3 × 600 mL). The combined organic layers were washed with brine, dried on sodium sulfate, and concentrated under vacuum. The resulting residue was purified by chromatography using neutralized silica gel (60-120 mesh) and elution with petroleum ether / ethyl acetate, yielding 8-methylquinazoline (60 g, 61%) as a low-melting-point 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-methylquinazoline8-methylquinazoline (50 g, 0.347 mol) was added in small portions at 0°C to a stirred solution of silver sulfate (151.5 g, 0.486 mol) in concentrated sulfuric acid (700 mL). Bromine (21.3 mL, 0.382 mol) was added dropwise, and the reaction mixture was stirred at RT for 16 hours. The reaction was monitored at regular intervals by LC-MS. After 16 hours, LC-MS showed 40% starting material, 7% isomers, 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 under vacuum. The crude substance was purified by column chromatography using neutralized silica gel (60-120 mesh) and eluted with petroleum ether / ethyl acetate, yielding 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 800 mL of CCl4 under nitrogen, N-bromosuccinimide (94.1 g, 0.522 mol) was added, followed by AIBN (7.8 g, 0.048 mol), at RT. The reaction mixture was heated at 90°C for 12 hours. After completion, the reaction mixture was cooled to RT, filtered, and washed with CCl4. The filtrate was concentrated and recrystallized to yield 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 Silver nitrate (110 g) was added in small increments at 0°C to a stirred solution of 5-bromo-8-dibromomethylquinazoline (110 g, crude mixture) in acetone (1 L) and water (200 mL). The reaction mixture was stirred at RT for 2 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered, 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 under vacuum to yield 5-bromoquinazoline-8-carboaldehyde. This 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-carboaldehyde (25 g, 0.105 mol) in DMF (125 mL), hydroxylamine (7.3 g, 0.105 mol), triethylamine (89 mL, 0.633 mol), and T3P (100 mL, 0.158 mol) were added. The reaction mixture was heated at 100 °C for 3 hours. The reaction proceeded as follows: 1The reaction was monitored by 1H NMR. After completion, the reaction mixture was cooled to RT and quenched with ice. The reaction mixture was filtered, the filtrate was made basic with sodium bicarbonate, and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum to yield 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-carbonitride [ka]

[0330] 5-Bromo-quinoline-8-carbaldehyde oxime Sodium acetate (1.9 g; 23.3 mmol), 5-bromoquinoline-8-carboaldehyde (5.0 g; 21.2 mmol), and hydroxylamine hydrochloride (1.6 g; 23.3 mmol) were added to anhydrous 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, the mixture was cooled to 0°C, and 1N sodium hydroxide aqueous 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, yielding 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-carbonitride Acetic acid (1.4 mL; 24.4 mmol) was added to a mixture of 5-bromo-quinoline-8-carboaldehyde oxime (5.1 g; 20.3 mmol) and copper(II) acetate monohydrate (81.1 mg; 0.41 mmol) in anhydrous acetonitrile (40 mL), and the reaction mixture was heated under 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 sodium hydroxide aqueous 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, and 5-bromo-quinoline-8-carbonitrile (1.22 g; 26%) was provided 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-quinazolineA 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 prepared by adding potassium carbonate (1.8 g; 12.9 mmol) and a 4 Å molecular sieve (650 mg). The reaction mixture was heated under reflux overnight. The resulting suspension was cooled, filtered through Celite, washed with acetonitrile to remove solids, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography using a PuriFlash column (40 g, 15 μm) with hexane and ethyl acetate, and 5-bromo-8-trifluoromethyl-quinazoline (222 mg, 22%) was provided as a bright 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 A mixture of 5-bromo-2-methylpyridine-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 prepared by adding sulfuric acid (5.6 mL; 96.2 mmol) dropwise. The resulting mixture was heated overnight at 120°C. The reaction mixture was treated with ice, 2N sodium hydroxide solution, ethyl acetate, and dichloromethane. After filtration to remove dark brown solids, the organic layer was separated, washed with brine, dried, and concentrated. The crude substance was purified by chromatography on silica gel with ethyl acetate and hexane to yield 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-naphthyridine-4-yl)piperidine-4-carboxamide) [ka]

[0335] Method H Ethyl 1-(1,8-naphthyrizin-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 at room temperature to a solution of 4-bromo-1,8-naphthiridine (190 mg, 0.91 mmol) in ethanol (10 mL). 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 x 3). The organic phases were combined, washed with brine, and dried over Na₂SO₄. The solvent was removed under reduced pressure, yielding 1-(1,8-naphthiridine-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 be in the range of 95°C to 130°C.)

[0337] Method I 1-(1,8-naphthyridine-4-yl)piperidine-4-carboxylic acidTo a solution of ethyl 1-(1,8-naphthiridine-4-yl)piperidine-4-carboxylate (210 mg, 0.74 mmol) in ethanol (9 mL), sodium hydroxide (147 mg, 3.67 mmol) and water (3 mL) were added 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 x 3), the organic phases were combined, washed with brine, and dried on Na2SO4. The solvent was removed under reduced pressure, yielding 1-(1,8-naphthiridine-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, and the solvent may be methanol or a mixture of methanol and THF instead of ethanol, and the reaction temperature may be in the range of room temperature to 50°C.)

[0339] Method J N-(2-(diethylamino)ethyl)-1-(1,8-naphthyridine-4-yl)piperidine-4-carboxamideTo a solution of 1-(1,8-naphthyridine-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. At the end of the reaction, it was quenched by adding water (10 mL). The resulting mixture was extracted with DCM (50 mL x 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 according to 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) with a 10% to 50% gradient over 10 minutes; Detector, UV 254 nm. N-[2-(diethylamino)ethyl]-1-(1,8-naphthyrizin-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 using a similar method:

[0342] Compound 2 ((4-(diethylamino)piperidine-1-yl)(1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-4-yl)methanone) From 8-chloropyrido[2,3-b]pyrazine, ethyl piperidine-4-carboxylate, and N,N-diethylpiperidine-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-quinoline-5-yl)-piperidine-4-carboxylic acid [2-(2,6-dimethyl-piperidine-1-yl)-ethyl]amide) From 5-bromo-quinoline-8-carbonitride, ethyl piperidine-4-carboxylate, and 2-(3,5-dimethyl-piperidine-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-quinoline-5-yl)-piperidine-4-carboxylic acid (2-dimethylaminoethyl)-amide) From 5-bromo-quinoline-8-carbonitride, piperidine-4-carboxylate ethyl, 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-quinoline-5-yl)-piperidine-4-carboxylic acid [2-(ethyl-methyl-amino)-ethyl]amide) From 5-bromo-quinoline-8-carbonitride, piperidine-4-carboxylate ethyl, 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-quinoline-5-yl)-piperidine-4-carboxylic acid (2-morpholine-4-yl-ethyl)-amide) From 5-bromo-quinoline-8-carbonitride, piperidine-4-carboxylate ethyl, 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-quinoline-5-yl)-piperidine-4-carboxylic acid (2-dimethylamino-1-methyl-ethyl)-amide) From 5-bromo-quinoline-8-carbonitride, piperidine-4-carboxylate ethyl, 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-quinoline-5-yl)-piperidine-4-carboxylic acid [2-(4-methyl-piperazine-1-yl)-ethyl]amide) From 5-bromo-quinoline-8-carbonitride, piperidine-4-carboxylate ethyl, 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-quinoline-5-yl)-piperidine-4-carboxylic acid (2-pyrrolidine-1-yl-ethyl)-amide) From 5-bromo-quinoline-8-carbonitride, piperidine-4-carboxylate ethyl, 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-quinoline-5-yl)-piperidine-4-carboxylic acid [2-(4,4-difluoro-piperidine-1-yl)-ethyl]amide) From 5-bromo-quinoline-8-carbonitride, ethyl piperidine-4-carboxylate, and 2-(4,4-difluoropiperidine-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-quinoline-5-yl)-piperidine-4-carboxylic acid (1-methyl-pyrrolidine-2-ylmethyl)amide) From 5-bromo-quinoline-8-carbonitride, ethyl piperidine-4-carboxylate, and (1-methylpyrrolidine-2-yl)methaneamine. 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-quinoline-5-yl)-piperidine-4-carboxylic acid (1-cyclopropylmethylpyrrolidine-3-yl)-amide) From 5-bromo-quinoline-8-carbonitride, ethyl piperidine-4-carboxylate, and 1-(cyclopropylmethyl)pyrrolidine-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-quinoline-5-yl)-piperidine-4-ylmethyl]amide) From 5-bromoquinoline-8-carbonitride, 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-quinoline-5-yl)-piperidine-4-carboxylic acid (2-azetidine-1-yl-ethyl)-amide) From 5-bromo-quinoline-8-carbonitride, ethyl piperidine-4-carboxylate, and 2-(azetidine-1-yl)ethane-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-quinoxaline-5-yl)-piperidine-4-carboxylic acid (2-piperidine-1-yl-ethyl)-amide) From 8-bromo-quinoxaline-5-carbonitride, piperidine-4-carboxylate ethyl, 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-quinoxaline-5-yl)-piperazine-1-yl]-N,N-dimethyl-4-oxo-butylamide)From 8-bromo-quinoxaline-5-carbonitride, 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-fluoropyrido[3,4-b]pyrazine-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]pyrimidine-4-yl)-N-(2-(piperidine-1-yl)ethyl)piperidine-4-carboxamide) [ka]

[0359] Method K 1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-N-(2-(piperidine-1-yl)ethyl)piperidine-4-carboxamide At 0°C, MeI (53 mg, 0.37 mmol) and Cs2CO3 (100 mg, 0.31 mmol) were added to a solution of N-[2-(piperidine-1-yl)ethyl]-1-[1H-pyrazolo[3,4-d]pyrimidine-4-yl]piperidine-4-carboxamide (67 mg, 0.19 mmol) in acetone (5 mL). The resulting solution was stirred at 0°C for 1.5 hours. When the reaction was complete, it was quenched by adding water (10 mL). The resulting mixture was extracted with DCM (30 mL x 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 according to 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) with a 10% to 23% gradient over 10 minutes; Detector, UV254. 1-[1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-N-[2-(piperidine-1-yl)ethyl]piperidine-4-carboxamide, yellowish-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]pyrazine-8-yl)piperidine-4-yl)methyl)piperidine-4-amine) [ka]

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

[0362] Method L (1-(Pyrido[2,3-b]pyrazine-8-yl)piperidine-4-yl)methylmethanesulfonate To a solution of (1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-4-yl)methanol (250 mg, 1.02 mmol) and triethylamine (155 mg, 1.53 mmol) in dichloromethane (15 mL), methylsulfonyl chloride (152 mg, 1.33 mmol) was added in several batches at room temperature. The resulting solution was stirred at room temperature for 2 hours. When the reaction was complete, it was quenched by adding water (20 mL). The resulting mixture was extracted with dichloromethane (40 mL × 3), the organic phases were combined, washed with brine, and dried over Na₂SO₄. The solvent was removed under reduced pressure, yielding (1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-4-yl)methylmethanesulfonate 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]pyrazine-8-yl)piperidine-4-yl)methyl)piperidine-4-amineTo a solution of (1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-4-yl)methylmethanesulfonate (170 mg, 0.53 mmol) in N,N-dimethylformamide (5 mL), N,N-diethylpiperidine-4-amine (330 mg, 2.11 mmol) and DIEA (136 mg, 1.05 mmol, 2.00 equivalents) were added 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 x 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 under 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) with a 10% to 23% gradient over 18 minutes; Detector, UV 254 nm. N,N-diethyl-1-[(1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-4-yl)methyl]piperidine-4-amine was obtained as a brown solid (47 mg, 23%).

[0364] (Note: The reaction temperature for method M may be in the range of 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-(quinoline-4-yl)piperidine-4-yl)methyl)piperidine-4-amine) [ka]

[0366] (1-(Quinoline-4-yl)piperidine-4-yl)methylmethanesulfonate (1-(quinoline-4-yl)piperidine-4-yl)methylmethanesulfonate was prepared from 4-chloroquinoline, piperidine-4-yl methanol, and methanesulfonyl chloride using methods H and L. [1-(quinoline-4-yl)piperidine-4-yl]methylmethanesulfonate was obtained as a yellow solid (550 mg, crude). MS: m / z = 321.0 [M+H] + .

[0367] Method N N,N-diethyl-1-((1-(quinoline-4-yl)piperidine-4-yl)methyl)piperidine-4-amineTo a solution of [1-(quinoline-4-yl)piperidine-4-yl]methylmethanesulfonate (450 mg, crude) in acetonitrile (8 mL), N,N-diethylpiperidine-4-amine (209 mg, 1.34 mmol) and Cs2CO3 (651 mg, 2.00 mmol) were added at room temperature. The resulting mixture was stirred overnight at 80°C. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with DCM (40 mL x 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 according to 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) with a 15% to 60% gradient over 8 minutes; Detector, UV 254 nm. N,N-diethyl-1-[[1-(quinoline-4-yl)piperidine-4-yl]methyl]piperidine-4-amine was obtained as a bright 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 be in the range of 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-(piperidine-1-yl)ethoxy)methyl)piperidine-1-yl)quinolone) [ka]

[0370] Method O 4-(4-((2-(piperidine-1-yl)ethoxy)methyl)piperidine-1-yl) To a solution of [1-(quinoline-4-yl)piperidine-4-yl]methanol (190 mg, 0.78 mmol) in N,N-dimethylformamide (20 mL), sodium hydride (59 mg, 2.48 mmol) was added at room temperature. The resulting suspension was stirred at room temperature for 30 minutes, after which 1-(2-chloroethyl)piperidine hydrochloride (304 mg, 1.65 mmol) was added. The reaction mixture was stirred at room temperature for a further 20 hours. At the end of the reaction, it was quenched by adding water (10 mL). The resulting mixture was extracted with DCM (50 mL x 3), the organic phase was combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC according to 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) with a 41% to 50% gradient over 9 minutes; Detector: UV 254 nm. 4-(4-[[2-(piperidine-1-yl)ethoxy]methyl]piperidine-1-yl)quinoline, yellowish-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-(Quinoline-4-yl)piperidine-4-yl)methyl)ethanamine) [ka]

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

[0373] Method P 2-Morpholino-N-((1-(quinoline-4-yl)piperidine-4-yl)methyl)ethaneamineTo a solution of N-[2-(morpholine-4-yl)ethyl]-1-(quinoline-4-yl)piperidine-4-carboxamide (374 mg, crude) in tetrahydrofuran (5 mL), BH3-THF (10 mL, 1 M, 1.00 mmol) was added 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 x 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 using MeOH in DCM (0% to 25% gradient) to obtain 2-morpholino-N-((1-(quinoline-4-yl)piperidine-4-yl)methyl)ethaneamine as a bright yellow solid (50 mg, 10% for each of the four 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-(Quinoline-4-yl)piperidine-4-yl)methyl)ethanamine) [ka]

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

[0376] Method Q (1-(quinoline-4-yl)piperidine-4-yl)methanamine To a solution of tert-butyl N-[[1-(quinoline-4-yl)piperidine-4-yl]methyl]carbamate (557 mg, 1.63 mmol) in MeOH (10 mL), concentrated HCl solution (12 M, 1.5 mL) was added at room temperature. The resulting solution was stirred at room temperature for 24 hours. At the end of the reaction, the reaction mixture was concentrated under reduced pressure, yielding [1-(quinoline-4-yl)piperidine-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 may be a 1:1 mixture of dioxane / MeOH or dioxane instead of MeOH.)

[0378] 2-(piperidine-1-yl)-N-((1-(quinoline-4-yl)piperidine-4-yl)methyl)acetamide2-(piperidine-1-yl)-N-((1-(quinoline-4-yl)piperidine-4-yl)methyl)acetamide was prepared from (1-(quinoline-4-yl)piperidine-4-yl)methanamine hydrochloride and 2-(piperidine-1-yl)acetic acid using Method J. The crude product was purified by preparative HPLC under 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) with a 40% to 55% gradient over 10 minutes; Detector, UV 254 nm. 2-(piperidine-1-yl)-N-[[1-(quinoline-4-yl)piperidine-4-yl]methyl]acetamide was obtained as a bright 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 using a similar method:

[0381] Compound 388 (2-piperidine-1-yl-N-(1-pyrido[2,3-b]pyrazine-8-yl-piperidine-4-ylmethyl)acetamide) From 8-chloropyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine, and piperidine-1-ylacetic 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]pyrazine-8-yl-piperidine-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]pyrazine-8-ylpiperidine-4-ylmethyl)-benzamide)From 8-chloropyrido[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]pyrazine-8-ylpiperidine-4-ylmethyl)amide) From 8-chloropyrido[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]pyrazine-8-ylpiperidine-4-ylmethyl)acetamide) From 8-chloropyrido[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]pyrazine-8-yl-piperidine-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]pyrazine-8-ylpiperidine-4-ylmethyl)-butylamide)From 8-chloropyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine, and 3,3-dimethylbutyrate. 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-piperidine-1-yl-1-(4-pyrido[2,3-b]pyrazine-8-yl-piperazine-1-yl)-butan-1-one) From 8-chloropyrido[2,3-b]pyrazine, 1-boc-piperazine, and 4-(piperidine-1-yl)butanoate. 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-azetidine-1-yl-N-(1-pyrido[2,3-b]pyrazine-8-ylpiperidine-4-ylmethyl)acetamide)From 8-chloropyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine, and 2-(azetidine-1-yl) acetate 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]pyrazine-8-ylpiperidine-4-ylmethyl)acetamide) From 8-chloropyrido[2,3-b]pyrazine, tert-butyl methyl(piperidine-4-ylmethyl)carbamate, and 2-(diethylamino)acetate 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]pyrazine-8-ylpiperidine-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 minutes. MS: m / z = 343 [M+H]<0000​​​​​​ Compound 409 (N-[1-(8-cyanoquinoline-5-yl)-piperidine-4-ylmethyl]-2-piperidine-1-ylacetamide) From 5-bromo-quinoline-8-carbonitride, 4-(boc-aminomethyl)piperidine, and piperidine-1-ylacetic 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-cyanoquinoline-5-yl)-piperidine-4-ylmethyl]-2-(ethyl-methyl-amino)-acetamide) From 5-bromo-quinoline-8-carbonitride, 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]pyrazine-8-ylpiperidine-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-cyanoquinoline-5-yl)-piperidine-4-ylmethyl]acetamide) From 5-bromo-quinoline-8-carbonitride, 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-azetidine-1-yl-N-[1-(8-cyanoquinoline-5-yl)-piperidine-4-ylmethyl]acetamide) From 5-bromo-quinoline-8-carbonitride, 4-(boc-aminomethyl)piperidine, and 2-(azetidine-1-yl) acetate 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-quinoline-5-yl)-piperidine-4-ylmethyl]amide) From 5-bromo-quinoline-8-carbonitride, 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]pyridine-4-yl)-5-methylpiperidine-3-amine)

Chem.

[0398] Method R tert-butyl (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-methylpiperidine-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), tert-butyl N-[(3R,5S)-5-methylpiperidine-3-yl]carbamate (237 mg, 1.11 mmol), Pd2(dba)3·CHCl3 (115 mg, 0.11 mmol), DavePhos (87 mg, 0.22 mmol), and K3PO4 (588 mg, 2.77 mmol) were added at room temperature. The resulting mixture was stirred at 130 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 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 using ethyl acetate in petroleum ether (0% to 2% gradient) to obtain tert-butyl N-[(3R,5S)-1-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-5-methylpiperidine-3-yl]carbamate as a yellow solid (150 mg, 38%). MS: m / z = 359.1 [M+H] + .

[0399] (Note: The catalyst in method R may be Pd2(dppf)Cl2·CHCl3 instead of Pd2(dba)3·CHCl3).

[0400] (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-methylpiperidine-3-amine(3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-methylpiperidine-3-amine was prepared from tert-butyl (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-methylpiperidine-3-yl carbamate using Method Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep column, 5 μm, 19 mm × 250 mm; Mobile phase, methanol in water (containing 10 mmol / L NH4HCO3) with a gradient of 3% to 65% over 8 minutes; Detector, UV 254 nm. (3R,5S)-1-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl]-5-methylpiperidine-3-amine was obtained as a yellowish-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]pyridine-4-yl)-5-methylpiperidine-3-amine) [ka]

[0402] (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine(3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine was prepared from (3R,5S)-5-methylpiperidine-3-ylcarbamate tert-butyl and 8-chloropyrido[2,3-b]pyrazine using methods H and Q. The crude product was purified by preparative HPLC under 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) with a 3% to 22% gradient over 9 minutes; detector, UV 254 nm. (3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-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 using a similar method:

[0405] Compound 11 ((3R,5S)-5-methyl-1-(quinoline-4-yl)piperidine-3-amine) From (3R,5S)-5-methylpiperidine-3-ylcarbamate tert-butyl 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-methylpiperidine-1-yl)quinoxaline-5-carbonitrile) From 8-chloroquinoxaline-5-carbonitride and (3R,5S)-5-methylpiperidine-3-ylcarbamate tert-butyl. 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]pyridine-4-yl)-5-methylpiperidine-3-yl)-2-hydroxyacetamide) [ka]

[0407] N-((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-methylpiperidine-3-yl)-2-hydroxyacetamideN-((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-methylpiperidine-3-yl)-2-hydroxyacetamide was prepared from (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-methylpiperidine-3-amine and 2-hydroxyacetic acid using Method J. The crude product was purified by preparative HPLC under 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]pyridine-4-yl]-5-methylpiperidine-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 using a similar method:

[0410] Compound 14 (2-hydroxy-N-((3R,5S)-5-methyl-1-(quinoline-4-yl)piperidine-3-yl)acetamide)From (3R,5S)-5-methyl-1-(quinoline-4-yl)piperidine-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]pyrazine-8-yl)piperidine-3-yl)acetamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)-2-hydroxy-3-methylbutanamide)From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)-2-hydroxy-3-methylbutanamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl)piperidine-3-yl)butanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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]pyrazine-8-yl)piperidine-3-yl)butanamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)-2-(dimethylamino)acetamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl)piperidine-3-yl)acetamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)-3-methyloxetane-3-carboxamide) From 8-chloroquinoxaline-5-carbonitride, (3R,5S)-5-methylpiperidine-3-ylcarbamate tert-butyl, 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]pyrazine-8-yl)piperidine-3-yl)oxetane-3-carboxamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)-3,3-dimethylbutanamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl)piperidine-3-yl)butanamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-hydroxyacetamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(morpholine-4-yl)acetamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-methylpiperazine-1-yl)acetamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride and 2-(4-methylpiperazine-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]pyrazine-8-yl]piperidine-3-yl]-2-(morpholine-4-yl)acetamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3,3,3-trifluoropropanamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl]piperidine-3-yl]propanamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(1H-imidazole-4-yl)acetamide hydrochloride) From 2-(1H-imidazole-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-imidazole-4-yl)-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-3-yl]acetamide)From 2-(1H-imidazole-4-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(1-methyl-1H-imidazole-4-yl)acetamide) From 2-(1-methyl-1H-imidazole-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl]piperidine-3-yl]-2-(1-methyl-1H-imidazole-4-yl)acetamide) From 2-(1-methyl-1H-imidazole-4-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-methoxyacetamide) From 2-methoxyacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-methanesulfonamideacetamide) From 2-(methylsulfonamide)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-methanesulfonamide-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-3-yl]acetamide) From 2-(methylsulfonamide)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]acetamide)From 2-(tert-butylamino)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl]piperidine-3-yl]acetamide) From 2-(tert-butylamino)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-[(2-hydroxyethyl)(methyl)amino]acetamide)From 2-((2-hydroxyethyl)(methyl)amino)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl]piperidine-3-yl]acetamide) From 2-((2-hydroxyethyl)(methyl)amino)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-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]pyrazine-8-yl]piperidine-3-yl]acetamide)From 2-tert-butoxyacetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2,2-difluorocyclopropane-1-carboxamide) From 2,2-difluorocyclopropanecarboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(oxolan-2-ylmethoxy)acetamide) :2-(oxolan-2-ylmethoxy)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2,3-dimethylbutanamide) From 2,3-dimethylbutanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl]piperidine-3-yl]butanamide) From 2,3-dimethylbutanoic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(1H-pyrazole-1-yl)acetamide) From 2-(1H-pyrazole-1-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl]piperidine-3-yl]-2-(1H-pyrazole-1-yl)acetamide) From 2-(1H-pyrazole-1-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-1-methylpyrrolidine-2-carboxamide) From 1-methylpyrrolidine-2-carboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride. 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]pyrazine-8-yl]piperidine-3-yl]pyrrolidine-2-carboxamide) From 1-methylpyrrolidine-2-carboxylic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-cyclopropylpiperidine-3-yl]-3,3-dimethylbutanamide) From 3,3-dimethylbutanoic acid and cis-8-(3-amino-5-cyclopropylpiperidine-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-cyanoquinoxaline-5-yl)-5-cyclopropylpiperidine-3-yl]-2-(dimethylamino)acetamide) From 2-(dimethylamino)acetate hydrochloride and cis-8-(3-amino-5-cyclopropylpiperidine-1-yl)quinoxaline-5-carbonitride. 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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-1-hydroxycyclopropane-1-carboxamide) From 1-hydroxycyclopropane-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitride. 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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(1-methylpiperidine-4-yl)acetamide) From 2-(1-methylpiperidine-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(1,4-dimethylpiperidine-4-yl)acetamide)From 2-(1,4-dimethylpiperidine-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-[1-(2,2-difluoroethyl)piperidine-4-yl]acetamide) From 2-(1-methylpiperidine-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3,3-difluorocyclobutane-1-carboxamide) From 3,3-difluorocyclobutan-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitride. 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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-1-methylpyrrolidine-3-carboxamide) From 3,3-difluorocyclobutan-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitride. 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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-hydroxypropanamide) From 2-hydroxypropanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(1-methylpiperidine-3-yl)acetamide hydrochloride)From 2-(1-methylpiperidine-3-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(1-methylpyrrolidine-3-yl)acetamide) From 2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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)piperidine-1-yl)quinoxaline-5-carbonitrilate hydrochloride) [ka]

[0460] Method S tert-butyl (3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl(methyl)carbamate To a solution of tert-butyl N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidine-3-yl]carbamate (152 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (18 mg, 0.74 mmol, 1.78 equivalents) was added at room temperature. This 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. When the reaction was complete, it was quenched by adding water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, yielding tert-butyl N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-N-methylcarbamate as a yellow solid (180 mg, crude).

[0461] 8-((3S,5R)-3-methyl-5-(methylamino)piperidine-1-yl)quinoxaline-5-carbonitrile hydrochloride 8-((3S,5R)-3-methyl-5-(methylamino)piperidine-1-yl)quinoxaline-5-carbonitric hydrochloride was prepared from tert-butyl (3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl(methyl)carbamate and iodomethane using Method Q. The crude product was purified by preparative HPLC under 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) with a 30% to 40% gradient over 10 minutes; Detector, UV 254 nm. 8-[(3S,5R)-3-methyl-5-(methylamino)piperidine-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 using a similar method:

[0464] Compound 17 ((3R,5S)-N,5-dimethyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine) From tert-butyl (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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]pyrazine-8-yl)piperidine-3-amine) [ka]

[0465] (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine was prepared from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine and 1-bromo-2-methoxyethane using Method N. The crude product was purified by preparative HPLC under 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) with a gradient of 3% to 80% over 8 minutes; Detector, UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-3-amine, yellow oily substance (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 using a similar method:

[0468] Compound 19 (8-((3R,5S)-3-(2-methoxyethylamino)-5-methylpiperidine-1-yl)quinoxaline-5-carbonitrile)From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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-methylpiperidine-1-yl)quinoxaline-5-carbonitrile) From 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl)piperidine-3-ylamino)acetonitrile hydrochloride) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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]pyrazine-8-yl]piperidine-3-yl]aminoacetamide) :(3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]aminoacetamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl]piperidine-3-yl]amino]pyrrolidine-2-one) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine and 3-bromo-1-methylpyrrolidine-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]piperidine-1-yl]quinoxaline-5-carbonitrile) From 3,3-dimethylbutanoic acid and cis-8-(3-amino-5-cyclopropylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)propanamide) [ka]

[0475] (R)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)propanamide (R)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)propanamide was prepared from 8-((3R,5S)-3-amino-5-methylpiperidine-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 under the following conditions: column, XBridge C18 OBD Prep column, 5um, 19mm × 250mm; gradient of MeOH in water (containing 10 mmol / L NH4HCO3) over 10 minutes from 30% to 80%; detector, UV 254nm. (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]propanamide was obtained as a yellow solid (25 mg, 26% for both 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 using a similar method:

[0478] Compound 25 ((S)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)propanamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl)piperidine-3-yl)propanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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]pyrazine-8-yl)piperidine-3-yl)propanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)-2-(methylamino)acetamide hydrochloride) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl)piperidine-3-yl)-2-(methylamino)acetamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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]pyrazine-8-yl)piperidine-3-yl)cyclopropanecarboxamide hydrochloride) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)cyclopropanecarboxamide hydrochloride) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl)piperidine-3-yl)acetamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)acetamide hydrochloride) From 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3-methylbutanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3-methylbutanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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]pyrazine-8-yl]piperidine-3-yl]butanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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]pyrazine-8-yl]piperidine-3-yl]butanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3-hydroxypropanamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl]piperidine-3-yl]propanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3-(pyridine-3-yl)propanamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride and (S)-2-(tert-butoxycarbonylamino)-3-(pyridine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-phenylacetamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl]piperidine-3-yl]-3-(pyridine-3-yl)propanamide) From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-3-amine and (S)-2-(tert-butoxycarbonylamino)-3-(pyridine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-phenylacetamide) From 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride 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]pyrazine-8-yl]piperidine-3-yl]oxetane-3-carboxamide)From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazine-8-yl)piperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]oxetane-3-carboxamide) From 3-(tert-butoxycarbonylamino)oxetane-3-carboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-1-yl)quinoxaline-5-carbonitride. 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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-cyclopropylacetamide)From 2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3,3-dimethylbutanamide) From 4-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidine-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]pyrazine-8-yl)piperidine-3-yl)pyrrolidine-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). 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. Once the reaction was complete, it was quenched by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (300 mL x 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 in a C18 reversed-phase column by eluting with acetonitrile in water (0% to 50% gradient over 30 minutes), yielding (2R)-2-[[(benzyloxy)carbonyl]amino]-4-(methylsulfanyl)butanoic acid as a yellow oily substance (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 CH3I (15 mL, 0.48 mol). The resulting solution was stirred at room temperature for 15 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure to yield [(3R)-3-[[(benzyloxy)carbonyl]amino]-3-carboxypropyl]dimethylsulfanium as a brown oily substance (3.50 g, crude). This crude substance was used directly in the next step without further purification.

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

[0503] Benzyl (R)-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazine-8-yl)piperidine-3-yl)-2-oxopyrrolidine-3-ylcarbamate Benzyl (R)-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazine-8-yl)piperidine-3-yl)-2-oxopyrrolidine-3-ylcarbamate was prepared from ((R)-3-(benzyloxycarbonylamino)-4-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazine-8-yl)piperidine-3-ylamino)-4-oxobutyl)dimethylsulfonium using Method N. The crude product was purified using a C18 reverse-phase column with elution in acetonitrile water (0% to 80% gradient over 45 minutes), yielding benzyl N-[(3R)-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-3-yl]-2-oxopyrrolidine-3-yl]carbamate as a yellow solid (270 mg, 5% for each of the three steps).

[0504] (R)-3-amino-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazine-8-yl)piperidine-3-yl)pyrrolidine-2-oneTo a solution of benzyl N-[(3R)-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-3-yl]-2-oxopyrrolidine-3-yl]carbamate (125 mg, 0.27 mmol) in acetic acid (2 mL), a solution of HBr in AcOH (40%, 7 mol / L, 3 mL, 21 mmol) was added dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours. At the end of the reaction, the reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC according to 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 30% to 80% gradient over 10 minutes; Detector, UV 254 nm. (3R)-3-amino-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazine-8-yl]piperidine-3-yl]pyrrolidine-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]pyrazine-8-yl)morpholine) [ka]

[0506] (2S,6R)-2,6-dimethyl-4-(pyrido[2,3-b]pyrazine-8-yl) (2S,6R)-2,6-dimethyl-4-(pyrido[2,3-b]pyrazine-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 under 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 25% to 75% gradient over 10 minutes; detector, UV 254 nm. (2R,6S)-2,6-dimethyl-4-[pyrido[2,3-b]pyrazine-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 under the following conditions: column, XBridge C18 OBD Prep column, 5 μm, 19 mm × 250 mm; mobile phase, MeOH in water (10 mmol / L NH4HCO3) with a gradient of 30% to 80% over 10 minutes; 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 using a similar method:

[0511] compound 45 ((2S,6R)-2,6-dimethyl-4-(quinoline-4-yl)morpholine): Derived 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]pyridine-4-yl)-2,6-dimethylmorpholine) [ka]

[0512] (2S,6R)-4-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-2,6-dimethylmorpholine (2S,6R)-4-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-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 × 250 mm; mobile phase, MeOH in water (10 mmol / L NH4HCO3) with a 25% to 70% gradient over 10 minutes; detector, UV 254 nm. (2R,6S)-4-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine-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-methylpiperazine-1-yl)methyl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine) [ka]

[0514] (R)-1-amino-3-(benzyloxy)propane-2-ol At room temperature, a solution of (2R)-2-[(benzyloxy)methyl]oxirane (5.22 g, 31.82 mmol) in ethanol (25 mL) was sequentially added to a solution of NH3 (25 mL, 7 M, 175 mmol) in MeOH, followed by NH3.H2O (28%, 14.8 mol / L, 53 mL, 0.78 mol). The resulting solution was stirred at room temperature for 16 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure, yielding (2R)-1-amino-3-(benzyloxy)propan-2-ol as a colorless oil (6.2 g, crude).

[0515] (R)-1-amino-3-(benzyloxy)propane-2-ol To a solution of (2R)-1-amino-3-(benzyloxy)propan-2-ol (6.20 g, crude) in ethanol (50 mL), (2S)-2-methyl chloropropanoate (3.33 g, 54.42 mmol) was added 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 by elution with siRNA in petroleum ether (0%~50% gradient) to obtain (2S)-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide as a bright yellow oil (5.65 g, 65% for both steps).

[0516] (2R,6R)-6-(benzyloxymethyl)-2-methylmorpholine-3-oneTo a solution of (2S)-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide (4.12 g, 15.18 mmol) in tetrahydrofuran (30 mL), sodium hydride (1.02 g, 42.50 mmol) was added in small amounts at room temperature. The resulting mixture was stirred at room temperature for 2 hours. When the reaction was complete, it was quenched by the slow addition of water (30 mL). The mixture was extracted with ethyl acetate (100 mL x 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 by elution with ELISA in petroleum ether (0%~100% gradient), yielding (2R,6R)-6-[(benzyloxy)methyl]-2-methylmorpholine-3-one as a bright yellow oil (2.68 g, 75%).

[0517] (2R,6R)-2-(benzyloxymethyl)-6-methylmorpholine To a solution of (2R,6R)-6-[(benzyloxy)methyl]-2-methylmorpholine-3-one (5.40 g, 22.93 mmol) in tetrahydrofuran (50 mL), LiAlH4 (2.00 g, 52.56 mmol) was added in small amounts at room temperature. The resulting mixture was stirred at room temperature for 2 hours. When the reaction was complete, it was quenched by adding water (40 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with brine, and dried on Na2SO4. The solvent was removed under reduced pressure, yielding (2R,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine as a light yellow oil (5.40 g, crude).

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

[0519] ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methanol ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methanol was prepared from ((2R,6R)-6-methylmorpholine-2-yl)methanol and 8-chloropyrido[2,3-b]pyrazine using Method M. The crude product was purified by flash chromatography with elution in petroleum ether with ELISA (0% to 50% gradient) to obtain [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-8-yl]morpholine-2-yl]methanol as a yellow oily substance (2.00 g, 28% for each of the three steps).

[0520] Method T

[0521] ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonateAt 5°C, sodium hydride (203 mg, 8.45 mmol) was added in small amounts to a solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-8-yl]morpholine-2-yl]methanol (638 mg, 2.45 mmol) in N,N-dimethylformamide (30 mL). 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. When the reaction was complete, it was quenched by adding water (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, yielding [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-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-methylpiperazine-1-yl)methyl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholineTo a solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-8-yl]morpholine-2-yl]methyl 4-methylbenzene-1-sulfonate (60 mg, crude) in N,N-dimethylformamide (5 mL), 1-methylpiperazine (21 mg, 0.21 mmol) and TEA (42 mg, 0.41 mmol) were added at room temperature. The resulting solution was stirred at 130 °C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with DCM (30 mL x 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 according to the following conditions: Column, SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm, 10 nm; mobile phase, MeOH in water (containing 10 mmol / L NH4HCO3) with a 25% to 75% gradient over 10 minutes; detector, UV 254 nm. (2R,6S)-2-methyl-6-[(4-methylpiperazine-1-yl)methyl]-4-[pyrido[2,3-b]pyrazine-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]pyrazine-8-yl)morpholine) [ka]

[0525] (2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine (2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine was prepared from ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methyl 4-methylbenzenesulfonate and piperazin-1-carboxylate tert-butyl using methods U and Q. The crude product was purified by preparative HPLC under the following conditions: column, XBridge C18 OBD Prep column, 5um, 19mm × 150mm; mobile phase, MeOH in water (containing 0.02% v / v HCl) with a 3% to 8% gradient over 10 minutes; detector, UV 254nm. (2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-[pyrido[2,3-b]pyrazine-8-yl]morpholine was obtained as a light brown solid (15 mg, 22% for the 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-(piperazine-1-ylmethyl)-4-(quinoline-5-yl)morpholine) [ka]

[0527] (2R,6S)-2-methyl-6-(piperazine-1-ylmethyl)-4-(quinoline-5-yl)morpholine(2R,6S)-2-methyl-6-(piperazine-1-ylmethyl)-4-(quinoline-5-yl)morpholine was prepared from ((2R,6R)-6-methylmorpholine-2-yl)methanol, 5-chloroquinoline, 4-methylbenzene-1-sulfonyl chloride, and tert-butyl piperazine-1-carbonate using methods M, T, U, and Q. The crude product was purified by preparative HPLC under 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) with a gradient of 30% to 80% over 10 minutes; Detector, UV 254 nm. 4-[(2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)morpholine-4-yl]quinoline was obtained as a yellowish-white solid (35 mg, 15% for each of the four 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-methylpiperazine-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile) [ka]

[0529] 8-((2R,6S)-2-methyl-6-((4-methylpiperazine-1-yl)methyl)morpholino)quinoxaline-5-carbonitric acid8-((2R,6S)-2-methyl-6-((4-methylpiperazine-1-yl)methyl)morpholino)quinoxaline-5-carbonitride hydrochloride was prepared from ((2R,6R)-6-methylmorpholin-2-yl)methanol, 8-bromoquinoxaline-5-carbonitride, 4-methylbenzene-1-sulfonyl chloride, and 1-methylpiperazine using methods M, T, and U. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep column, 5um, 19mm × 150mm; Mobile phase, MeOH in water (containing 0.02% v / v HCl) with a gradient of 15% to 40% over 10 minutes; Detector, UV 254nm. 8-((2R,6S)-2-methyl-6-((4-methylpiperazine-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile hydrochloride was obtained as a black solid (50 mg, 20% for each of the three 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-methylpiperazine-1-yl)methyl)-4-(quinoline-5-yl)morpholine) [ka]

[0531] (2R,6S)-2-methyl-6-((4-methylpiperazine-1-yl)methyl)-4-(quinoline-5-yl)morpholine(2R,6S)-2-methyl-6-((4-methylpiperazine-1-yl)methyl)-4-(quinoline-5-yl)morpholine was prepared from ((2R,6R)-6-methyl-4-(quinoline-5-yl)morpholine-2-yl)methyl 4-methylbenzenesulfonate and 1-methylpiperazine using Method U. The crude product was purified by preparative HPLC under 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) with a 20% to 40% gradient over 8 minutes; Detector, UV 254 nm. 4-[(2R,6S)-2-methyl-6-[(4-methylpiperazine-1-yl)methyl]morpholine-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 using a similar method:

[0534] Compound 52 ((2R,6S)-2-methyl-6-((4-propylpiperazine-1-yl)methyl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine) From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-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-dimethylpiperazine-1-yl)methyl)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine) From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methyl 4-methylbenzene sulfonate 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]pyrazine-8-yl)-6-((3,3,4-trimethylpiperazine-1-yl)methyl)morpholine)From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-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]pyrazine-8-yl)morpholine-2-yl)methyl)piperidine-4-amine) From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and N,N-dimethylpiperidine-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]pyrazine-8-yl)-6-((4-(pyrrolidine-1-yl)piperidine-1-yl)methyl)morpholine) From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 4-(pyrrolidine-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-(pyrrolidine-1-yl)piperidine-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile) From ((2R,6R)-4-(8-cyanoquinoxaline-5-yl)-6-methylmorpholine-2-yl)methyl 4-methylbenzenesulfonate and 4-(pyrrolidine-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'-bipiperidine-1'-ylmethyl)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine) From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-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'-bipiperidine-1'-ylmethyl)-6-methylmorpholino)quinoxaline-5-carbonitrile) From ((2R,6R)-4-(8-cyanoquinoxaline-5-yl)-6-methylmorpholine-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-morpholinopiperidine-1-yl)methyl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine) From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methyl 4-methylbenzenesulfonate and 4-(piperidine-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-(morpholine-4-yl)piperidine-1-yl]methyl}morpholine-4-yl]quinoxaline-5-carbonitricFrom [(2R,6R)-4-(8-cyanoquinoxaline-5-yl)-6-methylmorpholine-2-yl]methyl 4-methylbenzene-1-sulfonate and 4-(piperidine-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]pyrazine-8-yl)morpholine-2-yl)methyl)piperidine-4-yl)isobutylamide) [ka]

[0544] N-(1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methyl)piperidine-4-yl)isobutylamideN-(1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methyl)piperidine-4-yl)isobutylamide was prepared from 4-aminopiperidine-1-carboxylate tert-butyl, isobutyric acid, and ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methyl trifluoromethanesulfonate using methods J, Q, and U. The crude product was purified by preparative HPLC under the following conditions: column, XBridge C18 OBD Prep column, 5um, 19mm × 150mm; mobile phase, MeOH in water (containing 10 mmol / L NH4HCO3) with a gradient of 30% to 80% over 8 minutes; detector, UV 254nm. (2R,6S)-2-methyl-6-[[4-(morpholine-4-yl)piperidine-1-yl]methyl]-4-[pyrido[2,3-b]pyrazine-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]pyrazine-8-yl)morpholine-2-yl)methyl)piperidine-4-carboxamide) [ka]

[0546] 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 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 mixed with 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. At the end 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), the organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, yielding 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]pyrazine-8-yl)morpholin-2-yl)methyl)piperidine-4-carboxamide N-ethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methyl)piperidine-4-carboxamide was prepared from 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, ethaneamine, and ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methyltrifluoromethanesulfonate using methods J, Q, and U. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep column, 5um, 19mm × 150mm; Mobile phase, MeOH in water (containing 10 mmol / L NH4HCO3) with a gradient of 30% to 80% over 10 minutes; Detector, UV 254nm. N-ethyl-1-[[(2S,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-8-yl]morpholine-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-aminoazetidine-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methanone)

change

[0549] (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-carboxylic acidAt 10°C, (acetyloxy)(phenyl)-lambda-3-iodanyl acetate (234 mg, 0.73 mmol) and TEMPO (11 mg, 0.07 mmol) were added to a solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-8-yl]morpholin-2-yl]methanol (90 mg, 0.35 mmol) in dichloromethane (15 mL). The resulting solution was stirred at 10°C for 30 minutes, then warmed to room temperature, and stirred at room temperature for a further 17 hours. When the reaction was complete, it was quenched with saturated Na2S2O4 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 x 3), and the combined aqueous phase was diluted with BuOH (10 mL). The pH of this aqueous solution was adjusted to 5 with H2SO4 (5M), and the resulting solution was extracted with BuOH (10 mL x 3). The organic phase was combined and concentrated under reduced pressure to obtain (2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-8-yl]morpholine-2-carboxylic acid as a yellow solid (76 mg, crude). MS: m / z = 275.0 [MH] + This crude product was used in the next step without further purification.

[0550] (3-aminoazetidine-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholin-2-yl)methanone (3-aminoazetidine-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-yl)methanone was prepared from (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-carboxylic acid and tert-butylazetidine-3-ylcarbamate hydrochloride using methods J and Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep column, 5um, 19mm × 150mm; Mobile phase, MeOH in water (10 mmol / L NH4HCO3) with a gradient of 30% to 70% over 10 minutes; Detector, UV 254nm. 1-[[(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazine-8-yl]morpholine-2-yl]carbonyl]azetidine-3-amine was obtained as a bright 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 using a similar method:

[0553] Compound 64 ((2R,6R)-6-methyl-N-((R)-piperidine-3-yl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-carboxamide) From (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-carboxylic acid and (R)-3-aminopiperidine-1-carboxylic acid tert-butyl. 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-methylpiperidine-4-yl)-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-carboxamide) From (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazine-8-yl)morpholine-2-carboxylic acid and 1-methylpiperidine-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-cyanoquinoxaline-5-yl)-6-methyl-N-(1-methylpiperidine-4-yl)morpholine-2-carboxamide) From (2R,6R)-4-(8-cyanoquinoxaline-5-yl)-6-methylmorpholine-2-carboxylic acid and 1-methylpiperidine-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)quinoline-5-yl]piperidine-3-amine)

Chem.

[0556] tert-butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamateAt room temperature, tert-butyl N-[(3R,5S)-5-methylpiperidine-3-yl]carbamate (718 mg, 3.35 mol), K3PO4 (2.19 g, 10.29 mmol), Pd2(dba)3CHCl3 (356 mg, 0.34 mmol), and DavePhos (270 mg, 0.69 mmol) were added to a solution of 5-bromo-8-(trifluoromethyl)quinoline (950 mg, 3.44 mmol) in DMF (10 mL). The resulting mixture was heated to 130 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 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 using phenylethylamine in hexane (0% to 14% gradient) to obtain tert-butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamate as a yellow solid (1.10 g, 77%). MS: m / z = 410.2 [M+H] + .

[0557] (3R,5S)-1-[8-(trifluoromethyl)quinoline-5-yl]-5-methylpiperidine-3-amine At room temperature, a solution of tert-butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamate (787 mg, 1.92 mmol) in methanol (10 mL) was mixed with a solution of hydrogen chloride (5 mL, 4 M) in 1,4-dioxane. 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 under 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) with a 30% to 60% gradient over 10 minutes; Detector, UV 254 nm. (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine was obtained as a bright 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-methoxyquinoxaline-5-yl)-5-methylpiperidine-3-amine) [ka]

[0559] 3-Methoxybenzene-1,2-diamine At room temperature, Pd / C (10%, 500 mg) was added to a solution of 2-methoxy-6-nitroaniline (4.75 g, 28.25 mmol) in methanol (150 mL) under nitrogen atmosphere. The reaction flask was evacuated and flushed with hydrogen. The reaction mixture was hydrogenated using a hydrogen balloon under H2 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 yield 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 H2O (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). Then, NaHSO3 (7.59 g, 72.94 mmol) was slowly added. The resulting solution was stirred at room temperature for 15 minutes. Upon completion of the reaction, the insoluble solids in the reaction mixture were filtered. The filtrate was extracted using DCM (300 mL x 3), the organic phase was combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using elution with siRNA in hexane (0%~100% gradient) to yield 5-methoxyquinoxaline as a dark red oily substance (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), NBS (5.04 g, 28.29 mmol) was added at room temperature. The resulting solution was then stirred at 50 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 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 by elution with toluene in hexane (0% to 100% gradient), yielding 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-methoxyquinoxaline-5-yl)-5-methylpiperidine-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-methylpiperidine-3-yl]carbamate (1.52 g, 7.09 mmol), K3PO4 (5.13 g, 24.17 mmol), Pd2(dba)3CHCl3 (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 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL). The resulting mixture was extracted using DCM (100 mL x 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 using phenyl in hexane (0% to 100% gradient) to obtain tert-butyl N-[(3R,5S)-1-(8-methoxyquinoxaline-5-yl)-5-methylpiperidine-3-yl]carbamate as a dark red oil (1.11 g, 37%). MS: m / z = 373.1 [M+H] + .

[0563] (3R,5S)-1-(8-methoxyquinoxaline-5-yl)-5-methylpiperidine-3-amine To a solution of tert-butyl N-[(3R,5S)-1-(8-methoxyquinoxaline-5-yl)-5-methylpiperidine-3-yl]carbamate (429 mg, 1.15 mmol) in dioxane (10 mL), a 4 M hydrogen chloride solution (30 mL) in dioxane was added at room temperature. The resulting solution was then stirred at room temperature for 1 hour. When the reaction was complete, it was quenched by adding H2O (50 mL). The pH of the resulting mixture was then adjusted to 8 with saturated sodium bicarbonate solution. This mixture was extracted using DCM (100 mL x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, yielding (3R,5S)-1-(8-methoxyquinoxaline-5-yl)-5-methylpiperidine-3-amine as a dark red oily substance (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-methoxyquinoxaline-5-yl)-5-methylpiperidine-3-amine To a solution of (3R,5S)-1-(8-methoxyquinoxaline-5-yl)-5-methylpiperidine-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 adding water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 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 according to 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) with a 35% to 65% gradient over 10 minutes; detector, UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinoxaline-5-yl)-5-methylpiperidine-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...

Claims

1. Compounds of formula I or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula: Ring A is, 【Chemistry 2】 And, Ring B is, 【Transformation 3】 And, X is CH 2 , O, or C(R 4 ) 2 And here R 4 One of them is -H; Each R 4 is -H, halogen, haloalkyl, 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 Independently selected from the group consisting of, Each R 5 These are independently -H, C 1-6 It is alkyl, halogen, or haloalkyl; k is 0; n is 0; p is 0; r is 0, 1, or 2; and (t is 0, 1, or 2).

2. X is CH 2 The compound according to claim 1.

3. The compound according to claim 1, wherein X is O.

4. R 5 is independently -H, methyl, cyclopropyl, -F, or -CF 3 ​

5. The following table: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 A compound selected from the group consisting of the compounds described above, or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

7. A composition for inhibiting the activity of TLR7 / 8 or variants thereof in a patient or biological sample, comprising a compound according to any one of claims 1 to 5 or a physiologically acceptable salt thereof, wherein the compound or a physiologically acceptable salt thereof is administered to the patient or comes into contact with the biological sample.

8. A composition for treating TLR7 / 8-mediated disorders in patients requiring treatment for TLR7 / 8-mediated disorders, the composition comprising a compound according to any one of claims 1 to 5 or a physiologically acceptable salt thereof.

9. The composition according to claim 8, wherein the disorder is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, lupus, 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), hyperglycemia and periodic fever syndromes, cryopine periodic fever syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, Sjögren's disease, polymyositis, dermatomyositis, and cancer.

10. A composition for treating cancer in a subject, comprising a compound according to any one of claims 1 to 5 or a physiologically acceptable salt thereof.

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